introduction

1 A role of novel drug delivery system in various diseases

NOVEL DRUG DELIVERY SYSTEM

The method by which a drug is delivered can have a significant effect on its efficacy. Some drugs have an optimum concentration range within which maximum benefit is derived, and concentrations above or below this range can be toxic or produce no therapeutic benefit at all. On he other hand, the very slow progress in the efficacy of the treatment of severe diseases, has suggested a growing need for a multidisciplinary approach to the delivery of therapeutics to targets in tissues. From this, new ideas on controlling the pharmacokinetics, pharmacodynamics, non specific toxicity, immunogenicity, biorecognition, and efficacy of drugs were generated. These new strategies, often called drug delivery systems (DDS), are based on interdisciplinary approaches that combine polymer science, pharmaceutics, bioconjugate chemistry, and molecular biology.

To minimize drug degradation and loss, to prevent harmful side-effects and to increase drug bioavailability and the fraction of the drug accumulated in the required zone, various drug delivery and drug targeting systems are currently under development. Among drug carriers one can name soluble polymers, microparticles made of insoluble or biodegradable natural and synthetic polymers, microcapsules, cells, cell ghosts, lipoproteins, liposomes, and micelles. The carriers can be made slowly degradable, stimuli-reactive (e.g., pH- or temperature-sensitive), and even targeted (e.g., by conjugating them with specific antibodies against certain characteristic components of the area of interest). Targeting is the ability to direct the drug-loaded system to the site of interest. Two major mechanisms can be distinguished for addressing the desired sites for drug release: (i) passive and (ii) active targeting. An example of passive targeting is the preferential accumulation of chemotherapeutic agents in solid tumors as a result of the enhanced vascular permeability of tumor tissues compared with healthy tissue. A strategy that could allow active targeting involves the surface functionalization of drug carriers with ligands that are selectively recognized by receptors on the surface of the cells of interest. Since ligand–receptor interactions can be highly selective, this could allow a more precise targeting of the site of interest.

Controlled drug release and subsequent biodegradation are important for developing successful formulations. Potential release mechanisms involve: (i) desorption of surface-bound /adsorbed drugs; (ii) diffusion through the carrier matrix; (iii) diffusion (in the case of nanocapsules) through the carrier wall; (iv) carrier matrix erosion; and (v) a combined erosion /diffusion process. The mode of


delivery can be the difference between a drug’s success and failure, as the choice of a drug is often influenced by the way the medicine is administered. Sustained (or continuous) release of a drug involves polymers that release the drug at a controlled rate due to diffusion out of the polymer or by degradation of the polymer over time. Pulsatile release is often the preferred method of drug delivery, as it closely mimics the way by which the body naturally produces hormones such as insulin. It is achieved by using drug-carrying polymers that respond to specific stimuli (e.g., exposure to light, changes in pH or temperature).

For over 20 years, researchers have appreciated the potential benefits of nanotechnology in providing vast improvements in drug delivery and drug targeting. Improving delivery techniques that minimize toxicity and improve efficacy offers great potential benefits to patients, and opens up new markets for pharmaceutical and drug delivery companies. Other approaches to drug delivery are focused crossing particular physical barriers, such as the blood brain barrier, in order to better target the drug and improve its effectiveness; or on finding alternative and acceptable routes for the delivery of protein drugs other than via the gastro-intestinal tract, where degradation can occur.

Drug Delivery SystemsThe global market for advanced drug delivery systems was more than €37.9 billion in 2000 and is estimated to grow and reach €75B by 2005 (i.e., controlled release €19.8B, needle-less injection €0.8B, injectable/impantable polymer systems €5.4B, transdermal €9.6B, transnasal €12.0B, pulmonary €17.0B, transmucosal €4.9B, rectal €0.9B, liposomal drug delivery €2.5B, cell/gene therapy €3.8B, miscellaneous €1.9B). Developments within this market are continuing at a rapid pace, especially in the area of alternatives to injected macromolecules, as drug formulations seek to cash in on the €6.2B worldwide market for genetically engineered protein and peptide drugs and other biological therapeutics.

Drug Delivery Carriers

Colloidal drug carrier systems such as micellar solutions, vesicle and liquid crystal dispersions, as well as nanoparticle dispersions consisting of small particles of 10–400 nm diameter show great promise as drug delivery systems. When developing these formulations, the goal is to obtain systems with optimized drug loading and release properties, long shelf-life and low toxicity. The incorporated drug participates in the microstructure of the system, and may even influence it due to molecular interactions, especially if the drug possesses amphiphilic and/or


mesogenic properties.

Figure 1. Pharmaceutical carriersMicelles formed by self-assembly of amphiphilic block copolymers (5-50 nm) in aqueous solutions are of great interest for drug delivery applications. The drugs can be physically entrapped in the core of block copolymer micelles and transported at concentrations that can exceed their intrinsic water- solubility. Moreover, the hydrophilic blocks can form hydrogen bonds with the aqueous surroundings and form a tight shell around the micellar core. As a result, the contents of the hydrophobic core are effectively protected against hydrolysis and enzymatic degradation. In addition, the corona may prevent recognition by the reticuloendothelial system and therefore preliminary elimination of the micelles from the bloodstream. A final feature that makes amphiphilic block copolymers attractive for drug delivery applications is the fact that their chemical composition, total molecular weight and block length ratios can be easily changed, which allows control of the size and morphology of the micelles. Functionalization of block copolymers with crosslinkable groups can increase the stability of the corresponding micelles and improve their temporal control. Substitution of block copolymer micelles with specific ligands is a very promising strategy to a broader range of sites of activity with a much higher selectivity.


Figure 2. Block copolymer micelles.Liposomes are a form of vesicles that consist either of many, few or just one phospholipid bilayers. The polar character of the liposomal core enables polar drug molecules to be encapsulated. Amphiphilic and lipophilic molecules are solubilized within the phospholipid bilayer according to their affinity towards the phospholipids. Participation of nonionic surfactants instead of phospholipids in the bilayer formation results in niosomes. Channel proteins can be incorporated without loss of their activity within the hydrophobic domain of vesicle membranes, acting as a size-selective filter, only allowing passive diffusion of small solutes such as ions, nutrients and antibiotics. Thus, drugs that are encapsulated in a nanocage-functionalized with channel proteins are effectively protected from premature degradation by proteolytic enzymes. The drug molecule, however, is able to diffuse through the channel, driven by the concentration difference between the interior and the exterior of the nanocage.

Figure 3. Drug encapsulation in liposomes.


Figure 4. A polymer-stabilized nanoreactor with the encapsulated enzyme.Dendrimers are nanometer-sized, highly branched and monodisperse macromolecules with symmetrical architecture. They consist of a central core, branching units and terminal functional groups. The core together with the internal units, determine the environment of the nanocavities and consequently their solubilizing properties, whereas the external groups the solubility and chemical behaviour of these polymers. Targeting effectiveness is affected by attaching targeting ligands at the external surface of dendrimers, while their stability and protection from the Mononuclear Phagocyte System (MPS) is being achieved by functionalization of the dendrimers with polyethylene glycol chains (PEG).

Liquid Crystals combine the properties of both liquid and solid states. They can be made to form

different geometries, with alternative polar and non-polar layers (i.e., a lamellar phase) where aqueous drug solutions can be included.

Nanoparticles (including nanospheres and nanocapsules of size 10-200 nm) are in the solid state and are either amorphous or crystalline. They are able to adsorb and/or encapsulate a drug, thus protecting it against chemical and enzymatic degradation. Nanocapsules are vesicular systems in which the drug is confined to a cavity surrounded by a unique polymer membrane, while nanospheres are matrix systems in which the drug is physically and uniformly dispersed. Nanoparticles as drug carriers can be formed from both biodegradable polymers and non-biodegradable polymers.

In recent years, biodegradable polymeric nanoparticles have attracted considerable attention as potential drug delivery devices in view of their applications in the controlled release of drugs, in targeting particular organs / tissues, as carriers of DNA in gene therapy, and in their ability to deliver proteins, peptides and genes


through the peroral route.

Hydrogels are three-dimensional, hydrophilic, polymeric networks capable of imbibing large amounts of water or biological fluids. The networks are composed of homopolymers or copolymers, and are insoluble due to the presence of chemical crosslinks (tie-points, junctions), or physical crosslinks, such as entanglements or crystallites.

Hydrogels exhibit a thermodynamic compatibility with water, which allows them to swell in aqueous media. They are used to regulate drug release in reservoir-based, controlled release systems or as carriers in swellable and swelling-controlled release devices.

On the forefront of controlled drug delivery, hydrogels as enviro-intelligent and stimuli-sensitive gel systems modulate release in response to pH, temperature, ionic strength, electric field, or specific analyte concentration differences.

In these systems, release can be designed to occur within specific areas of the body (e.g., within a certain pH of the digestive tract) or also via specific sites (adhesive or cell-receptor specific gels via tethered chains from the hydrogel surface). Hydrogels as drug delivery systems can be very promising materials if combined with the technique of molecular imprinting.

Figure 5. Pegylated and pH sensitive micro- or nanogels.The molecular imprinting technology has an enormous potential for creating satisfactory drug dosage forms. Molecular imprinting involves forming a pre-


polymerization complex between the template molecule and functional monomers or functional oligomers (or polymers) with specific chemical structures designed to interact with the template either by covalent, non-covalent chemistry (self-assembly) or both. Once the pre-polymerization complex is formed, the polymerization reaction occurs in the presence of a cross-linking monomer and an appropriate solvent, which controls the overall polymer morphology and macroporous structure. Once the template is removed, the product is a heteropolymer matrix with specific recognition elements for the template molecule.

Examples of MIP-based drug delivery systems involve: (i) rate-programmed drug delivery, where drug diffusion from the system has to follow a specific rate profile, (ii) activation-modulated drug delivery, where the release is activated by some physical, chemical or biochemical processes and (iii) feedback-regulated drug delivery, where the rate of drug release is regulated by the concentration of a triggering agent, such as a biochemical substance, the concentration of which is dependent on the drug concentration in the body. Despite the already developed interesting applications of MIPs, the incorporation of the molecular imprinting approach for the development of DDS is just at its incipient stage. Nevertheless, it can be foreseen that, in the next few years, significant progress will occur in this field, taking advantage of the improvements of this technology in other areas. Among the evolution lines that should contribute more to enhance the applicability of imprinting for drug delivery, the application of predictive tools for a rational design of imprinted systems and the development of molecular imprinting in water may be highlighted.

Figure 6. The volume phase transition of the hydrogel -induced by an external


stimuli (e.g., a change in pH, temperature or electrical field) modifies the relative distance of the functional groups inside the imprinted cavities. This alters their affinity for the template.

Figure 7. (A) Induced Swelling - As analyte (A) binds, the enzymatic reaction (E denotes covalently attached enzyme) produces a local pH decrease. For the cationic hydrogel, which is weakly basic, the result is ionization, swelling, and release of drug, peptide, or protein (filled circle). When A decreases in the bulk

concentration, the gel shrinks. (B) Loss of Effective Cross-links - Analyte competes for binding positions with the protein (P). As free analyte binds to the

protein, effective cross-links are reversibly lost and release occurs.Conjugation of biological (peptides/proteins) and synthetic polymers is an efficient means to improve control over nanoscale structure formation of synthetic polymeric materials that can be used as drug delivery systems. Conjugation of suitable biocompatible polymers to bioactive peptides or proteins can reduce toxicity, prevent immunogenic or antigenic side reactions, enhance blood circulation times and improve solubility. Modification of synthetic polymers or polymer therapeutics with suitable oligopeptide sequences, on the other hand, can prevent random distribution of drugs throughout a patient’s body and allow active targeting. Functionalization of synthetic polymers or polymer surfaces with peptide sequences derived from extracellular matrix proteins is an efficient way to mediate cell adhesion. The ability of cationic peptide sequences to complex and condense DNA and oligonucleotides offers prospects for the development of non-viral vectors for gene-delivery based on synthetic polymeric hybrid materials.


Figure 8. Bioconjugates.The field of in-situ forming implants has grown exponentially in recent years. Liquid formulations generating a (semi-)solid depot after subcutaneous injection, also designated as implants, are an attractive delivery system for parenteral application because, they are less invasive and painful compared to implants. Localized or systemic drug delivery can be achieved for prolonged periods of time, typically ranging from one to several months. Generally, parenteral depot systems could minimize side effects by achieving constant, ‘infusion-like’ plasma-level time profiles, especially important for proteins with narrow therapeutic indices. From a manufacturing point of view, in-situ forming depot systems offer the advantage of being relatively simple to manufacture from polymers. Injectable in-situ forming implants are classified into four categories, according to their mechanism of depot formation: (i) thermoplastic pastes, (ii) in-situ cross-linked polymer systems, (iii) in-situ polymer precipitation, and (iv) thermally induced gelling systems.

The ultimate goal in controlled release is the development of a microfabricated device with the ability to store and release multiple chemical substances on demand. Recent advances in microelectro-mechanical systems (MEMS) have provided a unique opportunity to fabricate miniature biomedical devices for a variety of applications ranging from implantable drug delivery systems to lab-on-a-chip devices. The controlled release microchip has the following advantages: (i) multiple chemicals in any form (e.g., solid, liquid or gel) can be stored inside and released from the microchip, (ii) the release of chemicals is initiated by the disintegration of the barrier membrane via the application of an electric potential, (iii) a variety of highly potent drugs can potentially be delivered accurately and in a safe manner, (iv) complex release patterns (e.g., simultaneous constant and


pulsatile release) can be achieved, (v) the microchip can be made small enough to make local chemical delivery possible thus achieving high concentrations of drug at the site where it is needed while keeping the systemic concentration of the drug at a low level and (vi) water penetration into the reservoirs is avoided by the barrier membrane and thus the stability of protein-based drugs with limited shelf-life is enhanced.

Administration Routes

The choice of a delivery route is driven by patient acceptability, the properties of the drug (such as its solubility), access to a disease location, or effectiveness in dealing with the specific disease. The most important drug delivery route is the peroral route. An increasing number of drugs are protein- and peptide-based. They offer the greatest potential for more effective therapeutics, but they do not easily cross mucosal surfaces and biological membranes; they are easily denatured or degraded, prone to rapid clearance in the liver and other body tissues and require precise dosing. At present, protein drugs are usually administered by injection, but this route is less pleasant and also poses problems of oscillating blood drug concentrations. So, despite the barriers to successful drug delivery that exist in the gastrointestinal tract (i.e., acid-induced hydrolysis in the stomach, enzymatic degradation throughout the gastrointestinal tract by several proteolytic enzymes, bacterial fermentation in the colon), the peroral route is still the most intensively investigated as it offers advantages of convenience and cheapness of administration, and potential manufacturing cost savings.

Pulmonary delivery is also important and is effected in a variety of ways - via aerosols, metered dose inhaler systems (MDIs), powders (dry powder inhalers, DPIs) and solutions (nebulizers), all of which may contain nanostructures such as liposomes, micelles, nanoparticles and dendrimers. Aerosol products for pulmonary delivery comprise more than 30% of the global drug delivery market. Research into lung delivery is driven by the potential for successful protein and peptide drug delivery, and by the promise of an effective delivery mechanism for gene therapy (for example, in the treatment of cystic fibrosis), as well as the need to replace chlorofluorocarbon propellants in MDIs. Pulmonary drug delivery offers both local targeting for the treatment of respiratory diseases and increasingly appears to be a viable option for the delivery of drugs systemically. However, the pulmonary delivery of proteins suffers by proteases in the lung, which reduce the overall bioavailability, and by the barrier between capillary blood and alveolar air (air-blood barrier).


Transdermal drug delivery avoids problems such as gastrointestinal irritation, metabolism, variations in delivery rates and interference due to the presence of food. It is also suitable for unconscious patients. The technique is generally non-invasive and aesthetically acceptable, and can be used to provide local delivery over several days. Limitations include slow penetration rates, lack of dosage flexibility and / or precision, and a restriction to relatively low dosage drugs.

Parenteral routes (intravenous, intramuscular, subcutaneous) are very important. The only nanosystems presently in the market (liposomes) are administered intravenously. Nanoscale drug carriers have a great potential for improving the delivery of drugs through nasal and sublingual routes, both of which avoid first-pass metabolism; and for difficult-access ocular, brain and intra-articular cavities. For example, it has been possible to deliver peptides and vaccines systemically, using the nasal route, thanks to the association of the active drug macromolecules with nanoparticles. In addition, there is the possibility of improving the occular bioavailability of drugs if administered in a colloidal drug carrier.

Trans-tissue and local delivery systems require to be tightly fixed to resected tissues during surgery. The aim is to produce an elevated pharmacological effect, while minimizing systemic, administration-associated toxicity. Trans-tissue systems include: drug-loaded gelatinous gels, which are formed in-situ and adhere to resected tissues, releasing drugs, proteins or gene-encoding adenoviruses; antibody-fixed gelatinous gels (cytokine barrier) that form a barrier, which, on a target tissue could prevent the permeation of cytokines into that tissue; cell-based delivery, which involves a gene-transduced oral mucosal epithelial cell (OMEC)-implanted sheet; device-directed delivery - a rechargeable drug infusion device that can be attached to the resected site.

Gene delivery is a challenging task in the treatment of genetic disorders. In the case of gene delivery, the plasmid DNA has to be introduced into the target cells, which should get transcribed and the genetic information should ultimately be translated into the corresponding protein. To achieve this goal, a number of hurdles are to be overcome by the gene delivery system. Transfection is affected by: (a) targeting the delivery system to the target cell, (b) transport through the cell membrane, (c) uptake and degradation in the endolysosomes and (d) intracellular trafficking of plasmid DNA to the nucleus.

Future Opportunities and Challenges

Nanoparticles and nanoformulations have already been applied as drug delivery


systems with great success; and nanoparticulate drug delivery systems have still greater potential for many applications, including anti-tumour therapy, gene therapy, AIDS therapy, radiotherapy, in the delivery of proteins, antibiotics, virostatics, vaccines and as vesicles to pass the blood-brain barrier.

Nanoparticles provide massive advantages regarding drug targeting, delivery and release and, with their additional potential to combine diagnosis and therapy, emerge as one of the major tools in nanomedicine. The main goals are to improve their stability in the biological environment, to mediate the bio-distribution of active compounds, improve drug loading, targeting, transport, release, and interaction with biological barriers. The cytotoxicity of nanoparticles or their degradation products remains a major problem, and improvements in biocompatibility obviously are a main concern of future research.

There are many technological challenges to be met, in developing the following techniques:

Nano-drug delivery systems that deliver large but highly localized quantities of drugs to specific areas to be released in controlled ways;

Controllable release profiles, especially for sensitive drugs; Materials for nanoparticles that are biocompatible and biodegradable; Architectures / structures, such as biomimetic polymers, nanotubes; Technologies for self-assembly; Functions (active drug targeting, on-command delivery, intelligent drug

release devices/ bioresponsive triggered systems, self-regulated delivery systems, systems interacting with the body, smart delivery);

Virus-like systems for intracellular delivery; Nanoparticles to improve devices such as implantable devices/nanochips for

nanoparticle release, or multi reservoir drug delivery-chips; Nanoparticles for tissue engineering; e.g. for the delivery of cytokines to

control cellular growth and differentiation, and stimulate regeneration; or for coating implants with nanoparticles in biodegradable polymer layers for sustained release;

Advanced polymeric carriers for the delivery of therapeutic peptide/proteins (biopharmaceutics),

And also in the development of: Combined therapy and medical imaging, for example, nanoparticles for diagnosis and manipulation during surgery (e.g. thermotherapy with magnetic particles);

Universal formulation schemes that can be used as intravenous,


intramuscular or peroral drugs Cell and gene targeting systems. User-friendly lab-on-a-chip devices for point-of-care and disease prevention

and control at home. Devices for detecting changes in magnetic or physical properties after

specific binding of ligands on paramagnetic nanoparticles that can correlate with the amount of ligand.

Better disease markers in terms of sensitivity and specificity.

Medicated Chewing Gum

Now-a-days most of the drugs are formulated into various solid dosage forms including the most popular ones like Tablets, capsules etc. and semi-solid dosage forms such as creams, ointments, gels etc. Chewing gum is being used worldwide since ancient times after man experienced the pleasure of chewing a variety of substance. It can be used as a convenient modified release drug delivery system. Chewing gum has been used for centuries to clean the mouth and freshen the breath (Jacobsen et al., 2004). One thousand years ago the Mayan Indians chewed the tree resin (Chicle) from the sapodilla tree to clean their teeth and freshen their breath .

The first commercial chewing gum “State of Maine pure spruce gum” was marketed in 1948 in the U.S.A. The first patent was filed in 1869 (Conway et al., 2003). The gum was intended as dentifrices but it has never been marketed. The first Medicated chewing gum “Aspergum” was launched in 1928. This chewing gum is still available and contains acetylsalicylic acid. Another commercially available medicated chewing gum is dimenhydrinate – containing chewing gum for motion sickness. However, chewing gum did not gain acceptance as a reliable drug delivery system until 1978, when nicotine chewing gum became available. In 1991, Chewing Gum was approved as a term for pharmaceutical dosage form by the commission of European Council. Moreover, there is need of reformulation of existing drug into New Drug Delivery Systems (NDDS) to extend or protect product patents thereby delaying, reducing or avoiding generic erosion at patent expiry. Today improved technology and extended know how have made it possible to develop and manufacture medicated-chewing gum with pre-defined properties. MCG is one of them. Owing to new social and behavioral trends in the past modern age, such as the growing consumer health awareness and increasing


attention to safety products, chewing gum has been known for a new image and potential. Chewing gum today is gaining consideration as a vehicle or a delivery system to administer active principles that can improve health and nutrition.

MCG represents the newest system with potential uses in pharmaceuticals, over the counter medicines and nutraceuticals (Lee et al., 2001). The drugs intended to act in oral cavity often have low water/saliva solubility and chewing gum constitute a valuable delivery system for such drugs.

DefinitionMedicated Chewing Gum (MCG) is a novel drug delivery system containing masticatory gum base with pharmacologically active ingredient and intended to use for local treatment of mouth diseases or systemic absorption through oral mucosa. MCG is considered as vehicle or a drug delivery system to administer active principles that can improve health and nutrition.

Why Use Chewing Gum As A Drug Delivery System?

Chewing gum provides new competitive advantages over conventional drug delivery system: Fast onset of action and high bioavailability Pleasant taste Higher compliance (easy and discreet administration without water) Ready for use High acceptance by children (Lamb et al., 1993)

Fewer side effectsLow dosage gives high efficacy as hepatic first pass metabolism is avoided. The controlled release rate also reduces the risk of side effects, as high plasma peak concentrations are avoided.

Systemic effectActive substances can be absorbed through the buccal mucosa and/or through the GI tract when saliva is swallowed. Once the active substance is present in the blood, systemic affect can be obtained (Lamb et al., 1993).

Fast onset of actionFast onset of systemic effect is seen for active substances absorbed through the buccal mucosa, as the active substances pass by the jugular veins directly to the systemic circulation.


Local effectChewing gum is an obvious drug delivery system for local treatment of diseases in the oral cavity and in the throat, as sustaining the release of active substances may deliberately prolong exposure.

Effect on dry mouth ( xerostomia)Dry mouth is a side effect of many types of medicament (e.g. antidepressants) and it is also part of the symptomatology of several diseases (e.g. sjogren’s syndrome-an autoimmune disorder characterized by lymphocytic infiltration of the salivary and lacrimal glands) (Sjögren et al., 2002). Chewing gum stimulates salivary secretion thereby decreasing dryness in the mouth.

MERITS OF THE MCG (PHARMACOLOGICAL)

The active component absorbed at the oral level avoids the enterohepatic circulation and the associated metabolism (Conway et al., 2003).

The product is rapidly released from the gum after a short period of mastication; some absorption takes place directly through the oral mucosa depending upon the active ingredient. Importantly, not being swallowed, the gum does not reach the stomach, which means that the GIT suffers less from the excipients and the iatrogenic effects. (observed with some galenical form) (Conway et al., 2003).

Moreover the stomach does not suffer from direct contact with high concentration of the active principle, thus reducing the risk of intolerance of the gastric mucosae (Conway et al., 2003).The fraction of the product reaching the stomach is conveyed by the saliva and delivered continuously and regularly. Others: Relaxes and eases tension. Freshens the breath. Decreases ear discomfort when flying. Satisfies snack craving. Cleans teeth after meals. It’s fun.


DEMERITS OF THE MCG (PHARMACOLOGICAL)

If you chew gum on a regular basis, please consider the following:

Chewing gum causes unnecessary wear and tear of the cartilage that acts as a shock absorber in the jaw joints. Once damaged this area can create pain and discomfort for lifetime (Weil et al., 1978).You use eight different facial muscles to chew. Unnecessary chewing can create chronic tightness in 2 of these muscles located close to the temples. This can put pressure on the nerves contributing to chronic intermittent headaches (Weil et al., 1978).You have six salivary glands located throughout mouth that are stimulated to produce and release saliva whenever you chew. Producing a steady stream of saliva for chewing gum is a waste of energy and resources that otherwise could be used for essential metabolic activities.

Most of the chewing gums are sweetened with aspartame: long use causes cancer, diabetes, neurological disorder and birth defects.Flavor color etc. may cause allergic reaction. Long term frequent use causes increase release of mercury vapor from dental amalgam filling. However medicated chewing gums do not normally require extensive chewing or consumption to a great extent.

MERITS OF THE MCG (OVER OTHER DOSAGE FORMS) Dose not requires water to swallow. Hence can be taken anywhere (Morjaria

et al., 2004). Advantageous for patients having difficulty in swallowing. Excellent for acute medication (Conway et al., 2003). Counteracts dry mouth, prevents candidiasis and caries. Highly acceptable by children (Morjaria et al., 2004). Avoids First Pass Metabolism and thus increases the bioavailability of drugs

(Conway et al., 2003). Fast onset due to rapid release of active ingredients in buccal cavity and

subsequent absorption in systemic circulation (Conway et al., 2003). Gum does not reach the stomach. Hence G.I.T. suffers less from the effects

of excipients.


Stomach does not suffer from direct contact with high concentrations of active principles, thus reducing the risk of intolerance of gastric mucosa (Conway et al., 2003).

Fraction of product reaching the stomach is conveyed by saliva delivered continuously and regularly. Duration of action is increased.

Aspirin, Dimenhydrinate and Caffeine shows faster absorption through MCG than tablets.

DEMERITS OF THE MCG (OVER OTHER DOSAGE FORMS)

Risk of over dosage with MCG compared with chewable tablets or lozenges that can be consumed in a considerable number and within much shorter period of time (Jacobsen et al., 2004).

Sorbitol present in MCG formulation may cause flatulence, diarrhoea. Additives in gum like flavouring agent, Cinnamon can cause Ulcers in oral

cavity and Licorice cause Hypertension. Chlorhexidine oromucosal application is limited to short term use because of its unpleasant taste and staining properties to teeth and

tongue. Chewing gum have been shown to adhere to different degrees to enamel

dentures and fillers. Prolong chewing on gum may result in pain in facial muscles and earache in

children.

Mechanism of Drug Transport (Rathbone et al., 1996; Squier et al., 1996)During the chewing process, most of the medications contained within the drug product are released into the saliva and are either absorbed through buccal mucosa or swallowed or absorbed through GIT.Major pathways of drug transport across buccal mucosa follow simple fickian diffusion. Passive diffusion occurs in accordance without the pH partition theory. Some carrier mediated transport also observed. Equation for drug flux is:

J = DKp/ΔCe

Where,J = drug fluxD = diffusivityKp = partition coefficient


ΔCe = concentration gradienth = diffusional path length

It shows (h) that the flux may be increased by decreasing the diffusional resistance of the membrane by making it more fluid, increasing the solubility of the drug in the saliva immediately adjacent to the epithelium or enhancing the lipophilicity through pro-drug modification. Because of the barrier properties of the tight buccal mucosa, the rate limiting step is the movement of the drug molecules across the epithelium.Two pathways of permeation across the buccal mucosa are transcellular and paracellular. Permeability coefficient typically ranges from 1x10-5 to 2x10-10 cm/s. The pathway of drug transport across oral mucosa may be studied using:

Microscopic techniques using fluorescent dyes Autoradiography and Confocal laser scanning microscopic procedures.

COMPONENTS OF THE MCGChewing gum is a mixture of natural or synthetic gums and resins, sweetened with sugar, corn syrup, artificial sweeteners and may also contain colouring agents and flavour. The basic raw material for all CG is natural gum Chicle, obtained from the sapodilla tree. Chicle is very expensive and difficult to procure therefore other natural gum or synthetic materials like polyvinylacetate and similar polymers can be used as gum base.

Typically Chewing Gum comprises two parts Water insoluble chewable gum base portion (Zyck et al., 2003) Water-soluble bulk portion (Zyck et al., 2003)

Water insoluble gum base generally comprises of(Conway et al., 2003; Zyck et al., 2003)Elastomers (40-70% by wt. of gum base).Elastomer provides elasticity and controls gummy texture. Natural elastomer: Natural rubbers like Latex or Natural gums such as Jelutong, Lechi Caspi, Perillo, and Chicle.

Plastisizers (3-20% by wt. of gum base). These are used to regulate cohesiveness of product.


These are again divided into Natural and Synthetic. Natural Plastisizers include Natural rosin esters like Glycerol Esters or Partially hydrogenated Rosin, Glycerol Esters of Polymerized Esters, Glycerol Esters of Partially dimerized Rosin & Pentaerythritol Esters of Rosin. Synthetic Plastisizers include Terpene Resins derived from α-pinene and/or d-limonene.

APPLICATIONS OF THE MCG

The MCGs can also be used as an alternative tool to buccal and sublingual tablets which are intended to act systemically because active ingredient is released more uniformly and cover greater area of absorption in oral cavity. Oral diseases are prevented or cured with MCG. MCGs can be used for systemic effect in conditions like vitamin C deficiency, pain & fever, alertness, motion sickness, smoking cessation, as well as for local effect in conditions like plaque acid neutralization, fresh breath, dental caries, antiplaque, fungal, and bacterial infections.Prevention and cure of oral diseases is a prime target for chewing gum formulations.

Local TherapyChewing Gum can control the release rate of active substances providing a prolonged local effect. It also re-elevates plaque pH which lowers intensity and frequency of dental caries. Fluoride containing gums have been useful in preventing dental caries in children and in adults with xerostomia. Chlorhexidine chewing gum can be used to treat gingivitis, periodontitis, oral and pharyngeal infections. It can also be used for inhibition of plaque growth. Chlorhexidine chewing gum offers large flexibility in its formulation as it gives less staining of the teeth and is distributed evenly in the oral cavity. The bitter taste of chlorhexidine can be masked quite well in a chewing gum formulation (Pedersen et al., 1990; Rindum et al., 1993) Clinical trials involving patients with oral candidiasis have shown that miconazole chewing gum is at least as sufficient as miconazole oral gel in the treatment of fungal infections in the mouth. A miconazole chewing gum is yet to be launched (Pedersen et al., 1990; Rindum et al., 1993)

Systemic therapyChewing gum can be used in treatment of minor pains, headache and muscular aches. Chewing gum formulation containing nicotine (Nemeth et al., 1988) and Lobeline have been clinically tested as aids to smoking cessation. Active substances like chromium, guaran and caffeine are proved to be efficient in treating


obesity. Chromium is claimed to reduce craving for food due to an improved blood-glucose balance. Caffeine and guaran stimulate lipolysis and have a thermogenic effect (increased energy expenditure) and reduce feeling of hunger. Xerostomia, Allergy, Motion sickness, Acidity, Cold and Cough, Diabetes, Anxiety, etc are all indications for which chewing gum is a means of drug delivery. Medicated chewing gum is used to counteract dental caries by stimulation of saliva secretion. Non-medicated chewing gums increases plaque pH, stimulates saliva flow and decrease decay.

FUTURE TRENDSChewing gum is no longer seen simply as confectionary. It not only offers clinical benefits but also is an attractive, discrete and efficient drug delivery system.

A few decades ago, the only treatment for some diseases was surgical procedure but now more and more diseases can be treated with Novel Drug Delivery Systems. Generally, it takes time for a new drug delivery system to establish itself in the market and gain acceptance by patients, however chewing gum is believed to manifest its position as a convenient and advantageous drug delivery system as it meets the high quality standards of pharmaceutical industry and can be formulated to obtain different release profiles of active substances. The potential of MCG for buccal delivery, fast onset of action and the opportunity for product line extension makes it an attractivedelivery form. Reformulation of an existing product is required for patent protection, additional patient benefits and conservation of revenues. Dental health chewing gum is here to stay, as is medicated gum for smoking cessation and travel sickness. A bright future for a preparation with a long history.

NANOTECHNOLOGY: Applications in medicine and possible Side-Effects

Nanotechnology provides the field of medicine with promising hopes for assistance in diagnostic and treatment technologies as well as improving quality of life. Humans have the potential to live healthier lives in the near future due to the innovations of nanotechnology. Some of these innovations include:


• Disease diagnosis• Prevention and treatment of disease• Better drug delivery system with minimal side effects• Tissue Reconstruction

Researchers and scientists alike are constantly searching for new methods to improve the current medical system to offer patients better care, and to improve the efficiency of care delivery of physicians. When observed superficially the nano-technological enhancements seem to be nothing but promising. They will provide individuals with an improved quality of life, which will most likely lead to greater lifetime productivity, given that people get more accomplished when they feel their best. The advancements of nanotechnology will also greatly improve the accuracy of medicine, which could significantly reduce the number of malpractice lawsuits. Physicians could revert to the days where they focused more on treating the patient instead of averting litigation.

Before these advancements occur, the ethical implications must be considered. The ethical questions presented here, like many others involved in the nanotechnology debate, are not unanswerable. If the questions presented here are answered appropriately then nanotechnology and medicine should develop concurrently and complimentarily. Once the ethicality of nanotechnology is resolved, the pursuit of developments in this arena will be fruitful and advantageous as long as frequent checks are made to ensure the development of nanotechnology is not unregulated chaos.

INTRODUCTION Nanotechnology is the study, design, creation, synthesis, manipulation, and

application of materials, devices, and systems at the nanometer scale (One meter consists of 1 billion nanometers). It is becoming increasingly important in fields like engineering, agriculture, construction, microelectronics and health care to mention a few. The application of nanotechnology in the field of health care has come under great attention in recent times. There are many treatments today that take a lot of time and are also very expensive. Using nanotechnology, quicker and much cheaper treatments can be developed. By performing further research on this technology, cures can be found for diseases that have no cure today. We could make surgical instruments of such precision and deftness that they could operate on the cells and


even molecules from which we are made - something well beyond today's medical technology. Therefore nanotechnology can help save the lives of many people.

The specific purpose of this report is to explain what nanotechnology is and how it can be used in the field of health care. Applications such as drug delivery system, tissue reconstruction and disease diagnosis shall be discussed. In addition to this, the report will outline some of the problems with using this technology. This report will be of particular interest to researchers in medicine and electronics and to undergraduate students from medicine, computer engineering, electrical engineering and mechanical engineering.The report contains background information on nanotechnology and its importance. Then thereport will discuss some of the applications of nanotechnology in the field of health care. Finally, problems with using nanotechnology will be discussed

Nanotechnology, when used with biology or medicine, is referred to as Nanobiotechnology. This technology should be used very carefully because the lives of human beings are being dealt with. If used properly, it can be very effective in providing treatments with minimal side-effects.

Assembly approaches

There are two main approaches for the synthesis of nano-engineered materials. They can be classified on the basis of how molecules are assembled to achieve the desired product.

1. Top – down techniqueThe top – down technique begins with taking a macroscopic material (the finished product) and then incorporating smaller scale details into them. The molecules are rearranged to get the desired property. This approach is still not viable as many of the devices used to operate at nanolevel are still being developed. (Silva, 2004)

2. Bottom – up approach The bottom – up approach begins by designing and synthesizing custom made molecules that have the ability to self- replicate. These molecules are then organized into higher macro-scale structures. The molecules self replicate upon the change in specific physical or chemical property that triggers the self replication. This can be a change in temperature, pressure, application of electricity or a chemical. The self replication of molecule has to be carefully controlled so it does not go out of hand


APPLICATION IN MEDICAL SCIENCE This section discusses the applications of nanotechnology in the field of health care. These applications can remarkably improve the current treatments of some diseases and help save the lives of many.

A. Drug Delivery System 1. What are nanorobots and why use them? Nanorobots are robots that carry out a very specific function and are just several nanometers wide. They can be used very effectively for drug delivery. Normally, drugs work through the entire body before they reach the disease-affected area. Using nanotechnology, the drug can be targeted to a precise location which would make the drug much more effective and reduce the chances of possible side-effects. Figure 1 below shows a device that uses nanorobots to monitor the sugar level in the blood.

Figure 2. Device Using Nanorobots for Checking Blood Contents (Amazing Nanroobots)

2. Drug delivery procedure

The drug carriers have walls that are just 5-10 atoms thick and the inner drug-filled cell is usually 50-100 nanometers wide. When they detect signs of the disease, thin wires in their walls emit an electrical pulse which causes the walls to dissolve and the drug to be released. Aston Vicki, manager of BioSante Pharmaceuticals, says “Putting drugs into nanostructures increases the solubility quite substantially”.

3. Advantages of using nanorobots for drug delivery


A great advantage of using nanorobots for drug delivery is that the amount and time of drug release can be easily controlled by controlling the electrical pulse. Furthermore, the walls dissolve easily and are therefore harmless to the body. Elan Pharmaceuticals, a large drug company, has already started using this technology in their drugs Merck’s Emend and Wyeth’s Rapamune.

B. Disease Diagnosis and Prevention

1. Diagnosis and ImagingNanobiotech scientists have successfully produced microchips that are coated with human molecules. The chip is designed to emit an electrical impulse signal when the molecules detect signs of a disease. Special sensor nanorobots can be inserted into the blood under the skin where they check blood contents and warn of any possible diseases. They can also be used to monitor the sugar level in the blood. Advantages of using such nanorobots are that they are very cheap to produce and easily portable.

2. Quantum dotsQuantum dots are nanomaterials that glow very brightly when illuminated by ultraviolet light. They can be coated with a material that makes the dots attach specifically to the molecule they want to track. Quantum dots bind themselves to proteins unique to cancer cells, literally bringing tumors to light.

Figure 3. A LIGHT IN DARK PLACES: Spectral imaging of quantum dots. Orange-red fluorescence signals indicate a prostate tumor growing in a live mouse


3. Preventing diseases

a. heart-attack prevention Nanorobots can also be used to prevent heart-attacks. Heart-attacks are caused by fat deposits blocking the blood vessels. Nanorobots can be made for removing these fat deposits (Harry, 2005). The following figure shows nanorobots removing the yellow fat deposits on the inner side of blood vessels.

Figure 4. Nanorobots Preventing Heart-attacks (Heart View)

b. frying tumors Nanomaterials have also been investigated into treating cancer. The therapy is based on “cooking tumors” principle. Iron nanoparticles are taken as oral pills and they attach to the tumor. Then a magnetic field is applied and this causes the nanoparticles to heat up and literally cook the tumors from inside out.

Figure 5. Cancer Cooker- Triton BioSystems is developing an anticancer therapy using antibody-coated iron nanoparticles.


C. Tissue ReconstructionNanoparticles can be designed with a structure very similar to the bone structure. An ultrasound is performed on existing bone structures and then bone-like nanoparticles are created using the results of the ultrasound (Silva, 2004). The bone-like nanoparticles are inserted into the body in a paste form (Adhikari, 2005). When they arrive at the fractured bone, they assemble themselves to form an ordered structure which later becomes part of the bone Another key application for nanoparticles is the treatment of injured nerves.

Samuel Stupp and John Kessler at Northwestern University in Chicago have made tiny rod like nano-fibers called amphiphiles. They are capped with amino acids and are known to spur the growth of neurons and prevent scar tissue formation. Experiments have shown that rat and mice with spinal injuries recovered when treated with these nano-fibers.

D. Medical ToolsNano-devices are nanoparticles that are created for the purpose of interacting with cells and tissues and carrying out very specific tasks . The most famous nano-devices are the imaging tools. Oral pills can be taken that contain miniature cameras. These cameras can reach deep parts of the body and provide high resolution pictures of cells as small as 1 micron in width (A red blood cell is 7 microns wide) . This makes them very useful for diagnosis and also during operations. Figure 4 below shows such cameras working with other nanoparticles to get rid of a disease.

Figure 6. Miniature Cameras Inside Blood Vessels(Blender Battles)

An accelerometer is a very useful nano-device that can be attached to the hip, knee or other joint bones to monitor movements and strain levels. Dressings can be coated with silver nanoparticles to make them infection-resistant. The nanoparticles kill bacteria and therefore reduce chances of infection.


PROBLEMS WITH USING NANOTECHNOLOGY

Environmental ProblemsThe greatest risk to the environment lies in the rapid expansion and development of nanoparticles using large scale production . A recent Rice University study showed that certain nanoparticles have a tendency to form aggregates that are very water soluble and bacteriocidal(capable of killing bacteria) and that can be catastrophic as bacteria are the foundation of the ecosystem.Scientists also fear that nanoparticles may damage the ozone layer . Many people fear that nanoparticles may self-replicate and cover the earth’s landscape with ‘grey goo’. However scientists assure that this cannot happen and is a scientific fantasy.

B. Health ProblemsThe risk of nanoparticles to the health of human beings is of far greater concern. James Baker, director of the Center for Biologic Nanotechnology at the University of Michigan, says “ Any time you put a material into something as complex as a human being, it has multiple effects ” (Perkel, 2004). Nanoparticles are likely to make contact with the body via the lungs, intestines and skin.

1. Risk to LungsNanoparticles are very light and can easily become airborne. They can easily be inhaled during the manufacturing process where dust clouds are a common occurrence. Particles passing into the walls of air passage can worsen existing air disease such as asthma and bronchitis and can be fatal. The following illustration shows how nanoparticles can be inhaled and travel throughout the body.


Figure 8. Tracing how nanoparticles can be inhaled and travel to the brain, lungs and the bloodstream

2. Effects on BrainSome nanoparticles that are inhaled through the nose can move upward into the base of the brain. This may damage the brain and the nervous system and could be fatal.

3. Problems in BloodNanoparticles flowing thorough the bloodstream may affect the clotting system which may result in a heart-attack. If these nanoparticles travel to organs like the heart or the liver, they may affect the functionality of these organs.

A BUCKY BALL: AS NOVEL NANOMATERIAL


Buckyball as a novel nanomaterial was discovered by Scientist Fuller, hence termed as Fullerenes. This new allotrope forms an extensive series of polyhedral cluster molecules, Cn (n even), comprising fused pentagonal and hexagonal rings of C atoms, which becomes base of nanotechnology. Pure fullerenes, derived fullerenes, metal endohedral fullerenes and carbon nanotube fullerenes are available for nanoscience.

They have different shapes showing surprising physical and chemical characteristic. The natural sources and synthetic sources are available for their production. They show many biomedical, therapeutic, diagnostic and miscellaneous applications. Enviromental toxicity and biological toxicity are also reported. The global market for fullerenes in 2005 worth over $60 million. Fullerenes are the futurefor nanomedicine and nanosurgery.

The notion of nanotechnology has evolved since its inception as a fantastic conceptual idea to its current position as a mainstream research initiative with broad application among all division of science. As the name indicate the nanoparticle form the base of nanotechnology and nanosciences.

These minute particles about 100Ato 2000Ain diameter were introduced by Krenter and Speiser in the 1970s as a controlled release drug carrier.[1] The nanomaterials currently being employed in pharmaceuticals includes: Micelles, Liposomes, Dendrimers, Fullerenes, Hydrogels, Nanoshells, Smart Surfaces, Quantum Dots, Colloidal Gold, Polymeric nanoparticles etc. Buckyballs are an integral and newly emerging part of nanomaterials. This new allotrope forms an extensive series of polyhedral cluster molecules, Cn (n even), comprising fused pentagonal and hexagonal rings of C atoms. The first member to be characterized was C60, which features 12 pentagons separated by 20 fused hexagons. It has full icosahedral symmetry and was given the name buckminsterfullerene in honour of the architect R. Buckminster Fuller whose buildings popularized the geodesic dome, which uses the same tectonic principle.

Fuller, who is shown on the cover of Time Magazine of January 10, 1964, was renowned for his geodesic domes that are based on hexagons and pentagons. The group actually tried to understand the absorption spectra of interstellar dust, which they suspected to be related to some kind of long-chained carbon molecules. Initially, C60 could only be produced in tiny amounts.


So there were only a few kinds of experiments that could be performed on the material. Things changed dramatically in 1990, when Wolfgang Krätschmer, Lowell Lamb, Konstantinos Fostiropoulos, and Donald Huffman discovered how to produce pure C60 in much larger quantities. This opened up completely new possibilities for experimental investigations and started a period of very intensive research. Nowadays it is relatively straightforward to mass-produce C60.

It opened up the new branch of Fullerene-Chemistry, which studies the new families of molecules that are based on Fullerenes. Knowledge of chemical modification, biological significance and materials application of functionalized fullerenes is growing rapidly and these compounds are emerging as new tools in the pharmaceutical field.

ClassificationFullerenes can be classified into following ways –

A. Pure Fullerenes: 1. Fullerene C60 or Buckminsterfullerene:Molecular wt: 720.66, Appearance: Granular, dark-brown powder. Sublimed appears as deep blue-black needle-like crystals. The diameter of a C60 molecule is about 1 nanometer. The C60 molecule has two bond lengths. The 6:6 ring bonds (between two hexagons) can be considered "double bonds" and are shorter than the 6:5 bonds (between a hexagon and a pentagon) given in Figure 1.

Figure 1: Fullerene C 60 or Buckminsterfullerene

2. Fullerene C70: Molecular wt: 840.77, Appearance: Granular, Sublimed black powder (Figure 2).


Figure 2: Fullerene C 70

3. Fullerene C76: Molecular wt: 912.84, Appearance: Granular, dark-brown powder.

4. Fullerene C78: Molecular wt.: 936.86, Appearance: Granular, black powder

(Figure 3).

5. Fullerene C84 : Molecular wt.:1008.92, Appearance: Granular, brown-black powder (Figure 4).

Derived fullerenes (functionalized fullerenes): Chemical groups can be attached to a fullerene carbon atom and this process is called functionalization, used for modifying the properties. The number of carbon atoms available to do this had led to the epithet “molecular pincushion”, especially within the context of medical application such as those being developed by the company C60.

Ferrocenes are compounds containing iron and organic groups that have attracted much interest in the decades since their discovery. The hybrids might create vesicles for drug delivery.

C. Metal Endohedrals:An area of research that has been as active as functionalization of fullerenes is that of putting atoms inside them. The results are called endohedral fullerenes (Figure 5). A huge number of elements have been encapsulated in fullerenes, including the


noble gases, which have no desire to bond with surrounding carbon atoms but can be used in application such as magnetic resonance imaging (MRI).

D. Carbon Nanotubes:Nanotubes are cylindrical fullerenes. These tubes of carbon (Figure 6) are usually only a few nanometers wide, but they can range from less than a micrometre to several millimetres in length.

Figure 6: Carbon Nanotube

Description

Shapes of Fullerenes:The structural motif of the fullerenes is a sequence of polyhedral clusters, Cn, each with 12 pentagonal faces and (1/2 n-10) hexagonal faces. C60 itself has 20 hexagonal faces. C70 has 25 hexagonal faces with 5 types of carbon atoms and 8 types of C-C bonds.

Systematic Names:Systematic names for the icosahedral C60 and the D5h (6) C70 fullerenes are (C60-Ih) [5,6] fullerene and (C70-D5h (6))[5,6] fullerene. Systematic Numbering is given in both 3-D and Schlegel format .

Production

I. Natural sources :


C60 and C70 have been detected in several naturally occurring minerals e.g. In carbon-rich semi-anthracite deposits from the yarrabee mine in Queens land, Australia. In Shungite, a highly metamorphosed metaanthracite from Shunga, Kerelia, Russia. Most recently, significant findings of naturally occurring fullerenes have been made in Sudbury (Canada) and New Zealand.

II. Synthetic Sources : They were first produced by man (at least knowingly) in the soot resulting from vaporizing graphite with a laser. The earliest bulk production process is the arc discharge (or Krätschmer-Huffman) method, using graphite electrodes, developed in 1990.

Other Routes:Heating naphthalene vapor (C10H8) in argon at about 1000oC followed by extraction with CS2. Burning soot in a benzene/oxygen flame at about 1500oC with argon as diluent.

Applications

A. Biomedical Applications:Fullerenes unique qualities have promise for certain type of drug design. The small size, spherical shape and hollow interior all provide therapeutic opportunities. Moreover, a cage of 60 carbon atoms has 60 places at which chemical groups can attach in almost any configuration. Such opportunity has led to the development of not only drug candidates for treating diseases including HIV, cancer and neurological conditions but also new diagnostic tools.

B.Therapeutic Applications:The relatively high tolerance of biological systems to carbon is one of the reasons for the potential of buckyballs in medical applications, in addition buckyballs are small enough to pass through kidneys and be excreted. The ability to chemically modify the sidewalls of buckytubes also leads to biomedical applications such as neuron growth and regeneration.

Self Assembled DNA Buckyballs for drug deliveryTiny geodesic spheres that could be used for drug delivery and as containers for chemical reactions have been developed. About 70% of the volume of the DNA


buckyball is hollow and drugs can be encapsulated in it to be carried into cells, where natural enzymes break down the DNA, releasing the drug. They might also be used as cages to study chemical reactions on the nanoscale.

Buckyballs to fight allergyThe buckyballs are able to interrupt the allergy/immune response by inhibiting a basic process in the cell that leads to release of an allergic mediator. Essentially, the buckyballs are able to prevent mast cells from releasing histamine. These findings advance the emerging field of medicine known as nanoimmunology.

Buckyballs as antioxidants:The unique structure of buckyballs enable it to bind to free radicals dramatically better then anyantioxidant currently available, such as vitamin E. Free radicals are molecules that cause oxidative stress, which experts believe may be the basis of aging therefore finds use in cosmetics.

Buckyballs as Passkey into Cancer cellsDrugs are far more effective if they are delivered through membrane, directly into the cells. The passkey developed contain a molecule called Bucky amino acid based on phenylalanine that are strung together like a beads on a necklace to build all proteins The peptides were found effective at penetration the defenses both liver cancer cells and neuroblastoma cells.

Buckyballs are the first targeted antibiotic ( New Defense Against Bioterrorism)A new variant of vancomycin that contains buckyballs -- tiny cage-shaped molecules of pure carbon could become the world's first targeted antibiotic, creating a new line of defense against bioweapons like anthrax.

Buckyball as HIV Protease Inhibitor:C Sixty's drug targets the human immunodeficiency virus (HIV) that causes AIDS by latching onto the enzyme necessary for viral reproduction. The fullerenes deactivate both the HIV-1 and HIV-2 types of virus, and don't seem to harm cells or organs, which is a problem with some other HIV inhibitors. Since a C60 molecule has approximately the same radius as the cylinder that describes the active site of HIVP and since C60 and its derivatives are primarily hydrophobic, an opportunity exists for a strong hydrophobic Vander Waals interaction between the nonpolar active-site surface and the C60 surface (Figure 8). In addition, however, there is an opportunity for increasing binding energy by the introduction of specific electrostatic interactions. One obvious possibility involves salt bridges between the catalytic aspartic acids on


the floor of the HIVP active site and basic groups such as amines introduced on the C60 surface. The key to exploiting this promising system will be the development of organic synthetic methodology to derivatize the C60 surface in highly selective ways.

Buckyballs as Neuroprotectants:Buckyball act as neuroprotectants-a drug that prevents or repair neurological damage. Diseases such as amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease and Parkinsonism are under trial.

Buckyball as Cytoprotective agentThe Water-soluble Buckyball derivative Radical Sponge exerts cytoprotective action against UVirradiation without visible light catalyzed cytotoxicity toward human skin keratinocytes.

Buckyball C60 α Alanine Adduct As Radical Scavenging AgentWater-soluble C60 α Alanine Adduct has been synthesized and scavenging ability for super oxide anion O- 2 (-) and hydroxyl radical has been demonstrated. It shows excellent efficiency in eliminating these anions and radicals and will be useful in radical related biomedical field.

Diagnostic ApplicationsBuckyballs may be especially useful for shuttling metal contrast agents through the body for magnetic resonance imaging (MRI) scans. Bolskar, Lon Wilson of Rice University in Houston, and other researchers have designed carbon-60 and other fullerene molecules with an atom of gadolinium inside and with chemical appendages that make them water-soluble. In typical MRI contrast agents, the metalgadolinium is linked to a non fullerene molecule. For most diagnostic tests, this molecule is excreted from the body quickly. However, fullerene-encapsulated gadolinium might one day be a safer option for certain diagnostic tests in which doctors leave the contrast agent in longer time.

Trimetaspheres are a larger version of the buckyball, with 80 carbons caging up to three metal or rare earth atoms, such as scandium, lanthanum or yttrium, which are covalently bonded to nitrogen. In trimetaspheres the nitrogen complex spins freely within the larger cage of carbons.They have potential uses as contrast agents for medical magnetic resonance imagining, as light emitting diodes, and potentially for molecular electronics and computing.

D. Miscellaneous Application


There is a wealth of other potential applications for Buckytubes, such as solar collection; nanoporous filters; and coatings of all sorts. Following are certain example:

1) Data storage devices: fullerene have interesting electrical properties’, which have led to the suggestion for use in a number of electronics related areas from data storage devices to solar cells.

2) Fuel cells: another use of electrical property of fullerene is in fuel cells exploiting their ability to help proton move around.3) Memory devices: fullerene have been inserted into nanotube, the result sometime referred to as‘peapods’, the properties can be modified by moving the location of the enclosed fullerens and research has even suggested using this to create memory devices.

4)Photonic devices5) Telecommunication devices6) Supreconducting devices

7) Fullerene can also be used as precursor for other materials such as diamond coating or nanotubes.8) Liquid crystal display these have potential in liquid crystal application which goes beyond Liquid crystal displays as there is growing interest in there use in areas such as non linear optics, photonics and molecular electronics.

Fullerenes are effective at mopping up free radicals, which damage liver tissue. This had led to the suggestion that they might protect the skin in cosmetics, or health hinder neural damage caused by radicals in certain diseases, research on which on rats has already shown promise.The size of C60 is similar to many biologically acting molecules, including drugs, such as Prozac and steroid hormone. This gives it potential as a foundation for creating a variety of biologically active variants. Buckyballs have a high physical and chemical affinity for the active site on an important enzyme for HIV, called HIV protease, and block the action of enzyme. Buckyballs target HIV protease differently so their effect should not be subject to resistance already developed. The neuroprotective potential for C60 has already been demonstrated, and vesicles made out of them could be used to deliver drugs. Applications for buckyballs with other atoms trapped inside them, referred to as endohedral fullerenes.


Toxicities Although C60 has been thought in theory to be relatively inert, the studies suggest the molecule may prove injurious to organisms.

I. Environmental ToxicityAn experiment by Eva Oberdörster at Southern Methodist University, which introduced fullerenes into water at concentrations of 0.5 parts per million, found that largemouth bass suffered a 17-fold increase in cellular damage in the brain tissue after 48 hours. The damage was of the type lipid peroxidation, which is known to impair the functioning of cell membranes. There were also inflammatory changes in the liver and activation of genes related to the making of repair enzymes. The overwhelming evidence of the essential non-toxicity of C60 (not nC60) in previously peer-reviewed articles of C60 and many of its derivatives indicates that these compounds are likely to have little (if any) toxicity, especially at the very low concentration at which it is≈ used (~1-10 μM).Desorption behavior of carbon nanotubes shows that high adsorption capacity and reversible adsorption of poly aromatic hydrocarbons on nanotubes imply the potential release of PAHs. If PAH-adsorbed CNTs are inhaled by animal and human beings it may lead to a high environmental and public health risk.

II. Biological ToxicityA study published in December 2005 in Biophysical Journal raises a red flag regarding the safety of C60 when dissolved in water. It reports the results of a detailed computer simulation that finds C60 binds to the spirals in DNA molecules in an aqueous environment, causing the DNA to deform, potentially interfering with its biological functions and possibly causing long-term negative side effects in people and other living organisms.

Despite of the hydrophobic behavior fullerenes strongly bound to the nucleotides. C60 bind singlestranded DNA and deform the nucleotides significantly.unexpectedly,when double stranded DNA is in A form ,fullerene penetrate into the double helix from the end, form stable hybrids, and frustrate the hydrogen bond between endgroup basepair in the nucleotide. The simulation results suggest the C60 molecules have potentially negative impact on the structure, stability and biological functions of DNA molecule.

Demerits

Buckyballs Hurt Cells


A new study of the revolutionary nano-sized particles known as 'buckyballs' predicts that the molecules are easily absorbed into animal cells, providing a possible explanation for how the molecules could be toxic to humans and other organisms. "Buckyballs are already being made on a commercial scale for use in coatings and materials but we have not determined their toxicity studies showing that they can cross the blood-brain barrier and alter cell functions, which raise alot of questions about their toxicity and what impact they may have if released into the environment." The resulting model showed that buckyball particles are able to dissolve in cell membranes, pass into cells and re-form particles on the other side where they can cause damage to cells .

Buckyballs' Have High Potential To Accumulate In Living TissueSynthetic carbon molecules called fullerenes, or buckyballs, have a high potential of being accumulated in animal tissue, but the molecules also appear to break down in sunlight, perhaps reducing their possible environmental dangers "Because of the numerous potential applications, it is important to learn how buckyballs react in the environment and what their possible environmental. The researchers mixed buckyballs in a solution of water and a chemical called octanol, which has properties similar to fatty tissues in animals. Findings indicated buckyballshave a greater chance of partitioning into fatty tissues than the banned pesticide DDT. However, while DDT is toxic to wildlife, buckyballs currently have no documented toxic effects... When nanotechnology is referred to relative to therapeutics, it generally means that the active agent is targeted to specific locations in the body and that we are working on the molecular basis or withvery small particles, such as, for example, gold nanoparticles .

Difficulty of targeting drug delivery to the locationOne major problem for current therapeutics is the difficulty of targeting drug delivery to the location where it is desired. The result of non-targeted delivery is that the drug can be active all over the body that means that large doses, larger than would otherwise be required, must be used, or that we realize a lot of peripheral damage to otherwise healthy parts, killing healthy cells or causing immune reactions. A second major problem for therapeutics is delivery of the active agent. This issue is related to the targeting problem but is broader than just that.

Currently, we design active drugs and expect them to circulate through the body, pass through barriers such as the digestive system, the cell, and the blood-brain barrier, and still to be active as a drug after doing all that and it is not surprising that many drugs cannot effectively do this.


The issue is even more critical for cancer treatment where drugs often do great damage at the wrong locations. We are all aware of the major side effect problems with most cancer drugs. This issue will have to be solved by new delivery agents, materials which will do several jobs—that will direct the drug to the desired location, that will help the active agent get through the barriers, that will protect the drug from degradation during delivery, and, finally, that will release the drugonce it is inside the cell or in the preferred location .

Uses

Carbon nanotubes can be modified to circulate well within the body. Such modifications can be accomplished with either covalent or non-covalent bonding. And the modifications can be such that they increase or decrease circulation time within the body. Many current drugs, especially for cancer treatment, circulate for only short times before excretion.

Carbon nanotube drug complexes are readily excreted from the body. Long-term data will be required, but initial studies indicate acceptable excretion.

Carbon nanotubes show no significant toxicity when they have been modified so as to be soluble in aqueous, body-type fluids.

Carbon nanotubes readily enter cells.

A wide range of active agents can be attached to carbon nanotubes and carried into cells along with the nanotubes. It appears that stable structures are formed which protect the active agents during transport. The active agents which can be carried by carbon nanotubes include many cancer drugs and also include short interfering RNA, which may be the hottest current area within therapeutics research.

Cancer cells in tumors are larger than normal cells and also exhibit leakage. This means that there is both leakage out of and leakage into the cells.

Mesoporous Silica Nanoparticles


Recent breakthroughs in the synthesis of mesoporous silica materials with controlled particle size, morphology, and porosity, along with their chemical stability, has made silica matrices highly attractive as the structural basis for a wide variety of nanotechnological applications such as adsorption, catalysis, sensing, and separation.[1–6] In addition, we and others have discoveredthat surface-functionalized mesoporous silica nanoparticle (MSN) materials can be readily internalized by animal and plant cells without posing any cytotoxicity issue in vitro.

These new developments render the possibility of designing a new generation of drug/gene delivery systems and biosensors for intracellular controlled release and imaging applications.Herein we review recent research efforts in developing new MSN-based materials with different surface functionalities targeted for the abovementioned applications.

Characteristics of Mesoporous Silica Nanoparticles

Since the discovery of MCM-41 by Mobil scientists, significant research progress has been made in controlling and modifying the properties of mesoporous silica materials. For example, several key structural characteristics of the material, including the size and morphology of pores and particles[ can be regulated. For example, we have synthesized MCM-41- type MSNs with a variety of shapes and sizes ranging from 20 to 500 nm, and with pore sizes ranging from 2 to 6 nm,.

Functionalization of these materials with a variety of organic groups inside of the mesopores or on the external surface of the particles[10,11] have been demonstrated.


Figure 1. Transmission electron microscopy images of three spherical MSNs with different particle and pore sizes: a) Particle size ca. 250 nm; pore diameter ca. 2.3 nm. b) Particle size ca. 200 nm; pore diameter ca. 6.0 nm. c) Particle size ca. 50 nm; pore diameter ca. 2.7 nm. Figure 1a reproduced with permission from [10]. Copyright 2003 American

The cylindrical mesopores of MSNsare arranged in a hexagonal structure, forming well-defined channels that are parallel to each other. These characteristics are typically observed by powder X-ray diffraction and transmission electron microscopy.Such unique features lead to high surface areas (900–1500 cm2 g–1), and large accessible pore volumes (0.5– 1.5 cm3 g–1), usually measured by nitrogen sorption analysis. The simple polycondensation chemistry of silica allows for covalent attachment of a wide variety of functional groups, commercially available as substituted trialkoxy- or trichloro-silanes, either by co-condensation during the initial synthesis of the material, or by post-synthesis grafting. By using these different methods, the loading and location of functional groups can be controlled. Decoration of the mesoporous channels and/or the external particle surface of MSNs with various functional groups allows a wide range of manipulation of the surface properties of these materials for controlled release delivery and biosensing applications.

Cellular Uptake of MSNsAfter our first study showing that MSNs were readily internalized by eukaryotic cells without detectable toxic effectsin vitro (Fig. 2), further studies were performed in order to understand the mechanism of cellular uptake of these materials. Mou and co-workers have shown that the endocytosis of fluorescein-


labelled MSNs by 3T3L1 and mesenchymal stem cells was clathrin-mediated and that the particles were able to escape the endolysosomal vesicles. Our recent work with HeLa cancer cells has demonstrated that the uptake efficiency and the uptake mechanism of the MSNs can be manipulated by the surface functionalization of the nanoparticles.We observed that functionalization of the external surface of MSNs with groups for which cells do express specific receptors, like folic acid, notably enhances the uptake efficiency of the material by cells. We also found that the functionalization of the particles with groups that alter their f-potentials affects not only the efficiency of their internalization, but the uptake mechanism and the ability of the particles to escape the endolysosomal pathway.

Hoekstra and co-workers have shown previously that nonphagocytic eukaryotic cells can endocytose latex beads up to 500 nm in size, and that the efficiency of uptake decreases with increasing particle size.They demonstrated that the highest efficiency was achieved with particles sized around 200 nm or smaller, whereas little, if any, uptake was observed for particles larger than 1 lm. Such information leads us to believe that MSNs can be efficiently employed as carriers for intracellular drug delivery as well as cell tracers and cytoplasmic biosensors.

Mesoporous Silica for Drug/Gene Delivery

It is well recognized that an efficient delivery system should have the capability to transport the desired guest molecules without any loss before reaching the targeted location. Upon reaching the destination, the system needs to be able to releasethe cargo in a controlled manner. Any premature release of guest molecules poses a challenging problem. For example, the delivery of many toxic antitumor drugs requires “zero release” before reaching the targeted cells or tissues. However, the release mechanism of many current biodegradable polymer-based drug delivery systems relies on hydrolysisinduced erosion of the carrier structure. The release of matrixencapsulated compounds usually takes place immediately upon dispersion of these composites in water. Also, such systems typically require the use of organic solvents for drug loading that can trigger undesirable modifications of the structure and/or function of the encapsulated molecules, such as protein denaturation and aggregation. In contrast, surface functionalized mesoporous silica materials offer, as mentioned before, several unique features, such as stable mesoporous structures, large surface areas, tunable pore sizes and volumes, and well-defined surface properties for site-specific delivery and for hosting molecules with various sizes, shapes, and functionalities.


Nanotubes: A New Carrier for Drug Delivery Systems

Nanotubes (NTs), nanometer-scale hollow cylinders, are emerging as promising drug vehicles offering many advantages over spherical particles .NTs are interesting for drug delivery for several reasons: (1) NTs have open mouths, which makes the inner surface accessible and incorporation of species within the tubes particularly easy; (2) There are no swelling or porosity changes with changes in pH, and they are not vulnerable to microbial attack. Therefore, the NTs are able to effectively protect entrapped molecules (enzymes, drugs, etc.) against denaturation induced by external environmental deterioration; (3) NTs have large inner volumes (relative to the dimensions of the tube), which can be filledwith any desired chemical or biochemical species ranging in size from proteins to small molecules, and allow for loading more one therapeutic agent in the same nanocarrier so that targeting molecules, contrast agents, drugs, or reporter molecules can be used at the same time; (4) The inner diameter and length of NTs can be precisely controlled to allow for altering the drug release profile and extending the effectiveness of drugs without increasing potency; (5) Two separated surfaces of NTs and facile surface functionalization create the possibility, for example, of loading and concentrating the inside of NTs with a particular biochemical payload but imparting chemical features to the outer surface that render it recognition capacity to allow for site-specific drug delivery to reduce toxic side effects .

This paper briefly highlights the recent performance of NTs in drug delivery. This discussion is by no means intended to be complete, an attempt is made to provide some illustrative examples on the basis and application of the NT delivery systems. The NT systems discussed includes silica NTs, self-assembling lipid NTs and polymer NTs as well as natural halloysite NT. Though it is still too early to establish NTs for clinical use, these novel carriers are undoubtedly interesting and deserve further investigation. As carbon NTs as biomolecule vehicles have been extensively reviewed ;the related content is not involved here.

There are several ways to fabricate NTs. The template synthesis is a general approach that involves chemical synthesis or electrochemical deposition of the desired material within the pores of a nanopore membrane such as alumina or polycarbonate . This method has been widely used to prepare NTs composed of many types of materials, including metals, polymers, semiconductors, carbons and composite nanostructures. One advantage of the template method is


that the template is tuneable, which means the outside diameter of the NT can be controlled by varying the pore diameter of the template membrane, the length of the NT can be controlled by varying the thickness of the template membranes, and the inside diameter of the NT can be controlled by varying the immersion time of precursors. Another advantage is that template method provides a particularly easyroute to accomplish differential functionalization on inner and outer surfaces.

Silica NTs are well known as an ideal vehicle for drug delivery and controlled release because they are easy to make, readily suspendable in aqueous solution and are of biocompatibility. They are usually prepared using a solgel template synthesis procedure .The template membrane is immersed into a silica precursor such as tetraethylorthosilicate sol so that the sol fills the pores. After the desired emersion time, the membrane is removed, dried in air, and then cured at 150 °C. This yields silica NTs lining the porewalls of the membrane plus silica surface films on both faces of the membrane. The surface films are removed by briefly polishing with slurry of alumina particles. The NTs are then liberated by dissolving the template membrane and collected by filtration.

Martin’s group elegantly demonstrated the smart NTs for bioseparations. Antibody functionalized silica NTs can provide the ultimate in extraction selectivitythe extraction of one enantiomer of a racemic pair .The Fab fragments of an antibody against the drug 4-[3-(4 fluorophenyl)-2- hydroxy-1-[1,2,4]-triazol-1-yl-propyl]-benzonitrile (FTB) were immobilized to both the inner and outer surfaces of the silica NTs. This was accomplished by dispersing silica NTs into a solution of the aldehyde-terminated silane trimethoxysilylbutanal.

The NTs were then dispersed into a solution of the Fab fragments, which resulted in attachment of the Fab to the NTs via Schiff base reaction between free amino groups on the protein and the surface-bound aldehyde. The Fab-functionalized NTs were added to racemic mixtures of the SR and RS enantiomers of the FTB. The tubes were then collected by filtration.

As the Fab fragment selectively binds the RS relative to the SR enantiomer, 75% of the RS enantiomer and none of the SR enantiomer was removed by the NTs. With the procedure described in,they also attached the Fab to only the inner surfaces of the NTs using the well-known glutaraldehyde coupling reaction. When these interior-only Fab-modified NTs were incubated with racemic mixture of the drug, 80% of the RS (and none of the SR) enantiomer was extracted.


Design of novel drug carriers with multi-functionalities is the key to the success of the drug delivery and controlled release field. Magnetic particles have been extensively studied in the field of biomedical and biotechnological applications, including drug delivery. By using an external, highgradient magnetic field, one can concentrate the nanocarriers of drugs at a particular point, such as a tumor site, to increase their possibility to interact with the targeted cells, and then release the loaded drug. However, conjugation of the magnetic nanoparticles to the conventional drug carriers is not easy to realize. Thanking to the large volume, the hollow cylinder of NTs are able to facilely load the magnetic NPs.

Son et al synthesized magnetic NTs (MNTs) with a layer of magnetite (Fe3O4) nanoparticles on the inner surface of the silica NT [12]. To do that, silica NTs still embedded in porous alumina film was dip-coated with a mixture solution of FeCl3 and FeCl2, dried in an Ar stream, immersed in NH4OH. They treated the inner NT surfaces of MNTs with octadecyltriethoxysilane (C18-silane) while MNTs were still embedded in the pores of the alumina template to obtain hydrophobic inner surface .

MNTs with C18- functionalized inside were added to a solution of 1,1’- dioctadecyl-3,3,3’,3’ tetramethylindocarbocyanine perchlorate (DiIC18) in water/methanol. These dye molecules was extracted into the MNTs by the strong hydrophobic interaction. The loaded MNT was then separated from the solution with a magnetic field. More than 95% of the dye was removed from the solution. MNTs functionalized with human IgG inside show a magnetic bioseparation for red Cy3- labeled anti-human IgG from the solution using antigenantibody interaction. 84% of Cy3-labeled anti-human IgG can be separated. The magnetic property of MNTs can also facilitate and enhance biointeractions between the outer surfaces of MNTs and a specific target surface. MNTs with an FITC-modified inner surface and a rabbit IgG-modified outer surface were incubated for 10 min onto the anti-rabbit IgG-modified glass slide with and without magnetic field from the bottom of the glass slide. About 4.2-fold binding enhancement was observed for the antigen-antibody interactions in the presence of magnetic field. This phenomenon implies that the magnetic field will improve the drug delivery efficiency.


The MNT also shows the controlled-release behavior with 5-Fluorouracil (5-FU), 4-nitrophenol, and ibuprofen as model drug molecules. The aminefunctionalized MNTs were immersed in the hexane (ibuprofen) or ethanol (5-FU, 4-nitrophenol) solutions of drugs. The amine functional groups make strong ionic and/or hydrogen-bonding interactions with the acid functional groups of drug molecules.

It was observed that less than 10% of ibuprofen was released in 1 h, and 80% was released after 24 h. In the cases of 5-FU and 4-nitrophenol, however, more than 90% was released in 1 h. These results conclude that the carboxylic acid group of ibuprofen makes the strongest interaction with the amine group inside MNT and ibuprofen released with a slow rate.

Heterostructured MNTs were also fabricated by the layer-by-layer (LBL) deposition of polyelectrolytes and magnetic Fe3O4 nanoparticles in the pores of track-etched polycarbonate membranes .Multilayers composed of poly(allylamine hydrochloride) (PAH) and poly(styrene sulfonate) (PSS) at high pH (pH > 9.0) were first assembled into the pores of track etched polycarbonate membranes, and then multilayers of magnetite nanoparticles and PAH were deposited .

The surface of the MNT were further modified by adsorbing a block copolymer, poly(ethylene oxide)-b-poly(methacrylic acid)(PEO-PMAA), to improve Fig. (1).


Fig. (2). Formation of LbL-assembled magnetic hollow tubes via the template method. (a) Assembly of multilayers on track-etched polycarbonate (TEPC) membranes. (b) Plasma etching of each surface of the multilayer-modified TEPC membranes. (c) Adsorption of Fe3O4 nanoparticle/PAH multilayers. (d) Dissolution of TEPC membranes. (e) Surface modification of magnetic hollow tubes with a PEO-PMAA block copolymer. An axial cross section of a typical NT is shown in the lower right corner. Reproduced with permission from Langmuir 2007, 23, 123. Copyright 2007 Am.

the colloidal stability of the MNTs. The MNTs proved to remove a large amount of an anionic dye (i.e., rose Bengal from solutionafter acid activation. Immobilization on silica can markedly improve the stability of enzymes under extreme condition . Chen and coworkers carried lysozyme on a template-synthesized silica NT .Under the neutral conditions of the experiment, both the negatively charged outer and inner surface of silica NTs could adsorb positively charged lysozyme via electrostatic interaction.

The lysozyme forms a multilayer adsorption with the weight ratio of lysozyme/silica 1:1 and 1:5 while a monolayer adsorption with lysozyme/silica 1:10 and 1:20. The enzymatic catalysis experiment shows that the lysozyme’s enzymatic activities first increased and then decreased with increasing surface coverage, in contrast to the common result, i.e enzymatic activity largely depends on the degree of adsorbent surface coverage; the specific activity decreases with decreasing surface coverage .This result reveals that the overlap and aggregation of the lysozyme molecules may reduce enzymatic activities at high surface coverage.


Lipid is the basic building blocks of biological membrane. In liquid media, lipid molecules self-assemble into diverse aggregate morphologies, depending on the molecular shape and solution condition such as lipid concentration, electrolyte concentration, pH, and temperature .Many lipid molecules can self-assemble into open ended, hollow cylindrical structures, named lipid NTs (LNTs), which are composed of rolled-up bilayer membrane wall .

The self assembly process involves a solid bilayer ribbon structure as an intermediate through fusion of vesicles in cooling process. The solid bilayer ribbon then twists into an open helix, which eventually closes to yield NTs in the way of either widening of the tape width and maintaining a constant helical pitch or shortening of the helical pitch of the ribbon and maintaining a constant tape width. In addition to the twisting-induced LNT, there is another route based on packing directed self-assembly without forming helically twisted or coiled ribbons during the course of self-assembly .

While LNTs have been widely utilized as scaffolds for synthesis of structured nanomaterials ;these biocompatible nanochannels are getting more and more intension as drug vehicles. Price et al loaded antibiotics used to prevent marine fouling into LNTs of 1(8,9) by capillary force . The tubes were then incorporated into a paint. This NTbased paint successfully proved to inhibit marine fouling during 6 months in ocean water. The applied biocides include bactericides, herbicides, molluskicides, insecticides, pesticides. Encapsulation of the biocides was accomplished by dispersing the desired biocide into a fluidic carrier. The selection of the carrier is determined by the viscosity of the carrier and the solubility of the active agent in the carrier. The carrier must possess a sufficiently low viscosity so that it can fill the lumen of the tubule as a result of capillary action. This carrier may be a monomer, a linear polymer or a polymerizable cross-linking material.

The release rate for a given agent is determined by the average inner diameter and length of the LNT, the viscosity of the carrier, the relative solubilities of the agent in the carrier and in the surrounding matrix (if present), and molecular weight of the active agents as well as that of the carrier. If the agent is soluble or mobile in the carrier, then the rate of release will mainly depend on the diffusion rate and solubility of the agent in the carrier and in the external matrix. If the agent is insoluble or immobile in the carrier, then the rate of release will mainly depend on


the rate of release of the carrier itself from the tubule. As another example of application of LNTs as a drug deliver nanocarrier, Kulkarni utilized the LNTs for topical delivery of drug into skin.

It is well known that skin is an excretory organ that often causes topical delivery of pharmacological or cosmetic agents difficult to penetrate against the natural ex-cretory forces. Moreover, the skin surface is enriched with sweat, bacteria, and cells that have been damaged or killed by ultraviolet light, creating a harsh environment for drug molecules and making the drug susceptible to degradation before reaching their target. The delivery system with LNTs confers special advantages for topical delivery of agents to the skin over other delivery vehicles. The diameter of human skin pores has been estimated to about 40 nm .Unlike traditional liposomal systems, LNTs have a significant size population under 100 nanometers in diameter, while still carrying significant quantities of active ingredient. These LNTs are therefore particularly useful as topical drug delivery vehicles because their small size permits rapid dermal penetration. In addition, the tubular delivery system described in Kulkarni’s work consists of lipids compatible with lipids in stratum corneum, which further facilitates skin penetration.

Furthermore, the delivery system with LNTs is capable of transporting a multitude of active ingredients, including drugs, genetic material or cosmaceuticals deep into the skin. Fluorescent LNTs can be used simultaneously as drug carriers and biomarkers to track and diagnose effectiveness of the treatment. We have made fluorescent NTs from a synthetic peptide lipid, the sodium salt of 2-(2-(2- tetradecanamidoacetamido) acetamido) acetic acid 2, which consist of CdSembedded bilayer membranes . The lipid 2 can self-assemble in aqueous solutions into a hollow cylindrical structure in the presence of proton (H+) (HLNT) or a series of transition metal cations (MLNT) . As illustrated in coordination of Cd2+ to two negatively charged COO groups of the lipid 2 allows it to form a Cdcomplexed LNT (CdLNT). Upon exposure to H2S vapor, the Cd2+ in the CdLNT were released as a result of competitive binding of the proton to the COO group, resulting in the formation of HLNT. The released Cd2+ subsequently reacted with S2 to initiate CdS nuclei, and finally grew into the CdS nanoparticles in all over the lipid bilayer membranes. The CdS nanoparticles have an average diameter around 45 nm with narrow distribution and separate from one another without any aggregation. The tubular nanocomposites clearly exhibited distinguishable fluorescfluorescence originating from electronic transition of the CdS nanoparticles. The fluorescence is resistant to photobleaching compared to other organic moiety-based fluorescence, and enables one to visualize for long time and to trace the localization in biological systems.


The fluorescent CdSLNT has proved to successfully act as a supramolecular nanotube host to encapsulate ferritin and gold nanoparticles, which is applicable for delivery of biomolecules.

The halloysite NT with the 115 μm of length and 10100 nm of inner diameter, a two-layered aluminosilicate chemically similar to kaolin, is a nature materials. Shchukin and Möhwald attained controlled release of a low-molecularweight inhibitor benzotriazole in the halloysite NTs . Halloysite powder was mixed with solution of benzotriazole to allow the biomolecule penetrate into the lumen. The surface of the halloysite-based NT was then modified by LBL deposition of polyelectrolyte bilayers, so the openings at the edges became blocked with the polyelectrolytes. With the polyelectrolyte shells composed of poly(diallyldimethylammonium chloride)(PDADMAC)/PSS, the halloysite NTs exhibit an increase of the bezotriazole release in aqueous solution at alkaline or acidic pH. At neutral condition the halloysite NTs showed the best upkeep characteristics almost complete suppression of the benzotriazole release saving more than 90% of the initial benzotriazole inside the inner cavity. The halloysite NTs also shows high reloading efficiency (up to 80%) compared to polyelectrolyte- modified SiO2 nanoparticles and polyelectrolyte capsules. The release rate was found to be strongly associated with the sort of the polyelectrolytes. The PDADMAC/PSScoated halloysite NTs have the slowest release of the benzotriazole, and the shell is stable for at least 40 min in the whole pH range.

For polyelectrolyte layers containing weak polyelectrolytes such as PAH/poly(methacrylic acid), the release rate increases and the shell stability decreases in acidic or alkaline pH regions. The result anticipates that for coatings where the immediate release of the inhibitor is necessary, halloysite NTs with a shell consisting of weak polyelectrolytes are preferable. When continuous, gradual release is required, halloysite NTs with the shell consisiting of one weak and one or two strong polyelectrolytes are preferred.

Abidian et al reported on a method to prepare poly(3,4- ethylendioxythiophene), PEDOT conducting-polymer NTs that can be used for precisely controlled dexamethasone drug release .

In order to produce the nanotubular PEDOT conducting polymers, nanofibers of biodegrable poly(Llactide) (PLLA) or poly(lactide-co-glycolide) (PLGA) were first electrospun onto the surface of a neutral probe followed by electrochemical deposition of conducting polymers around the electrospun nanofibers.


In a final step, the fiber templates can be removed by soaking in dichloromethane, providing additional means of controlled delivery of biologically active agents incorporated into the fibers themselves.

The controlled release can be accomplished either by passive delivery resulting from controlled degradation of the PLLA/PLGA or other matrix polymer used in the core or by actively actuating the drugloaded NTs with an applied electrical field.

Gold Nanoshells in Biomedical Applications

Gold nanoshells are spherical particles with diameters typically ranging in size from 10 to 200 nm .They are composed of a dielectric core covered by a thin gold shell. As novel nanostructures, they possess a remarkable set of optical, chemical and physical properties, which make them ideal candidates for enhancing cancer detection, cancer treatment, cellular imaging and medical biosensing.

Gold nanoshells are unique in that they combine many ideal features in a single particle. As a direct result of nanoscale resonance phenomena, gold nanoshells have very large optical absorption and scattering cross - sections, which render them highly suitable as contrast agents for imaging. They can be tuned to preferentially absorb or scatter light at specifi c wavelengths in the visible and near - infrared ( NIR ) regions of the spectrum. In the NIR ‘ tissue window ’ , light penetration into tissue is optimal. Nanoshells tuned to absorb NIR radiation are particularly useful as mediators of photothermal cancer therapy because they effi ciently convert absorbed radiation into heat, and are thermally stable at therapeutic temperatures. Furthermore, nanoshells preferentially accumulate at tumor sites due to their nanoscale dimensions. The inert gold surface of nanoshells provides


several advantages, including biocompatibility, noncytotoxicity, and it also facilitates conjugation to monoclonal antibodies or other biomolecules for both active tumor targeting and biosensing applications.The first Stage I clinical trials using nanoshells as therapeutic agents to treat head and neck cancers are set to commence in 2008 . Over the past few years, the pace of research in this fi eld has accelerated rapidly, as have the number of potential biomedical applications for nanoshells. It has been the present authors ’ best attempt to keep abreast of new developments in the fi eld but, given the pace of progress, this chapter will be partially outdated by the time it hits the press – which is good news! The chapter is designed with two distinct audiences in mind: researchers already in the fi eld who may use it as a quick reference; and ‘ early - stage ’ , who can use it as a fi rst read to gain a broader understanding of the field. It is organized in the following manner. The first section highlights the unique optical and material properties of nanoshells and explores the physics underlying the associated phenomena. The second section we describe the synthesis of nanoshells. The third section describes the transport, biodistribution and benign toxicity profi le of nanoshells in vivo , while the fourth section concludes with an extensive discussion on the various biomedical applications of nanoshells. Although the focus of the chapter is on gold nanoshells, their nanoparticle counterparts– gold nanorods, gold nanospheres and quantum dots – will also be discussed,in order to provide relevant comparisons and contrasts.

NANOROBOTS

The engineering of molecular products needs to be carried out by robotic devices, which have been termed as nanorobots. A nanorobot is essentially a controllable machine at the nanometer or molecular scale that is composed of nanoscale components. The field of nanorobotics studies the design, manufacturing, programming, and control of the nanoscale robots,

Nanorobots are nanodevices that will be used for the purpose of maintaining and protecting the human body against pathogens. They will have a diameter of about 0.5 to 3 microns and will be constructed out of parts with dimensions in the range of 1 to 100 nanometers. The main element used will be carbon in the form of diamond / fullerene nanocomposites because of the strength and chemical inertness of these forms.


Many other light elements such as oxygen and nitrogen can be used forspecial purposes. To avoid being attacked by the host.s immune system, the best choice for the exterior coating is a passive diamond coating. The smoother and more flawless the coating, the less the reaction from the body.s immune system.

Nanorobots would constitute any passive or active structure capable of actuation, sensing, signaling, information processing, intelligence, swarm behavior at the nano scale.

The nanorobots are invisible to naked eye, which makes them hard to manipulate and work with. Techniques like scanning electron microscopy (SEM) and atomic force microscopy (AFM) are being employed to establish a visual and haptic interface to enable us to sense the molecular structure of these nanoscaled devices.

Virtual reality (VR) techniques are currently being explored in nanoscience and biotechnology research as a way to enhance the operator’s perception (vision and haptics) by approaching more or less a state of “full immersion” or “telepresence.” The development of nanorobots or nanomachine components presents difficult fabrication and control challenges. Such devices will operate in microenvironments whose physical properties differ from those encountered by conventional parts.

Since these nanoscale devices have not yet been fabricated, evaluating possible designs and control algorithms requires using theoretical estimates and virtual interfaces/environments. Such interfaces/simulations can operate at variouslevels of detail to trade-off physical accuracy, computational cost, number of components and the time over which the simulation follows the nanoobject behaviors.

They can enable nanoscientists to extend their eyes and hands into the nanoworld and also enable new types of exploration and whole new classes of experiments in the biological and physical sciences. VR simulations can also be used to develop virtual assemblies of nano and bio-nanocomponents into mobile linkages and predict their performance.

Nanorobotswith completely artificial components have not been realized yet. The active area of research in this field is focused more on molecular robots, which are thoroughly inspired by nature’s way of doing things at nano scale. Mother Nature has her own set of molecular machines that have been working for centuries, and have been optimized for performance and design over the ages.


As our knowledge and understanding of these numerous machines continues to increase, we now see a possibility of using the natural machines, or creating synthetic ones from scratch, using nature’s components. This project focuses more on such molecular machines, called also bio-nanorobots, and explores various designs and research prevalent in this field.

The main goal in the field of molecular machines is to use various biological elements—whose function at the cellular level creates motion, force or a signal—as machine components. These components perform their preprogrammed biological function in response to the specific physiochemical stimuli but in an artificial setting.

In this way proteins and DNA could act as motors, mechanical joints, transmission elements, or sensors. If all these different components were assembled together in the proper proportion and orientation they would formnanodevices withmultipledegrees of freedom, able to apply forces and manipulate objects in the nanoscale world. The advantage of using nature’s machine components is that they are highly efficient and reliable. Nanorobotics is a field, which calls for collaborative efforts between physicists, chemists, biologists, computer scientists, engineers, and other specialists to work towards this common objective.

Nanorobotics is emerging as a demanding field dealing with miniscule things atmolecular level, and it is mainly used for medical applications. Nanorobots arenanoelectromechanical systems designed to perform a specific task with precision at nanoscale dimensions.

Bacteria travel to the food sources and move away from the areas where theydetected dangerous substances. They have a kind of sensors spread through their


cellular wall which detect the food and transmit signals to the motors that control the rotation of the flagella. As higher is the concentration of the molecules, the faster the bacteria will travel to the area where the nutrients are. If they found a place with dangerous substances like a salt concentration area, the sensors stop them with the flagella, and change their direction. They made a valance between the positive and negative molecules that they found and if the valance is positive they continue travelling forward, and if it is negative they turn around.

Nanorobots have chemical sensors which detect the target molecules. As a response theywould emit a power signal proportional to the detected amount. This signal would arrive to a programmed microprocessor which controls the direction and velocity of the nanorobot. This system would maintain the robot in the pursuit of its objective. Nanorobots allow drugs of nanosize to be used in lower concentration and have an earlier onset of therapeutic action. It also provides materials for controlled drug delivery by directing carriers to a specific location.

The nanorobots can be attacked by the host’s immune system. To avoid that, thebest choice is to have an exterior coating of passive diamond. The smoother andflawless the coating, the lesser is the reaction from the body’s immune system.Nanorobots have many applications, but there are

Cancer Detection and Treatment

Many companies related with biotechnology are trying to find the correct way tomanipulate the RNA (ribonucleic acid) and block genes which generate proteinsassociated with different diseases such as cancer, blindness or AIDS. However, this is the first mechanism which is able to enter in a cell and manipulate the RNA.

The nanorobots or nanoparticles are made with a mixture of a polymer and aprotein called transferrin which has the capacity of detecting tumor cells because of its molecular particularities. Once they are in the cells the chemical sensor gives the order to dissolve; and when nanoparticles are dissolved they let free some substances which actuate on the RNA of each cell disabling the gene responsible of the cancer.

Specifically, what the nanoparticles deactivate is the ribonucleic reductasa, the protein associated with the cancer growth which is fabricated by the disabled gene.It has been probed that the therapy with nanoparticles works, but it is very early to


say that this will be the definitive cure for the cancer.

There is another kind of nanoparticles for the treatment of the cancer: magneticparticles. These ones are used in a different way. When they arrive to the cancer cells,microwaves are applied from outside, the particles are excited and they burn the cancer cells.

Nanorobots in the Diagnosis and Treatment of Diabetes

Glucose carried through the blood stream is important to maintain the humanmetabolism working healthfully, and its correct level is a key issue in the diagnosis and treatment of diabetes.

The hSGLT3 molecule can serve to define the glucose levels for diabetes patients.This protein serves as a sensor to identify glucose.

The simulated nanorobot prototype model has embedded Complementary MetalOxide semi-conductor (CMOS) nanobioelectronics. It features a size of ~2μm, which permits it to operate freely inside the body. Whether the nanorobot is invisible or visible for the immune reactions, it has no interference for detecting glucose levels in blood stream.

Even with the immune system reaction inside the body, the nanorobot is not attacked by the white blood cells due biocompatibility. For the glucose monitoring the nanorobot uses embedded chemosensor that involves the modulation of hSGLT3 protein glucosensor activity.

Through its onboard chemical sensor, the nanorobot can thus effectively determine if the patient needs to inject insulin or take any further action, such as any medication clinically prescribed.

In the medical nanorobot architecture, the significant measured data can be thentransferred automatically through the RF signals to the mobile phone carried by thepatient. At any time, if the glucose achieves critical levels, the nanorobot emits an alarm through the mobile phone. In the simulation, the nanorobot is programmed also to emit a signal based on specified lunch times, and to measure the glucose levels in desired intervals of time.


An Artificial Oxygen Carrier Nanorobot

"Respirocyte" is the artificial mechanical red cell, an imaginary nanorobot whichfloats along in the blood stream. It is essentially a small pressure tank that can bepumped full of oxygen (O2) and carbon dioxide (CO2) molecules. Later on, these gases can be released from the small tank in a controlled manner.

These atoms are mostly carbon atoms arranged as diamond in a porous lattice structure inside the spherical shell. Outside of each device there are gas concentration sensors.

When the nanorobot passes through the lung capillaries, O2 partial pressure is high and CO2 partial pressure is low, so the onboard computer tells the sorting rotors to load the tanks with oxygen and to dump the CO2. When CO2 partial pressure is relatively high and O2 partial pressure relatively low the onboard computer commands the sorting rotors to release O2 and to absorb CO2. Respirocytes simulate the action of the natural hemoglobin-filled red blood cells, but they can deliver 236 times more oxygen per unit volume than a natural red cell.

Respirocytes have also some sensors to receive acoustic signals from the doctorwho will use some ultrasound-like transmitter to modify the behaviour of theRespirocytes when they are still inside the body of the patient.

Artificial Phagocytes – Microbivores Nanorobots

The primary function of a Microbivore is to destroy microbiological pathogensfound in the human bloodstream. They could patrol the bloodstream, seeking out and digesting unwanted pathogens including bacteria, viruses, or fungi. Given intravenously they would achieve complete disappearance of even the most severe septicemic infections in hours or less. This is much better than the weeks or months needed for antibiotic-assisted natural phagocytic defenses.

Chromallocyte: A Hypothetical Mobile Cell-Repair Nanorobot

Another nanorobot, the Chromallocyte would replace entire chromosomes inindividual cells thus reversing the effects of genetic disease and other accumulated damage to our genes, preventing aging. Inside a cell, a repair machine will first size up the situation by examining the cell's contents and activity, and then take action.


Quantum dots

Quantum dots are nanocrystals measuring around 2-10 nm which can be made to fluorescence when stimulated by light. Their structure consists of an inorganic core, the size of which determines the colour emitted, an inorganic shell and an aqueous organic coating to which biomolecules are conjugated. The biomolecule conjugation of the quantum dots can bemodulated to target various biomarkers.Quantum dots can be used for biomedical purposes as a diagnostic as well as therapeutic tool. These can be tagged with biomolecules and used as highly sensitive probes. A study done on prostate cancer developed in nude mice has shown accumulation of quantum dots probe by enhanced permeability and retention as well as by antibody directed targeting. The quantum dots conjugated with polyethylene glycol (PEG) and antibody to prostate specific membrane antigen (PSMA) were accumulated and retained in the graftedtumour tissue in the mouse.Quantum dots can also be used for imaging of sentinel node in cancer patients for tumour staging and planning of therapy. This method can be adopted for various malignancies like melanoma, breast, lung and gastrointestinal tumours. Quantum dot probes provide real time imaging of the sentinel node with Near Infra Red (NIR) fluorescence system. The NIR region of the electromagnetic spectrum produces reduced background noise and deeper penetration of rays, of up to 2 to 5 cm into the biological sample. However, the traditional fluorescence dyes yield low signal intensity when used in NIR region. This limitation is overcome, by using NIR fluorescence system with quantum dot probes. The fluorescence produced by quantum dots is much brighter than those produced by conventional dyes when used with NIR fluorescence system.However, the application of quantum dots in a clinical setting has limitations owing to its elimination factors. Functionalization of the quantum dots which protects from the toxic core, leads to increase in size of the nanoparticle greater than the pore size of endothelium and renal capillaries, thus reducing its elimination and resulting in toxicity. Also, in vivo studies are lacking on the metabolism and excretion of quantum dots.

Nanobubbles


Cancer therapeutic drugs can be incorporated into nanoscaled bubble like structures called as nanobubbles. These nanobubbles remain stable at room temperature and when heated to physiological temperature within the body coalesce to form microbubbles.

These have the advantages of targeting the tumour tissue and delivering the drug selectively under the influence of ultrasound exposure. This results in increased intracellular uptake of the drug by the tumour cells. It also provides an additional advantage of enabling visualisation of the tumour by means of ultrasound methods. Rapaport et al have demonstrated the utility of nanobubbles in delivery of drugs like doxorubicin based on in vitro and in vivo experiments using breast cancer cells MDA MB231 and mice with breast cancer xenograft respectively. On administration of nanobubble loaded doxorubicin, these reach the tumour tissue through leaky vasculature and get accumulated at the site of tumour. This is followed by formation of microbubbles by coalescing of nanobubbles which can be visualized by ultrasound techniques.

When the site is focused with high intensity focused ultrasound (HIFU), it causes disruption of the microbubbles resulting in release of the drug. The microbubbles retained the drug in a stable state until stimulated by HIFU. This results in attainment of higher levels of drug in the target cells and hence reduced toxicity and increased efficacy. This method needs further exploration for its utility in treatment of various malignancies. Liposomal nanobubbles and microbubbles are also being investigated for their role as effective non viral vectors for gene therapy. Nanobubbles combined with ultrasound exposure has shown improved transfer of gene in both in vitro and in vivo studies .

Nanobubbles are also being tried as a therapeutic measure for removal of clot in vascular system in combination with ultrasound, a process called as sonothrombolysis. This method has advantages of being non invasive and causing less damage to endothelium.

Drug Loaded Erythrocytes


Encapsulation of a drug into carriers permit delayed or controlled kinetics of release, increased specificity of delivery to target cells or organs and use of novel routes of drug into cells.

Erythrocytes are autologous and natural product of the body and are biodegradable as well as nonimmunogenic. The Cells carrying drug can circulate intravascularly for prolonged period of time. Hence rat erythrocytes have been loaded with 5-flurouracil (5-Fu), an anti cancer drug, to deliver drug to specific sites in the body. The method used was hypotonic preswelling and isotonic resealing.

Drug loaded cells were characterized in vitro for osmotic fragility, drug entrapment, drug and hemoglobin leakage and morphological characteristics. Drug was analyzed by HPLC and HPTLC. Hemoglobin release was measured by UV spectrophotometer.

Encapsulation of 65%drug was achieved by this method. Optical microscopic examination of the drug loaded cells revealed no difference in the morphological characteristics of the cells compared to the normal erythrocytes. Cells were discoid in shape. Osmotic fragility test of the loaded erythrocytes and normal erythrocytes were carried out at different sodium chloride concentration viz. 0.1% to 0.9%.

Normal erythrocytes released 50% of cellular hemoglobin at the chloride concentration of 0.35% whereas the drug-loaded erythrocytes released the same amount of hemoglobin at 0.5% sodium chloride concentration. Further shelf life of drug-loaded erythrocytes was prolonged by lyophilization. No difference was observed in the shape, size and drug content of loaded and lyophilized erythrocytes when compared with freshly loaded erythrocytes.


Iontophoretic drug delivery

IONTOPHORESISThe highly lipophilic nature of the skin restricts the permeation of hydrophilic, high molecular weight and charged compounds through the stratum corneum into the systemic circulation. However, many therapeutically active drug molecules are hydrophilic and possess high molecular weights for example, peptides (Sloan et al., 1986 and Williams et al., 1992).Iontophoresis simply defined is the application of an electrical potential that maintains a constant electric current across the skin and enhances the delivery of ionized as well as unionized moieties (Williams et al., 1992). This technique is capable of expanding the range of compounds that can be delivered transdermally. Along with the benefits of bypassing hepatic first pass effect, and higher patient compliance, the additional advantages that the iontophoretic technique offers can be summarized as follows (Williams et al., 1992, Williams et al., 1991 and Glikfeld et al., 1988).

Delivery of both ionized and unionized drugs.

Depending on the current applied it is enabling continuous or pulsatile delivery of drug.

Permitting easier termination of drug delivery.

Offering better control over the amount of drug delivered since the amount of compound delivered depends on applied current, duration of applied current, and area of skin exposed to the current.

Restoration of the skin barrier functions without producing severe skin irritation.

Improving the delivery of polar molecules as well as high molecular weight compounds.

Ability to be used for systemic delivery or local (topical) delivery of drugs.


Reducing considerably inter and/ or intra subject variability in view of the fact that the rate of drug delivery is more dependent on applied current than on stratum corneum

characteristics.

Principles of iontophoresisThe iontophoretic technique is based on the general principle that like charges repel each other. Thus during iontophoresis, if delivery of a positively charged drug (DC) is desired, the charged drug is dissolved in the electrolyte surrounding the electrode of similar polarity, i.e. the anode. On application of an electromotive force the drug is repelled and moves across the stratum corneum towards the cathode, which is placed elsewhere on the body. Communication between the electrodes along the surface of the skin has been shown to be negligible (Glikfeld et al., 1988) , i.e. movement of the drug ions between the electrodes occurs through the skin and not on the surface. When the cathode is placed in the donor compartment of a Franz diffusion cell to enhance the flux of an anion, it is termed cathodal iontophoresis and for anodal iontophoresis, the situation would be reversed. Neutral molecules have been observed to move by convective flow as a result of electro-osmotic and osmotic forces on application of electric current (Green et al.,1993).Electromigration of ions during iontophoresis causes convective solvent motion and this solvent motion in turn ‘drags’ neutral or even charged molecules along with it. This process is termed as electro-osmosis. At pH values above 4, the skin is negatively charged, implying that positively charged moieties like Na+ will be more easily transported as they attempt to neutralize the charge in the skin to maintain electroneutrality (Burnette et al., 1987). Thus the movement of ions under physiological conditions is from the anode to the cathode. For loss of each cation (sodium ion in this case) from the electrode in this process, a counter ion,. an anion, Cl −moves in the opposite direction from the cathode to the anode. It is the transport number of each ion, which describes the fraction of the total current transferred by the ion and depends on the physicochemical properties of the respective ions. t+ Na is greater than t- Cl and also the skin facilitates movement of Na+ more than Cl −, hence there is a net increase in the NaCl in thecathodal compartment and net decrease in NaCl on the anodal side. Due to this electrochemical gradient, osmotic flow of water is induced from the anode to the cathode. If any neutral drug molecules are present at the anode at this time they can be transported through the skin along with the water. Such water movement often


results in pore shrinkage at the anode and pore swelling at the cathode (R. Harris., 1967).

Merits

1. It is a non-invasive technique could serve as a substitute for chemical enhancers (Srinivasan et al., 1989).

2. It eliminates problems like toxicity problem, adverse reaction formulation problems associated with presence of chemical enhancers in pharmaceuticals (Bellantone et al., 1986).

3. It may permit lower quantities of drug compared to use in TDDS, this may lead to fewer side effects (Bodde et al., 1989).

4. TDDS of many ionized drug at therapeutic levels was precluded by their slow rate of diffusion under a concentration graduation, but iontophoresis enhanced flux of ionic drugs across skin under electrical potential gradient (Srinivasan et al., 1989).

5. Iontophoresis prevent variation in the absorption of TDDS (Bodde et al., 1989).

6. Eliminate the chance of over or under dosing by continuous delivery of drug programmed at the required therapeutic rate (Bodde et al., 1989).

7. Provide simplified therapeutic regimen, leading to better compliance (Phipps et al., 1989).8. Permit a rapid termination of the modification, if needed, by simply by stopping drug input from the iontophoretic delivery system (Bodde et al., 1989).

9. It is important in systemic delivery of peptide/protein based pharmaceuticals, which are very potent, extremely short acting and often require delivery in a circadian pattern arhythm, eg. Thyrotropin releasing hormone, somatotropine, tissue plasminogen activates, interferons, enkaphaline, etc (Phipps et al., 1989).

10. Provide predictable and extended duration of action (Bodde et al., 1989).

11. Reduce frequency of dosage (Yogeshvar et al., 2004).


12. Self-administration is possible (Yogeshvar et al., 2004).

13. A constant current iontophoretic system automatically adjust the magnitude of the electric potential across skin which is directly proportional to rate of drug delivery and therefore,intra and inter-subject variability in drug delivery rate is substantially reduced. Thus, minimize inter and intra-patient variation (Yogeshvar et al., 2004).

14. An iontophoretic system also consists of a electronic control module which would allow for time varying of free-back controlled drug delivery (Yogeshvar et al., 2004).15. Iontophoresis turned over control of local anesthesia deliveryin reducing the pain of needle insertion for local anesthesia(Bellantone et al., 1986).16. By minimizing the side effects, lowering the complexity of treatment and removing the need for a care to action, iontophoretic delivery improve adherence to therapy for the control of hypertension (Zakzewski et al., 1991).17. Iontophoretic delivery prevents contamination of drugs reservoir for extended period of time (Padmanabhan et al.,1990).

Demerits1. Iontophoretic delivery is limited clinically to those applications for which a brief drug delivery period is adequate (Sanderson et al., 1989).2. An excessive current density usually results in pain (Sanderson et al., 1989).3. Burns are caused by electrolyte changes within the tissues (Moliton et al., 1939).4. The safe current density varies with the size of electrodes (Moliton et al., 1939).5. The high current density and time of application would generate extreme pH, resulting in a chemical burn (Miller et al.,1987).6. This change in pH may cause the sweat duct plugging perhaps precipitate protein in the ducts, themselves or cosmetically hyperhydrate the tissue surrounding the ducts (Sanderson et al., 1989).7. Electric shocks may cause by high current density at the skin surface (Miller et al.,1989).8. Possibility of cardiac arrest due to excessive current passing through heart (Padmanabhan et al., 1990).9. Ionic form of drug in sufficient concentration is necessary for iontophoretic delivery (Padmanabhan et al., 1990).10. High molecular weight 8000-12000 results in a very uncertain rate of delivery (Moliton et al., 1939).to simulate


Liposomes

Liposomes, or phospholipid vesicles, have been recognized as a potential drug delivery vehicle for three decades. Depending on the drug of interest, liposomes can serve as a controlled release carrier or simply as a biocompatible solubilizing vehicle for poorly soluble agents. Because of their size, which typically ranges in mean diameter from 50 to 250 nm for the systemically administered vesicles, liposomes display some unique pharmacokinetic characteristics.These include clearance via the reticuloendothelial system, which results in a relatively long systemic circulation time, and hepatic and splenic distribution.

Furthermore, liposomes exhibit preferential extravasation and accumulation at the site of solid tumors due to increased endothelial permeability and reduced lymphatic drainage in these tissues, which has been defined as enhanced permeability and retention effect. Liposomal delivery is therefore a means to modify the pharmacokinetic and pharmacodynamic properties of therapeutic agents. Such modifications can, in some settings, improve the therapeutic efficacyof anticancer drugs and reduce or modulate their toxicity profile. For example, long circulating polyethylene glycol-coated liposomal formulation of doxorubicin has been shown to exhibit increased solid tumor accumulation due to the enhanced permeability and retention effect and decreased dose-limiting cardiac toxicity relative to the free drug.


Development of liposomes as a drug carrier has been marked by a number of key innovations. These includethe development of remote drug loading methodologies based on pH or ionic gradient , polyethylene glycol-coated long circulating liposomes, cationic liposomes for nucleic acid delivery, pH-sensitive liposomes for cytosolic drug delivery, temperaturesensitive liposomes for burst release in response to hyperthermia, and targeted liposomes for selective delivery to tumor cells or endothelium.

Liposomes discovered in mid 1960s were the original models of nanoscaled drug delivery devices. They are spherical nanoparticles made of lipid bilayer membranes with an aqueous interior but can be unilamellar with a single lamella of membrane or multilamellar with multiple membranes. They can be used as effective drug delivery systems.Cancer chemotherapeutic drugs and other toxic drugs like amphotericin and hamycin, when used as liposomal drugs produce much better efficacy and safety as compared to conventional preparations.

These liposomes can be loaded with drugs either in the aqueous compartment or in the lipid membrane. Usually water soluble drugs are loaded in aqueous compartment and lipid soluble drugs are incorporated in the liposomal membrane. The major limitation of liposome is its rapid degradation and clearance by the liver macrophages, thus reducing the duration of action of the drug it carries. This can be reduced to a certain extent with the advent of stealth liposomes where the liposomes are coated with materials like polyoxyethylene which prevents opsonisation of the liposome and their uptake by macrophages5. Other ways of prolonging the circulation time of liposomes are incorporation of substances like cholesterol, polyvinylpyrollidone polyacrylamide lipids and high transition temperature phospholipids distearoyl phosphatidylcholine.

Targeting of liposomal drugs: Liposomes can be targeted to specific organ or tissue by passive as well as active methods. As the liposomal drug acts minimally on other tissues, the safety profile is better than non-liposomal drug. The vascularity in tumour tissue is poorly organized and significant leak occurs from blood vessel in the tumour tissue. The liposomal drugs get accumulated in the tumour tissue passively and produce enhanced effects. Active targeting of the drug can be achieved by using immunoliposomes and ligand directed liposomes.Immunoliposomes are liposomes conjugated with an antibody directed towards the tumour antigen. The antibody can be conjugated to the surface of a stealth liposome, the polyoxyethylene coating of a stealth liposome or on the surface of a


non stealth liposome. These immunoliposomes when injected into the body, reaches the target tissue and gets accumulated in its site of action. This reduces unwanted effects and also increases the drug delivery to the target tissue, thus enhancing its safety and efficacy.

Antibody directed enzyme prodrug therapy (ADEPT) consists of liposomes conjugated with an enzyme to activate a prodrug and an antibody directed to a tumour antigen (enzyme linked immunoliposomes). These are administered prior to administration of a prodrug. The antibody directs the enzyme to the target tissue where it activates the prodrug selectively and converts it to its active form. This way, action of the drug is avoided in other normal tissues, thus minimizingthe toxicity of drug. Such studies are being tried with epirubicin and doxorubicin.Ligand bearing liposomes are conjugated with specific ligands which are directed towards target structures. In ovarian cancer, overexpression of folate receptors by the tumour tissue occurs. The liposomal drug can be conjugated with folate so as to direct the molecule to the tumour. This method is also being tried in the treatment of leishmaniasis where liposomal hamycin conjugated with mannosyl human serum albumin are targeted towards human macrophages.Asialofeutin conjugation is being tried to target liver cells for gene therapy. The targeted liposomal preparations are found to have a better efficacy than non targeted liposomes.

MICROCAPSULES:

Poor water solubility of many anticancer agents (such as paclitaxel, PCT; camptothecin, CPT; and certain porphyrins like meso tetraphenylporphine, TPP, used in photodynamic therapy, PDT) hinders their application and complicates direct parenteral administration. Various formulation strategies based on the use of drug carrier systems have been suggested to overcome their poor solubility, low stability, and toxic side effects . Among such systems, polymericmicelles have drawn much attention owing to their easily controlled properties and good pharmacological characteristics . Micelles prepared from PEGdiacyllipidsconjugates, such as PEGPE, are of particular interest . Here, we describe the preparation,properties, and activity against cancer cells in vitro of PCT-, CPT-, and TPPloaded PEG-PE micelles as well as mixed micelles made of PEG-PE and D-α- tocopheryl polyetheyene glycol 1000 succinate (TPGS).


MICROEMULSION:Microemulsions are liquid dispersions of water and oil that are made homogenous, transparent or translucent and thermodynamically stable by the addition ofrelatively large amounts of a surfactant and a cosurfactant and having diameter of the droplets in the range of 10 – 100 nm.

Microemulsions have been widely studied for drug targeting to the brain and to enhance the bioavailability of the poorly soluble drugs. They offer a cost effective approach in such cases.Microemulsions have very low surface tension and small droplet size which results in high absorption and permeation.

Interest in these versatile carriers is increasing and their applications have been diversified to various administration routes in addition to the conventional oral route. This can be attributed to their unique solubilization properties and thermodynamic stability which has drawn attention for their use as carrier for drug targeting to the brain.

Intranasal drug delivery is one of the focused delivery options for brain targeting, as the brain and nose compartments are connected to each other via the olfactory route and via peripheral circulation. Etoposide , an epipodophyllotoxin, is an anticancer drug useful for the treatment of small cell lung cancer and testicular carcinoma. Prior to administration, the drug has to be diluted in the infusion fluid; its low aqueous solubility thus acts as a constraint in the formulation of its parenteral dosage form. This attribute results in drug precipitation in the infusion fluid thereby proving detrimental to the health owing to the possibility of capillary blockade.


MICROSPHERES:Microspheres are an example of a drug delivery system that has been evaluated extensively in cancer chemotherapy. They are essentially solid porous particles (1 - 100 μm diameters) which can both target their drug cargo by physical trapping in blood vessels (chemoembolisation) and sustain the action of a therapeutic agent through controlled release. Microspheres can be made from a broad range of polymeric materials, including proteins, polysaccharides, polyesters and lipids by a variety of different techniques (emulsification, heat stabilisation, coacervation and phase inversion technology).

Their diversity identifies the microsphere as a drug delivery system with considerable flexibility. The present review develops the hypothesis that the matrix material and method of preparation are critical determinants in defining pharmaceutical characteristics, which in turn dictate biologic activity. Examples are cited of different approaches adopted with cytotoxic drugs (chiefly doxorubicin, mitomycin C, cisplatin and 5- fluorouracil) to achieve particular drug delivery profiles. However, it is clear that certain cytotoxic drugs are encapsulated in systems with pharmaceutical properties inappropriate for the particular mechanistic class. Also, studies demonstrating selective tumour targeting of cytotoxic drugs after systemic administration are rare. This review also focuses on the contribution that microspheres have made to delivery of immunomodulating cytokines, protein vaccines, antisense oligonucleotides and gene therapy. For these applications, new matrix materials such as bioadhesive polymers and more gentle methods of preparation have had to be developed to preserve the native conformation of these easily denatured biological molecules.

Nevertheless, these systems require to be subjected to pharmaceutical characterisation and need further optimisation to overcome persistent instability problems. Microspheres are anticipated to contribute significantly in the future to the systemic, oral and loco-regional treatment of cancer with cytotoxic drugs and biological response modifiers.


HYDROGELS:

Hydrogels are three-dimensional, cross-linked networks of water-soluble polymers. Hydrogels can be made from virtually any water-soluble polymer, encompassing a wide range of chemical compositions and bulk physical properties. Furthermore, hydrogels can be formulated in a variety of physical forms, including slabs, microparticles, nanoparticles, coatings, and films. As a result, hydrogels are commonly used in clinical practice and experimental medicine for a wide range of applications, including tissue engineering and regenerative medicine , diagnostics, cellular immobilization, separation of biomolecules or cells, and barrier materials to regulate biological adhesions . Hydrogels show minimal tendency to adsorb proteins from body fluids because of their low interfacial tension. Further, the ability of molecules of different sizes to diffuse into (drug loading) and out of (drug release) hydrogels allows the possible use of dry or swollen polymeric networks as drug delivery systems for oral, nasal, buccal, rectal, vaginal, ocular and parenteral routes of administration. Several terms have been coined for hydrogels, such as ‘intelligent gels’ or ‘smart hydrogels’.

The smartness of any material is the key to its ability to receive, transmit or process a stimulus, and respond by producing a useful effect . Once acted on, stimuli can result in changes in phases, shapes, optics, mechanics, electric fields, surface energies, recognition, reaction rates and permeation rates. Hydrogels are ‘smart’ or ‘intelligent’ in the sense that they can perceive the prevailing stimuli and respond by exhibiting changes in their physical or chemical behavior, resulting in the release of entrapped drug in a controlled manner. The unique physical properties of hydrogels have sparked particular interest in their use in drug delivery applications. Their highly porous structure can easily be tuned by controlling the density of cross-links in the gel matrix and the affinity of the hydrogels for the aqueous environment in which they are swollen. Their porosity also permits loading of drugs into the gel matrix and subsequent drug release at a rate dependent on the diffusion coefficient of the small molecule or macromolecule through the gel network. Indeed, the benefits of hydrogels for drug delivery may be largely pharmacokinetic e specifically that a depot formulation is created from which drugs slowly elute, maintaining a high local concentration of drug in the surrounding tissues over an extended period, although they can also be used for systemic delivery. Hydrogels are also generally highly biocompatible, as reflected in their successful use in the peritoneum and other sites invivo. Biocompatibility is promoted by the high water content of hydrogels and the physiochemical similarity of hydrogels to the native extracellular matrix, both compositionally (particularly in the case of carbohydrate-based hydrogels) and mechanically.


Biodegradability or dissolution may be designed into hydrogels via enzymatic, hydrolytic, or environmental (e.g. pH, temperature, or electric field) pathways; however, degradation is not always desirable depending on the time scale and location of the drug delivery device. Hydrogels are also relatively deformable and can conform to the shape of the surface to which they are applied. In the latter context, the muco- or bioadhesive properties of some hydrogels can be advantageous in immobilizing them at the site of application or in applying them on surfaces that are not horizontal. Despite these many advantageous properties, hydrogels also have several limitations. The low tensile strength of many hydrogels limits their use in load-bearing applications and can result in the premature dissolution or flow away of the hydrogel from a targeted local site.

Niosome – A Novel Drug Delivery System

The concept of drug targeting or site specific drug delivery was introduced first time by Paul Elrich in 1909, when he reported ‘magic bullet’ to deliver a drug to the desired site of action without affecting the non target organs or tissues (Juliano, 1980) by associating the drug with a pharmacologically “inactive carrier” capable of conveying the drug selectively towards its target cells. The main goal of a site specific drug delivery system is not only to increase the selectivity and drug therapeutic index, but also to reduce the toxicity of the drug.

Target oriented drug delivery systems are the areas of the major interest in the modern pharmaceutical research. The selective drug delivery to the target tissues increases the therapeutic efficacy of the drug and reduces its undesirable effect to non target tissues. The main goal of a site specific drug delivery system is not only to increase the selectivity and drug therapeutic index, but also to reduce the toxicity of the drug. (Widder et al., 1982).

Rheumatoid arthritis (RA) is a chronic, inflammatory condition of unknown eitiology that affects about 1% of general population (Feldmann et. al., 1996) and is the most common cause of chronic inflammatory synovitis (Watson-Clark et al., 1998).


Although spontaneous remission can occur, it often progresses to chronic state associated with significant functional disability (Geletka and Clair, 2003). A number of drugs are used in the treatment of RA over the past 10- 20 years. An ideal therapy in RA should ameliorate disease, prevent the development of extra-articular complications such as vasculitis, serositis and lung fibrosis and prevent premature death (Rabinovich, 2000).

Types Of Niosomes The niosomes are classified as a function of the number of bilayer (e.g. MLV, SUV) or as a function of size. (e.g. LUV, SUV) or as a function of the method of preparation (e.g. REV, DRV). The various types of niosomes (Weiner et al., 1989) are described below.i) Multi lamellar vesicles (MLV)ii) Large unilamellar vesicles (LUV)iii) Small unilamellar vesicles (SUV)

(i)Multilamellar vesicles (MLV): It consists of a number of bilayer surrounding the aqueous lipid compartment separately. The approximate size of these vesicles is 0.5-10 μm diameter. Multilamellar vesicles are the most widely used niosomes (Bangham et al., in 1974). It is simple to make and are mechanically stable upon storage for long periods. These vesicles are highly suited as drug carrier for lipophilic compounds(ii) Large unilamellar vesicles (LUV): Niosomes of this type have a high aqueous/lipid compartment ratio, so that larger volumes of bio-active materials can be entrapped with a very economical use of membrane lipids.(iii) Small unilamellar vesicles: These small unilamellar vesicles are mostly prepared from multilamellarvesicles by sonication method, French press extrusion method or, homogenization method. The approximate sizes of small unilamellar vesicles are 0.025-0.05 μcm diameter. They are thermodynamically unstable and are susceptible to aggregation and fusion. Their entrapped volume is small and percentage entrapment of aqueous solute is correspondingly low.

Methods Of Preparation For NiosomesThe methodology for niosome preparation has been evolved rapidly during the last few years as a response to prepare well defined niosomes for specific applications.


Multi Lamellar Vesicles (Mlv)Bangosomes popularly known as multilamellar vesicles are prepared as per the method described by Bangham et al., 1974. In this method the lipids are dissolved in an organic solvent in a round bottom flask. A thin lipid layer is formed on the inside wall of the flask after removal of the organic solvent by rotatory evaporation at reduced pressure.

Multilamellar vesicles are formed spontaneously when an excess volume of aqueous buffer is added to the dry lipid. After shaking (by hand or vortex mixer), it results in formation of dispersion of multilamellar vesicles. Duration and intensity of shaking, the presence of charge inducing agents in the bilayer, ionic strength of the aqueous medium and lipid concentration are the important parameters influencing the size and the encapsulating efficiency of multilamellar vesicles. The lipids formed are quite heterogeneous both in size and in the number of lamella.

Small Unilamellar Vesicles (Suv)(A) Sonication: In this method, the preparation of small lamellar vesicles has been reviewed by Bangham (Bangham et al., 1974). The usual multilamellar vesicles and large unilamellar vesicles are sonicated either with a bath type sonicator or a probe sonicator, under an inert atmosphere (usually nitrogen or argon) to get the small unilamellar vesicles. During sonication, the multilamellar vesicles are broken down and small unilamellar vesicles with high radius of curvatures are formed.(B) French press method: Dispersions of MLV’s can be converted to small unilamellar vesicles by passage through a small orifice under high pressure (Berenholz et al., 1977). A French pressure cell was used by Hamilton and Guo in 1984. Multilamellar vesicles dispersion is placed in the French press and extruded at about 20000 psi at 4oC(Hamilton and Guo, 1984): On passing through the cell, a heterogeneous population of vesicles are formed ranging from several micrometers in diameter to small unilamellar vesicles size. Multiple extrusions results in aprogressive decrease in the mean particle diameter (30-80nm) depending upon the pressure used. These niosomes are more stable than sonicated ones and can be used advantageously as drug delivery carriers.(C) Ethanol injection method: An alternative method for producing small niosomes that avoids both sonication and high pressure is the ethanol injection method, first described by Batzri and Korn in 1973. In this method, the lipid is dissolved in ethanol and is rapidly injected into an excess of buffer solution or other aqueous medium though a needle. The force of the injection is usually sufficient to achieve complete mixing, so that the ethanol is diluted almost instantaneously in water and the phospholipids molecules are dispersed evenly throughout the medium.


Large unilamellar vesicles (LUV)Large unilamellar vesicles provide a number of important advantages as compared to the multilamellar vesicles including high encapsulation of water soluble drugs with economy of lipid and reproducible drug release rates. However, large unilamellar vesicles are perhaps the most difficult type of niosomes to produce.

(A) Reverse phase evaporation method: Large Unilamellar vesicles can be prepared by forming water in oil emulsion of phospholipids and buffer in the excess organic phase followed by removal of the organic phase under reduced pressure. The two phases are usually emulsified by sonication. Removal of the organic solvent under vacuum causes phospholipid coated water droplets to cool and eventually form a viscous gel. The next step is to bring about the collapse of certain proportion of water droplets. (B) Calcium induced method: This method is used to produce unilamellar vesicles and it is of high interest for the present investigation as it has the advantage of aggregation of small vesicles in the presence of calcium followed by subsequently fusion.In this method (Papahadjopoulos et al., 1975) the drug encapsulation depends on the lipid concentration and approximately 30% of encapsulation of the drug is expected. The vesicles are obtained in the size range of 0.2-1 μcm diameter.

(C) Dehydration/rehydration of small unilamellar vesicles: In this method (Shew and Deamer,1985) sonicated vesicles are mixed in an aqueous solutions with the solute desired to be encapsulated and the mixture is dried under a stream of nitrogen. As the sample is dehydrated, the small vesicles fuse to form a multilamellar film that effectively sandwich’s the solute molecules between successive layers.

Upon rehydration, large vesicles are produced encapsulating a significant proportion of the solute. The optimal mass ratio of lipid to solute is approximately 1:2 to 1:3. This method has the potential application to large scale production, since it depends only on controlled drying and rehydration processes and does not require extensive use of organic solvents, detergents o dialysis system.


CONCLUSION:

For the last few years, advanced drug delivery systems have been investigated to overcome the limitation of the conventional systems. Cancer chemotherapy and DNA-based vaccines have been identified as special areas of need for improved drug delivery. Lipoproteins as drug delivery systems have become an attractive area of research and they are considered excellent candidates as novel drug delivery systems. Herbal drugs have enormous therapeutic potential which should be explored through some value added drug delivery systems. Lipid solubility and molecular size are the major limiting factors for drug molecules to pass the biological membrane to be absorbed systematically following oral or topical administration. Several plant extracts and phytomolecules, despite having excellent bio-activity in vitro demonstrate less or no in vivo actions due to their poor lipid solubility or improper molecular size or both, resulting poor absorption and poor bioavailability. Standardized plant extracts or mainly polar phytoconstituents like flavonoids, terpenoids, tannins, xanthones when administered through novel drug delivery system show much better absorption profile which enables them tocross the biological membrane, resulting enhanced bioavailability. Hence more amount of active constituent becomes present at the site of action (liver, brain, heart, kidney, etc.) at similar or less dose as compared to the conventional plant extract or phytomolecule. Hence, the therapeutic action becomes enhanced, more detectable and prolonged. Several excellent phytoconstituents have been successfully delivered using NDDS. Hence there is a great potential in the development of novel drug delivery systems for the plant actives and extracts.


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introduction

Documents

drug degradation

drug bioavailability

various drug delivery

drug targeting systems

controlled drug release

drugloaded system

drug delivery systems

mode of delivery