dendrimer: globular nanostructured materials for …62(432-451)jm12.pdf · polyester dendrimer,...

International Journal of PharmTech ResearchCODEN (USA): IJPRIF ISSN : 0974-4304

Vol.4, No.1, pp 432-451, Jan-Mar 2012

Dendrimer: Globular NanostructuredMaterials for Drug Delivery

B.N.Vedha Hari1*, K.Kalaimagal, R.Porkodi, Pradeep Kumar Gajula, J.Y.Ajay

Department of Pharmaceutical Technology, School of Chemical and Biotechnology,SASTRA University, Thanjavur-613 401.Tamil Nadu, India.

1Department of Pharmacy, School of Chemical and Biotechnology, SASTRA University,Thanjavur-613 401.Tamil Nadu, India.

*Corres.author: [email protected]

Abstract: Nanotechnology is an emerging research field that helps in reviving the structural design, synthesis andfabrication at the molecular magnitude. There are approximately 130 nanopharmaceutical products in developmentincluding~nanoparticles, nanocrystals, dendrimers, liposomes and micelles. The increase in the selectivity andstability of therapeutic agents can be achieved with the help of Nanoparticle drug-delivery system. But due toseveral factors such as drug leakage, reticuloendothelial system, (RES) uptake, immunogenicity, hydrophobicity,hemolytic toxicity, cytotoxicity, the use of nanostructures are restricted. These challenges can be overcome bysurface engineering the dendrimer with bioactive agents either encapsulating into the interior of the dendrimer orby physically adsorbing them onto the surface of the demdrimer. Thus this surface engineering help to achieve thedesired properties of the carrier as per the requirement of the active ingredient and it also gives an access for newpotentially relevant polymer architectecture Some of the examples for surface engineering of dendrimers arePolyester dendrimer, Arginine dendrimer, Glycodendrimers, Citric acid dendrimer ,PEGylated dendrimers, etc.Key words: Dendrimers, nanostructured drug carriers, drug delivery.

INTRODUCTIONDendrimers are repeatedly branched macromoleculesor nano-sized, radially symmetric molecules with well-defined, homogeneous and monodisperse structureconsisting of tree-like arms or branches. The namecomes from the~Greek~word Dendron whichtranslates to tree. Dendrimers are globular or spheroidnanostructures that are engineered to encapsulate themolecules into their interior void spaces or to attachonto the surface [1]. Shape, size, and reactivity aredetermined by interior branching, surfacefunctionalities, generation (shells) and chemicalcomposition of the core. Dendrimers are constructedthrough a set of repeating chemical synthesisprocedures that build up from the molecular level tothe nanoscale region under conditions that are easily

performed in a standard organic chemistry laboratory.The dendrimer diameter increases linearly where as thenumber of surface groups increases geometrically.Dendrimers are very uniform with extremely lowpolydispersities, and are generally created withdimensions incrementally grown in approximatenanometer steps from 1 to over 10nm. The controlover size, shape and surface functionality makesdendrimers one of the commercially available smartestnanotechnologies [2]. Divergent synthesis was the firstintroduced method for the production of dendrimers byVogtle in 1978, Denkewalter at~Allied Corporation~asin 1981 Donald Tomalia at Dow Chemical in 1983 [3]and 1985[4] and by Newkome [5,6] in 1985. In 1990 aconvergent synthetic approach was newly introducedby Jean Frechet after which dendrimer popularity

B.N.Vedha Hari et al /Int.J.PharmTech Res.2012,4(1) 433

increased to a rate of more than 5,000 scientific papersand patents by the year 2005.

CLASSIFICATION OF DENDRIMERS:

The following classification for the commonlyreported dendrimer types although few dendrimertypes may fit in one or more types of classes.a. Simple dendrimersb. Liquid crystalline dendrimersc. Chiral dendrimersd. Micellar dendrimerse. Hybride dendrimersf. Amphiphilic dendrimersg. Metallodendrimerrs

STRUCTURE

Dendrimer formation is initialised from an atom suchas nitrogen onto which carbon and other elements are

attached by repeating series of chemical reactions toproduce a spherical branching structure. The resultingdendrimers will have a size similar to albumin andhemoglobin, but smaller size than multimers such asthe IgM antibody complex.

Dendrimers possess three distinguishedcomponents[8],[9] namely, An initiator multi-functional core(i) Interior layers (generations) with repeated

branching units, which are radically attached to thecore

(ii) Exterior surface functional group (terminalfunctionality) attached to the outermost interiorlayers.

Figure 1: General structure of Dendrimer and Dendron.

Figure 2: The Dendritic Structure


COMPONENTS OF A DENDRIMERSTRUCTUREPINCERThe outer shell of dendrimers contains a varyingnumber of pincers formed by the last focal pointheaded before the dendrimer surface. Due to thedivision in the chain of dendrimers at the focal points,the number of pincers in the PPI and PAMAMdendrimers becomes half the number of the surfacegroups present.

SHELLThe dendrimer shell is the generation space (i.e thehomo-structural spatial segment) between the focalpoints. The space between the last outer branchingpoint and the surfaceis the outer shell and the innershells are generally known as the dendrimer interior.

GENERATIONIt is the hyperbranching when going from the centre ofthe dendrimer towards the periphery, resulting inhomostructural layers between the focal points

(branching points). Generation number is the numberof focal points present in the dendrimer counting fromthe core towards the dendrimer surface i.e a dendrimerhaving five focal points when moving from the centretowards the periphery is signified as the 5th generationdendrimer and abbreviated as G5-dendrimer.E.g: A 5th generation polypropylene imine isabbreviated to a G5-PPI dendrimers. The core of thedendrimer is sometimes designated as generation zero(G0) i.e the core structure have no focal points, ashydrogen substituents are not considered as focalpoints. Intermediates formed during the dendrimersynthesis are sometimes termed as half-generations;for example the PAMAM dendrimers terminated withcarboxylic acid.

END-GROUPEnd groups are generally referred as the the surfacegroup of the dendrimer or terminal group. Dendrimersterminated with amine end-groups are named asamino-terminated dendrimers.

Figure 3: Three dimensional projection of dendrimer core-shell architecture for G=4.5 PAMAM dendrimerwith principal architectural components (I) core, (II) interior and (III) surface


TYPES OF DENDRIMERS

Types Definition Synthesis Example Applications

PamamDendrimer

Poly (amidoamine)dendrimers possessamino groups on thesurface.

Divergent DendritechTM

(USA) Material Science andBiomedicineComputer toners

PamamosDendrimer

Inverted unimolecularmicelles consists ofhydrophilic nuclephilicPAMAM interiors andhydrophobicorganosilicon(OS)exteriors.

Convergentand Divergent

SARSOX Nano-lithographyElectronicsPhotonicsChemical catalysisPrecursor for honey-comb like networkpreparations.

PPIdendrimer

Poly-alkyl amineshaving primary aminesas end groups and itsinterior consists ofnumerous tertiary tris-propylene amines.

Divergent Asramol by DSM(Netherlands)

Material science andbiology

Tectodendrimer

Composed of a coredendrimer withmultiple dendrimers atits periphery

Divergent Stratus® CS AcuteCare TM,Starburst®,Mercapto

Diseased cell recognitionDiseased state drugdelivery diagnosisReporting location tooutcome of therapy

Chiraldendrimers

Chilarity is based onconstruction ofconstitutionallydifferent butchemically similarbranches to a chiralcore.

convergent chiral dendrimersderived frompentaerythritol.

Biomedical applications,chiral catalyst

Hybriddendrimers

Combination ofdendritic and linearpolymer in hybridblock or graftcopolymer forms

Divergent Hybrid dendriticlinear polymer,Polysilsesquioxanes

Biomedicals,Molecular electronics,Nanophotonics,Sensing.

Amphiphilicdendrimers

Unsymmetical globulardendrimers built withtwo segregated sites ofchain end.

Divergent SuperFect, Hydra-amphiphiles andbola-amphiphiles

Structure-directing agent,Use as polar part, cell andgene transfection.

Micellardendrimers

Unimolecular micellestructure of Watersoluble hyperbranchedpolyphenylene

Divergent Beclomethazonedipropionate, NX-200,Magnevist®

Biological and medicalapplications,Drugdelivery, Imaging agent.

Multipleantigenpeptidedendrimers

Dendron-likemolecular constructbased upon apolylysine skeleton.

Convergentsynthesis

VivaGel Used in vaccines anddiagnostic research.Biological applications.


Frechet-typedendrimers

Dendrimes havingcarboxylic acid groupsas surface groups andcontaining poly-benzylether hyperbrancedskeleton.

Convergentsynthesis

Frechet typedendron azides,PriostarTM

Drug carrier, Purifiers,Organic synthesis,detecting agent, drugdelivery.

Liquidcrystallinedendrimers

Consists of mesogenicmonomers

divergent Polycanter liquidcrystals, Mesogenfunctionalizedcarbosilanedendrimers

Science and Engineering.

Metallodendrimers

Dendrimers withincorporated metalatoms

Convergent Zinc Porphyrindendrimers(M=Zn)

Sensing Catalyticapplications, mimicbiomolecules, light-harvesting, Biomarkers.

Peptidedendrimers

Dendrimers havingpeptides on the surfaceand incorporatingamino acids asbranching or coreunits.

Convergentsynthesis

,Beta-Casomorphin(human)

Drug delivery contrastagents for MRI, MRA ,fluorogenic imaging andsero diagnosis, proteinmimetic.

SYNTHESISThree major portions in dendrimers are: a core, aninner shell and an outer shell. Ideally, a dendrimer withdifferent functionality in each of these components canbe synthesized to control properties such as thermalstability, solubility and attachment of compounds forcertain applications. Synthetic processes can alsoprecisely control the size and number of branches onthe dendrimer. Dendrimers are perfect artificialmacromolecules, which are synthesized by a stepwisemethod such as divergent and convergent synthesis.

The synthesis reactions include many steps required toprotect the active site and it is complicated tosynthesize dendrimers in all the methods. Thusdendrimers are hard to make and very expensive. Atpresent, only few companies commercialisedendrimers; eg Polymer Factory [12] commercializesbiocompatible bis-MPA dendrimers andDendritech[13] is the producers of PAMAMdendrimers. Figure 4: Schematic of divergent andconvergent method synthesis of dendrimers.

Figure 4: Schematic of divergent and convergent method synthesis of dendrimers


1. DIVERGENT METHODSThis method starts from a central core and extendstowards the surface by a series of reactions, commonlya Michael reaction [14]. Dendrimers are polymers thatradiate out from a central core, with the number ofbranch points on a given arm increasing exponentiallyfrom the core to the periphery. Every step of thereaction should reach an absolute completeness toprevent errors in the dendrimer, which might causetrailing generations (branches with unequal length).Such impurities can affect the functionality andsymmetry of the dendrimer, but due to the relativesmall size difference between perfect and imperfectdendrimers , they are extremely difficult to purify out.The divergent approach is a successful method for theproduction of large quantities of dendrimers.

2. CONVERGENT METHODSConstruction of dendrimer in thismethod is an stepwiseprocess which begins from the end groups andprogresses inwards[15. When the growing branchedpolymeric arms, called dendrons, are large enough,they are attached to a multifunctional core molecule.This method prevents the formation of high shells dueto the chance of steric problems that might take placein the reactions of the dendrons and the core molecule.This is a relatively easy approach to eliminate

impurities and to form shorter branches along the way,finally to form a monodispersed dendrimer.

GENERAL PROPERTIES OF DENDRIMERS:Dendritic molecules are characterized by structuralperfection. Dendrimers and dendrons aremonodisperse, usually highly symmetric and sphericalcompounds. The field of dendritic molecules can bedivided into high-molecular weight and low-molecularweight species. The former includes hyperbranchedpolymers, dendronized polymers and the polymerbrush while the latter includes dendrons , dendrimersetc.

The multiple interactions between surface amines andnucleic acid phosphates are also significant for theformation of dendrimers and DNA complexes.Solubility of the dendrimers depends on the nature ofsurface groups. Dendrimers with hydrophilic groups atends are soluble in polar solvents, while dendrimersthat terminate with hydrophobic groups are soluble innonpolar solvents. In a solubility test withtetrahydrofuran (THF) as the solvent, the solubility ofdendritic polyester was found remarkably higher thanthat of analogous linear polyester and a significantchemical reactivity also observed.

Table 1: Properties Of Dendrimer And Linear Polymers [16],[17],[18],[19],[20]

SerialNumber

Property Dendrimers Linear Polymers

1 Structure Compact and Globular Not compact2 Shape Spherical Random coil3 Architecture Regular Irregular4 Structural control Very high Low5 Synthesis Stepwise growth Single step polycondensation6 Crystallanity Non-crystalline and amorphous

materialsLower glass temperatures

Semi crystalline/crystallinematerials-Higher glass temperatures

7 Reactivity High Low8 Aqueous solubility High Low9 Nonpolar solubility High Low10 Viscosity Non linear relationship with

molecular weightLinear relation with molecularweight

11 Ionic conductivity High Low12 Compressibility Low High13 Polydispersity Monodi sperse Polydisperse


VARIOUS FACTORS AFFECTING THEPROPERTIES OF DENDRIMERS

1. EFFECT OF PH ON DENDRIMERS[22]At high pH the dendrimer is uncharged and theformation of any DNA-dendrimer complex is not seen.At neutral pH, when the dendrimer is positivelycharged due to the protonation of all the primaryamines, the strong electrostatics interaction helps theDNA strand collapse onto the dendrimer. Amino-terminated PPI and PAMAM dendrimers have basicsurface groups as well as a basic interior. PPI andPAMAM dendrimers that contains tertiary amines, theregion with low pH extends the conformations becauseof the electrostatic repulsion between the positivelycharged ammonium groups. Molecular dynamics canbe applied to find the structural behaviour of PAMAMdendrimers as a function of pH which show that thedendrimer has an extended conformation, based on ahighly ordered structure at low pH (pH<4). At this pH,the interior becomes hollow with the increase in thegeneration number due to the repulsion between thepositively charged amines both at the tertiary aminesin the interior and surface of the dendrimer. At neutralpH, back-folding occurs due to the hydrogen bondingbetween the positively charged amines at the surfaceand the uncharged tertiary amines in the interior. Athigher pH (pH>10) the dendrimer contracts as thecharge of the molecule gets neutralised, attaining amore spherical (globular) structure, where therepulsive forces between the surface groups and thedendrimer arms reaches a minimum.[23] At this pH,the conformation has a higher degree of back-foldingas a result of the weak inter-dendron repulsiveforces.[24],[25] The pH-dependent conformationalchanges of PPI dendrimers having acidic (carboxylicacid) end-groups is different as compared to amino-terminated counterparts. Measurement of self diffusionusing Small angle neutron scattering (SANS) and

NMR at different pH values show that the dendrimercore has the most extended conformation at pH 2 dueto the electrostatic repulsion between the positivelycharged protonated tertiary amines, leading to a largeradius of the core, whereas at pH 6 the dendrimerreaches its minimum radius, where the amount ofpositively charged amines equals the amount ofnegatively charged carboxylic groups (isoelectricpoint) forming a dense core conformation which ismore subjective to back-folding [26]. Thus, at pH 6due to the attractive interactions between thenegatively charged surface carboxy-groups and thepositively charged tertiary amines in the inner shells ofthe dendrimer , some degree of back-folding [26]. AtpH 11 the electrostatic repulsion between the negativecharged forces the surface groups apart to give a moreextended conformation with a highly expanded surfacearea.

2. EFFECT OF SOLVENT ON DENDRIMERSConformational state of the dendrimer can beinvestigated according to the solvent ability to solvatethe dendrimer structure. With the decrease in solvationdendrimers of all generations generally experience alarger extent of back-folding. The highest tendencytowards back-folding is shown by the low generationdendrimers due to poor solvation compared to thehigher generation dendrimers. NMR studies performedon PPI dendrimers reveals that a nonpolar solvent likebenzene, poorly solvates the dendrons favouringintramolecular interactions between the dendrimersegments and back-folding. In turn, a weakly acidicsolvent like chloroform can act as a hydrogen donorfor the interior amines in a basic dendrimer like PPI,leading to an extended conformation of the dendrimerbecause of extensive hydrogen bonding between thesolvent and the dendrimer amines[27].

Figure 5: Two dimensional depiction of conformational changes upon different pH of a carboxy-terminatedPPI-dendrimer


Figure 6: Two dimensional depiction of conformational changes upon different pH of a carboxy-terminatedPPI-dendrimer

Both experimental as well as theoretical studies onamino-terminated PPI and PAMAM dendrimers (polardendrimers) show that a higher molecular density isinduced when polar (good) solvents solvate thedendrimer arms whereas higher molecular densities inthe core regionis induced by nonpolar aprotic (poor)solvents as a result of back-folding [28].Decrease inthe surface polarity of back folded dendrimer can beachieved by the back-folding of the polar surfacegroups which may expose the more hydrophobicdendrimer parts to the surroundings [29],[30]. Figure6: Proposed scheme for solvation of a dendrimer underdifferent solvent conditions. (a) Solvation of a polardendrimer in a protic solvent ("good") leading toextended conformation exposing a polar surface. (b)Solvation of a polar dendrimer in an apolar aproticsolvent ("poor") leading to exposure of an apolarsurface consisting of alkyl chains by back-folding.

3. EFFECT OF SALT ON DENDRIMERSSalts with high ionic strength (high concentration ofsalts) has a strong effect on charged PPI dendrimersand favours a contracted conformation of dendrimers,with a high degree of back-folding somewhat similarto what is observed upon increasing pH or poorsolvation[31],[32]. At low salt conditions, in order tominimize charge repulsion in the structure therepulsive forces between the charged dendrimersegments forms an extended conformation.

4. EFFECT OF CONCENTRATION OFSOLVENTS, SALTS

In dendrimers with flexible structures theconformation is affected by small molecules likesolvents, salts or protons and larger objects, such asother dendrimers or surfaces which can have a greataffect on the molecular conformation and density of

the dendrimer. Small angle X-ray scattering (SAXS)experiments performed on PPI dendrimers (G4, G5)witih a polar solvent like methanol show that themolecular conformation of dendrimers contracts withincrease in the concentration. This molecularcontraction may minimize the repulsive forcesbetween the dendrimer molecules and also the abilityof the dendrimers to exhibit a more tightintermolecular packing can be increased [33].

METHODS FOR CHARACTERIZATION OFDENDRITIC POLYMERThe methods that can be used for characterization ofdendritic polymers are:[34]1. Spectroscopy and spectrometry methods~like

Nuclear Magnetic Resonance (NMR), Opticalrotation ,Infra-red (IR) and Raman, Ultra-violet-visible (UV-VIS), X-ray diffraction, Fluorescence,Chirality, Circular dichroism (CD) and Massspectrometry.Nuclear Magnetic Resonance (NMR): NuclearMagnetic Resonance is widely used incharacterizing dendrimers. NMR analysis are doneroutinely during the step by step synthesis ofdendrimers till higher generations as it givesinformation about the chemical transformationsundergone by the end groups.Infra-red (IR) and Raman: Infra-red spectroscopyis mainly used for the routine analysis of thechemical transformations occurring at the surfaceof dendrimers, such as the disappearance of nitrilegroups in the synthesis of PPI dendrimers, theoccurrence of hydrogen bonding in PPI glycinefunctionalized dendrimers, or the disappearance ofthe aldehydes during the synthesis of PMMHdendrimers.


Ultra-violet-visible (UV-VIS): UV-Visiblespectroscopy can be used to monitor the synthesisof dendrimers. UV-Visible spectrometry for itssimplicity, versatility, speed, accuracy and cost-effectiveness.Fluorescence: In fluorescence spectroscopy, thespecies is first excited, by absorbing a~photon,from its ground electronic state to one of thevarious vibrational states in the excited electronicstate. When collided with other molecules, thiscollision causes the excited molecule to losevibrational energy and reach the lowest vibrationalstate of the excited electronic state.The molecule then drops down to one of thevarious vibrational levels of the ground electronicstate again, emitting a photon in the process.Thus,the emitted photons will have differentenergies and frequencies. Fluorescentspectroscopy used to analyse the differentfrequencies of emitted light along with theirrelative intensities, the structure of the differentvibrational levels can be determined.Chirality: Chiral amino acids linked to the surfaceof PPI dendrimers induce a dramatic decrease ofoptical rotation on going from G1 to G5 [35], rigidparacyclophanes on the surface of PPI dendrimershave a nearly constant optical activity withincreasing generation [36], whereas chiralbenzylamine[37] or ferrocene [38] linked to thesurface of PMMH dendrimers give simply additiveoptical rotation values. When a single chiral groupsuch as aminophenylpropanediol [39] orbinaphthyl [40] is located at the core of PBzEdendrimers, the optical rotation decreases with theincrease in generation. In the latter case, the CDdata affords information about the variation of thedihedral angle u in the binaphthyl [41]. For fullychiral dendrimers (throughout the structure), thechiroptical properties of two series of chiralpolyarylether dendrimers from generation 0 to 3(up to 45 stereogenic centres) [42] and ofdendrimers based on dihydroxypyrrolidine [43]show that the CD spectra change dramatically,indicating conformational substructures in thebranches. On the other hand, the CD spectra of aseries of fully chiral dendrimers of phenylalaninetype up to G2 show little steric interaction, butmolar rotation divided by the number ofstereogenic centres decreases with increasing sizeof the dendritic structure [44]. On the contrary, themolar rotation of a series of polyether dendrimersup to G4 is approximately proportional to thenumber of chiral units [45]. For dendrimers havingone layer of chiral ferrocenes located inside thestructure, the chiroptical properties are not

sensitive to the location of the chiral units insidethe dendrimers, up to G11.Circular dichroism (CD): Circular dichroism (CD)spectroscopy measures the difference in theabsorption of left-handed polarized light versusright-handed polarized light which occurs due tostructural asymmetry. The absence of regularstructure results in zero CD intensity, while anordered structure results in a spectrum which cancontain both positive and negative signals. X-ray diffraction: This technique should allowprecise determination of the chemical composition,size and shape of dendrimers. X-ray diffraction(XRD) is a versatile, non-destructive techniquethat reveals detailed information about thechemical composition and crystallographicstructure of natural and manufactured materials.Mass spectrometry: Classical mass spectrometrytechniques such as chemical ionization or fastatom bombardment (FAB) are used for thecharacterization of small dendrimers, whose massis below 3000 D due to their mass limitation [46].For higher molecular weights, techniquesdeveloped for the characterization of proteins andpolymers have to be applied. Electro-SprayIonisation (ESI) can be used for dendrimers able toform stable multicharged species. It has beenapplied to PPI dendrimers[47], and to PAMAMdendrimers up to generation 10 [48]. Thedendrimers were also characterized by massspectrometry using matrix-assisted laserdesorption ionization (MALDI). MALDI-TOFMass spectrometry was used to obtain themolecular weight information and to determine thepurity, existence of dimers, trimers, and trailinggenerations in the sample.

2. Electrical techniques like Electron paramagneticresonance (EPR), Electrochemistry, andElectrophoresis. Electron paramagnetic resonance(EPR): Stable radicals have been either grafted onthe surface of dendrimers or generated inside thestructure at the branching points and analysed byEPR. EPR was used for the quantitativedetermination of the substitution efficiency on thesurface of PAMAM dendrimers [49] or was able todetect interactions between the end groups of largePPI dendrimers[50].Electrochemistry: Exhaustive coulometry has beenused to measure the number of electroactivegroups. The degree of burying of electroactivegroups inside dendrimers can be detected by cyclicvoltammetry. Electrochemistry gives informationabout the possibility of interaction [51] ofelectroactive end groups between them, traducinga close proximity.


Electrophoresis: This technique was used for theassessment of purity and homogeneity of severaltypes of water-soluble dendrimers such asPAMAM dendrimers having NH3 + or CO2_ endgroups[52] PLy dendrimers [53], PPI dendrimers[54], nucleic acid dendrimers [55], orphenylacetylene dendrimers [56]. Gelelectrophoresis was also used for studying theinteraction between positively charged dendrimersand DNA.

3. Scattering techniques like Small angle neutronscattering (SANS),Small angle X-ray scattering(SAXS) and Laser light scattering (LLS).Small angle X-ray scattering (SAXS): The SAXStechnique is often used for the characterization ofpolymers [57]; applied to dendrimers it givesinformation about their average radius of gyration(Rg) in solution.The intensity of the scattering as afunction of angle also provides information on thearrangement of polymer segments, hence on thesegment density distribution within the molecule.This technique was applied to fluorinatedcarbosilane dendrimers [58] and PAMAMdendrimers [59] to afford their Rg values. Theangular dependence of the scattered intensityindicates a relatively diffuse, open boundary forG3 PAMAM, and a very sharp outer boundary forG10, with a gradual transition from star-like (G3)to sphere-like (G10) entities [60].Small Angle Neutron Scattering (SANS): TheSANS technique also gives access to the radius ofgyration, but may also reveal more accurateinformation than SAXS about the internal structureof the entire dendrimer. In particular, SANS mayindicate the molecular weight; such experimentshave been conducted with PPI [61], PAMAM [62]and PBzE dendrimers [63]. The location of the endgroups has also been determined by SANSexperiments conducted with PAMAM dendrimersand PPI dendrimers having labelled (deuterated) orunlabelled end groups; in the former case, the endgroups are concentrated near the periphery [64],whereas in the latter cases the end groups arelocated throughout the structure [65]. A recentextension of this technique (neutron spin-echo)was applied to PAMAM dendrimers[66].This alsobeen applied to aggregates of PBzE dendrimershaving a phthalocyanine core, and to vesiclesformed by the self-assembly.Laser light Scattering (LLS): In most cases, theLaser Light Scattering technique is used as adetector coupled to size exclusion chromatographyapparatus (see later), to determine thehydrodynamic radius of dendrimers. However, insome cases, it has been used for the direct analysisof samples of dendrimers in solution; for instance,

the molecular weight (Mw) of PPI dendrimers hasbeen evaluated with low-angle LLS [67]. DynamicLLS is mainly used for the detection of aggregates;it has been applied to aggregates of PBzEdendrimers having a phthalocyanine core [68], andto vesicles formed by the self-assembly of somewater soluble PMMH dendrimers [69].

4. Microscopy like Scanning electron microscopy,Transmission electron microscopyand atomic forcemicroscopyTransmission electron microscopy: InTransmission Microscopy, electrons or lightproduce images that amplify the original, with aresolution ultimately limited by the wavelength ofthe source. Scanning electron microscopy: Inscanning microscopy such as Atomic ForceMicroscopy (AFM), the images are produced bytouch contact Q at a few angstroms of a sensitivecantilever arm with the sample.Atomic force microscopy: The AFM, however, hasthe advantage of imaging almost any type ofsurface, including polymers, ceramics, composites,glass, and biological samples.

5. Size exclusion chromatography(SEC) SizeExclusion (or Gel Permeation) Chromatographyallows the separation of molecules according tosize. A detector such as a differential refractiveindex or a LLS detector (see above) is connectedto the SEC apparatus for the determination of thepolydispersity, which is generally very close tounity. Most types of dendrimers werecharacterized by SEC, even self-assembleddendrimers.

6. Rheology, physical properties by Dielectricspectroscopy (DS) and Differential ScanningCalorimetry (DSC)Differential Scanning Calorimetry (DSC): TheDSC technique is generally used to detect the glasstransition temperature (Tg), which depends on themolecular weight, entanglement and chain-endcomposition of polymers. The Tg is affected bythe end group substitutions, and the molecularmass for PBzE dendrimers [70], and correlateswith ne /M (ne is the number of chain ends) [71].The same behaviour was observed for phosphorusdendrimers [72], and to a lesser extent for PPIdendrimers [73], whereas the generation haspractically no influence on the Tg values of liquidcrystal dendrimers based on poly(phenylacetylene) [74] or carbosilazane dendrimers [75].DSC and Temperature Modulated Calorimetry(TMC) were also used to detect physical aging ofPMMH dendrimers [76].Dielectric spectroscopy (DS): Dielectricspectroscopy gives information about moleculardynamic processes in polymers (a-, h-, g-, and y-


relaxation). This technique was applied to varioustypes of dendrimers, and it was generally foundthat the a-relaxation values obtained by DS agreewell with those obtained in Differential ScanningCalorimetry measurements. Carbosilane [77],ARB [78], poly(ether amide) [79] PMMH[80],[81]and carbosilazane dendrimers [82] were analyzedby DS; in most cases, both the a- and hrelaxationswere obtained and identified.

7. Miscellaneous: X-ray Photoelectron Spectroscopy(XPS): it s useful for the measurements of dipolemoments, titrimetry, and uses soft x-rays (with aphoton energy of 200-2000 eV) to examine core-levels .The XPS technique is highly surfacespecific due to the short range of thephotoelectrons that are excited from the solid. Theenergy of the photoelectrons leaving the sampleare determined using a~CHA~and this gives aspectrum with a series of photoelectron peaks. Thebinding energy of the peaks are characteristic ofeach element. The peak areas can be used (withappropriate sensitivity factors) to determine thecomposition of the materials surface. The shape ofeach peak and the binding energy can be slightlyaltered by the chemical state of the emitting atom.Hence XPS can provide chemical bondinginformation as well. XPS is not sensitive tohydrogen or helium, but can detect all otherelements.

APPLICATION OF DENDRIMERS:1. DENDRIMERS DRUG DELIVERY:

TARGETED AND CONTROLLED RELEASEDRUG DELIVERY

here are attempts to use dendrimers in the targeteddelivery of drugs and other therapeutic agents. Drugmolecules can be loaded both in the interior of thedendrimers as well as attached to the surface groups.

Dendrimers have drawn attention as drug carriers dueto their unique properties mainly their well definedthree-dimensional structure, their low polydispersity ,the availability of many functional surface groups andtheir ability to mimic. Dendrimers can act as drugcarriers either by interacting with drugs at theirterminal functional groups via covalent bonds orelectrostatic forces (prodrug) or by the encapsulationof drugs within the dendritic structure. Dendrimers canbe used as coating agents to protect or deliver drugs tospecific sites in the body or as time-release vehicles forbiologically active agents. Therapeutic agents can alsobe attached to a dendrimer to direct the delivery. Agood example of such application is using dendrimersin Boron Neutron Capture Therapy (Bnct).

2. DELIVERY OF ANTICANCER DRUGS BYDENDRIMERS AND DENDRITICPOLYMERS

Cancer is caused by damage of genes which controlthe growth and division of cells. Cancer can be curedby rectifying the damaging mechanism of the genes orby stopping the blood supply to the cell or bydestroying completely using the conventionaltreatments such as surgery, radiation therapy andchemotherapy. These treatments have their ownlimitations. Hence certain nanoparticles can bedesigned to absorb certain wavelength of radiation,which burns the cancer cells.In specific Nanoparticles ,a single dendrimer can carry a molecule that recognizecancer cells, a therapeutic agent to kill those cells anda molecule that recognize the signal of cell death.Researchers hope to manipulate dendrimers to releasetheir contents only in the presence of certain triggermolecules associated with cancer [84].

Table 2: Major Technologically Important Factors

Key to symbols: ++, best technique for measurement: +, acceptable technique for measurement: -, unsuitable formeasurement.

Factor Application Small angleneutronscattering

Small angleneutronscattering

Transmissionelectronmicroscopy

Segment Distribution Solubilization + ++ +Type of Branching Major cost

Diffferences+ + +

Terminal Group location AttachmentNetworks

++ + -

Dendrimer-dendrimer Interactions OrderingNanostructures

+ ++ +

Size VariationWith solvent

StandardsRelease

+ + -


The star polymer gave the most promising resultsregarding cytotoxicity and systemic circulatory half-life (72 h). With the improvement of drug propertiessuch as plasma circulation time and solubility,polymeric carriers can also facilitate the passivetargeting of drugs to solid tumors. Combined, thesefactors lead to the selective accumulation ofmacromolecules in tumor tissue - a phenomenontermed the Enhanced Permeation and Retention (EPR)effect [72]. Therefore, the anticancer drug doxorubicinwas covalently bound to this carrier via an acid-labilehydrazone linkage. Hence the drug doxorubicin wassuccessfully taken up by several cancer cell lines atreduced cytotoxicity. The studies on adriamycin andmethotrexate anticancer drugs on the encapsulationbehavior of these demdrimers shows that the highestencapsulation efficiency, with on average 6.5adriamycin molecules and 26 methotrexate moleculesper dendrimer, was achieved for the G4 PAMAMterminated with PEG2000 chains. 5-Fluorouracil(5FU) is known to have remarkable antitumouractivity, but it has high toxic side effects. PAMAMdendrimers after acetylation can form dendrimer-5FUconjugates . The dendrimers are water soluble andhydrolysis of the conjugates releases free 5FU. Theslow release reduces 5FU toxicity. Such dendrimersseem to be potentially useful carriers for antitumourdrugs. The anticancer drug 5-fluorouracil encapsulatedinto G4 PAMAM dendrimers with carboxymethylPEG5000 surface chains showed a reasonable drugloading with reduction in the release rate andhemolytic toxicity compared to the non-PEGylateddendrimer[88]. In contrast, up to 24 drug moleculeswere encapsulated into the hyper branched polyol andsuccessful delivery of the drug into lung epithelialcarcinoma cells was achieved by the dendrimers.Recent studies shows that low generation PAMAMdendrimers using Caco-2 cell lines cross cellmembranes mostly by a combination of two processes,i.e., paracellular transport and adsorptive endocytosis,while cell efflux systems have a minor effect.[85] Theencapsulation of anticancer drugs methotraxate and 5-fluorouracil into PEGylated generation 3 and 4PAMAM dendrimers

3. DENDRIMER AS SOLUBILITYENHANCERS

Poly(lysine) dendrimers attached with sulfonatednaphthyl groups as antiviral drugs seems to beeffective against the herpes simplex virus which canpotentially decrease the transmission of HIV and othersexually transmitted diseases (STD) [88]. Studies alsoshow that when PAMAM dendrimer surface iscovalently modified with naphthyl sulfonate residues itshows antiviral activity against HIV. This dendrimerbased nano-drug can thus inhibit the early stages of

virus cell adsorption and later stages of viralreplication by hindering the reverse transcriptaseand/or integrase enzyme activities. PPI dendrimersmodified with tertiary alkyl ammonium groups at thesurface is found to be an effective antibacterial biocideagainst Gram positive and Gram negative bacteria.Poly (lysine) dendrimers with mannosyl groupsattached to the surface found to be potent inhibitors ofthe E. coli adhesion to horse blood cells in ahaemagglutination assay, making these structurespotential antibacterial agents. Chitosan dendrimerhybrids reveal to act as promising carriers in the fieldof drug delivery systems, antibacterial agents and inother biomedical applications.

4. CELLULAR DELIVERY USINGDENDRIMER CARRIERS

Poor solubility of drugs in pharmaceutically acceptablesolvents restricts their use for therapeutic purposeseven with their strong therapeutic activity. But nowwater soluble dendrimers are able to bind andsolubilize small acidic hydrophobic molecules withantibacterial properties or antifungal. Unimolecularmicelles are Dendrimers with a hydrophobic core anda hydrophilic surface layer..As dendrimers don't have acritical micelle concentration it gives an opportunityfor poorly soluble drugs to solubilise by encapsulatingthem within the dendritic structure at all concentrationsof dendrimer. A hydrophilic and hydrophobic core-shell dendrimer with PAMAM interior and long alkanechain exterior was shown to bind 5-flurouracil, awater-soluble anti-tumor drug [86]. It was seen that theoral bioavailability in rats of 5-flurouracil was doubledcompared to free 5-flurouracil when the dendrimerfatty acid macromolecule was given with phospholipidcoating. Thus Dendrimer-based carriers can be apromising method to enhance the oral bioavailabilityof poorly soluble drugs.

5. DENDRIMERS AS NANO-DRUGShe studies on dynamics of cellular entry into A549human lung epithelial carcinoma cells with a range ofPAMAM dendrimers (G4-NH2, G3-NH2, G4-OH,PEGlayted G3 [G3-PEG]) and a hyper branchedpolymer (polyol) showed that G4-NH2and G4-OHdendrimers entered cells more rapidly than G3-NH2,polyol or G3-PEG. The rapid entry of G4-NH2~ intothe cells might be due to its cationic nature of theamine surface groups, that may interactelectrostatically with negatively charged epithelialcells and enter by pinocytosis [88]. Absence ofcationic surface groups on polyol and G3-PEG, theircellular entry occurs by non-specific adsorption to thecell membrane and subsequent endocytosis. It's alsoseen that dendrimers can efficiently carry thecomplexe drugs to the interior of the cells for example


Dendrimer ibuprofen complexes can enter morerapidly into the ceels than the pure drug (1 hr versus >3 hr).

6. DENDRIMERS IN PHOTODYNAMICTHERAPY

Scientists have also studied the use of dendrimers inthe sensor technologies. By attaching Thephotosensitizer 5-aminolevulinic acid to the surface ofdendrimers it can be used as an agent for PDT oftumorigenic keratinocytes .The photo sensitive dyesincorporated into dendrimers are utilized in PDTdevices[88]. For cancer treatment the light activatedphotosensitizing drug administered which selectivelyconcentrates in diseased tissue. Appropriateunfunctionalisation of dendrimers can make them apromising carrier for photosensitizers for exampleALA a natural precursor of the photosensitizerprotoporphyrin IX (PIX) administered to increasecellular concentrations of PIX [87].

7. DENDRIMERS IN GENE TRANSFECTIONIn the field of gene therapy dendrimers can act asvectors for example PAMAM dendrimers that has

been tested as carriers for the genetic material.Numerous reports reveals that to enhance thetransfection of DNA into the cell nucleus byendocytosis can be enhanced by using amino-terminated PAMAM or PPI dendrimers as non-viralgene transfer agents[88]. A transfection reagent calledSuperFectTM that have activated dendrimers can carrya larger amount of genetic material compared toviruses. SuperFect-DNA complexes have high stabilityand provide more efficient transport of DNA into thenucleus than liposomes. The cause for this hightransfection efficiency of dendrimers may be due totheir well-defined shape and low pK of the amines (3.9and 6.9). The low pK permit the dendrimer to bufferthe pH change in the endosomal compartment.Luciferase gene expression shown by PAMAMdendrimers functionalized with cyclodextrin seems tobe 100 times higher than for unfunctionalizedPAMAM or for non-covalent mixtures of PAMAMand cyclodextrin. Better gene delivery process wasshown by dendrimers with high structural flexibilityand partially degraded high generation dendrimers93

(i.e., hyper branched architectures) than the intact highgeneration symmetrical Dendrimers.

Figure 7: Dendrimer involved in gene transfection


ENCAPSULATION OF DRUGS INTO DENDRIMERS ARCHITECTURE

Table 3: Major Technologically Important Factors

Drug Therapeutic activity Nature of drug InferenceArtemether treat multi-drug resistant

strains of malariaPoor solubility Solubility enhancement between

factors 3-fold to 15-fold has beenobserved, depending onconcentration and size of thedendritic micelles.

Camptothecin anticancer drug thatdamages DNA, leading tocell destruction

very low watersolubility andadverse sideeffects

A newly developed dendrimerplatform,consisting ofpoly(etherhydroxylamine) (PEHAM)dendrimers, hasbeen employed to enhance the watersolubility of camptothecin[89].

Cisplatin The anticancer drug thatalters DNA structure thatpreventsreplication and initiatesapoptosis

The therapeuticeffect of cisplatinis limited by itspoor watersolubility (1mg/ml), lowlipophilicity,and thedevelopment ofdrug resistance

Encapsulationof cisplatin within PAMAMdendrimers resulted in complexeswithslower release, higher accumulationin solid tumors, and lowertoxicity than free cisplatin.

Diclofenacand mefenamicacid

reduce inflammation andact as analgesic

non-steroidal anti-inflammatorydrugs (NSAIDs) have beenencapsulated into dendrimers builtfrom citric acid-poly(ethyleneglycol)-citric acid triblock copolymers.

Diflunisal generic NSAID Low solubility significantly enhanced permeationof diflunisal,extremely low water solubilityof these NSAIDs has beensignificantly improved by PAMAMdendrimers

Dimethoxycurcumin ability to induce apoptosisin cancer cellswithout cytotoxic effects onhealthy cells

Poorly soluble inwater.

For improved water solubility,dimethoxycurcumin has been mixedwith PAMAM dendrimers

Doxorubicin to treat some leukemia,Hodgkin’slymphoma, as well ascancers of the bladder,breast, stomach,lung, ovaries, thyroid, softtissue sarcoma, and multiplemyeloma

Reduced solubilityand has sideeffects

doxorubicin has been encapsulatedinto PAMAM dendrimers G3 andG4, which had PEG-monomethylether chains of molecular weights550 and 2000 Da conjugated totheir surfaces

Etoposide treatment of malignanciessuch as Ewing’s sarcoma,lung cancer, testicularcancer, lymphoma, non-

Poor water soluble In order to increase the watersolubility ofetoposide, micelles composed ofblock copolymers, lipophilic


lymphocyticleukemia, and glioblastomamultiform

poly(e-caprolactone) (PCL) andhydrophilic PEG5000, conjugatedto a generation two PAMAM-OHdendrimer as the core, have beensynthesized.

5-Fluorouracil 5-Fluorouracil (5-FU; Fig.4) is a pyrimidine analoguethat belongsto the family of drugs calledantimetabolites

Poorly soluble A conjugate betweenPAMAM G4 dendrimer andPEG5000 chains has been utilized inorder to improve the solubility offluorouracil

Ketoprofen It belongs to the propionicacid class of NSAIDswith analgesic andantipyretic effects.

Poor solubility andbioavailability

The presence of PAMAMdendrimers enhanced the transdermaldelivery of ketoprofen, leadingto 2.73-fold higher bioavailabilitycompared to suspensions ofthe pure drug [90]. The solubility ofketoprofen was significantlyenhanced by association withPAMAM dendrimers.

Ibuprofen NSAID, analgesic and anti-inflammatory activity

Less soluble solubility of ibuprofen can besignificantly enhancedby encapsulation into PAMAMdendrimers

Indomethacin Indomethacin (Fig. 5) is amember of the arylalkanoicacid classof NSAIDs

Indomethacin ispoorly solublein water andsparingly solublein alcohol

Formulating indomethacinwith PAMAM dendrimers G4 withamino, hydroxyl,and carboxylate surface groupsenhanced the water solubility ofthe drug

Methotrexate an antimetabolite andantifolatedrug used in the treatmentof many cancers, acts byinhibitingthe metabolism of folicacid.

higher dosesof MTX often usedin cancerchemotherapy cancause toxic effectsto the rapidlydividing cells ofbone marrow andgastrointestinalmucosa.

methotrexate has been encapsulatedinto generations 3 and 4 PAMAMdendrimers, which hadPEG550 and PEG2000 monomethylether chains conjugated to theirsurfaces to modify bioavailability andtoxicity.

Naproxen used for the reduction ofmoderate to severe pain,fever, inflammationand stiffness caused byconditions such asosteoarthritis, rheumatoidarthritis and others.

Low soluble the solubility of naproxen wassignificantly enhancedby the association with PAMAMdendrimers

Niclosamide antimicrobial drug Niclosamide ispracticallyinsoluble in waterat physiologicalpH and becomessparingly solubleover the range ofpH 8–10

mixing with PAMAM dendrimers(8.0 mM) containing a primary aminesurface significantly enhancedthe water solubility of niclosamide

Nifedipine The NSAID nifedipine is adihydropyridine calcium

Poorly solubility the solubility of nifedipineincreased with the size of the


channelblocker.

dendrimers. PAMAMdendrimers enhanced the release rateof nifedipine, dependenton dendrimer size and concentration.

Quinolonesnadifloxacinand prulifloxacin

Quinolones are a family ofbroad-spectrum antibioticscovering a host of aerobicGram-negative, Gram-positive and evensome anaerobic speciesresponsible for variousinfections

Low solubility The solubility of nadifloxacin andprulifloxacin wassignificantly enhanced informulations containing PAMAMdendrimersG3–5 with amine surface,

Paclitaxel anticancer drug poor water soluble PTX encapsulation into polyglyceroldendrimersresulted in 400-fold improved watersolubility compared to thepure drug [91].

Silver salts antimicrobialactivity

The encapsulation of silver saltswithin PAMAM dendrimersproduced conjugates exhibiting slowsilver release rates and antimicrobialactivity against various Gram-positive bacteria [92].

Sulfamethoxazole sulfonamide antibacterialdrug

SMZ is sparinglysoluble in water,causingproblems in itsclinicalapplications.

Association with PAMAMdendrimersG2-4 in low (3–9 mM) concentrationrange enhanced theaqueous solubility ofsulfamethoxazole linearly with thedendrimerconcentration.SMZ–PAMAM complexes increasedthe antibacterial activity

CONCLUSIONThe dendrimers can have a promising future in variouspharmaceutical and diagnostic fields as they possessdistinct properties such as multivalenc, high degree ofbranching, globular architecture and well-definedmolecular weight, thus presenting new scaffolds fordrug delivery. The increasing challenges of newlydeveloped drugs such as poor solubility, bioavailability

and permeability can be resolved with the help ofdendrimers. The advancement in synthesis ofdendrimers help to produce different structure at lowcost and careful surface engineering can eliminate theproblem of biocompatibility and toxicity. Hence theincreased research in the field of dendrimers promisesits utility for wide range of application in drug deliverysystems.

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