Drug Delivery and Nanomedicine with

Nanomagnetic Material

Presented By,S.Shashank Chetty

2nd Year, M.Tech, NAST

Course: Nanomagnetic Materials and DeviceCode: NAST-736

OutlineBiomagnetismAdvantages and application of Magnetic materialSchematic illustration of MNP-based therapies.Special Features of Magnetic Nanoparticles.Synthesis and biofunctionalisation of magnetic nanoparticles.Modified Nanoparticle and tissue interaction.Size Dependence On Particle removal and particle deliveryMagnetic separation and drug carrier.Hyperthermia therapyConclusionReference

INTRODUCTION• Magnetism and magnetic materials have been used for many decades in many modern

medical applications.• Magnetic materials - cell separation, immunoassay, magnetic resonance imaging (MRI),

drug and gene delivery, minimally invasive surgery, radionuclide therapy, hyperthermia and artificial muscle applications.• Physical properties which make magnetic materials attractive for biomedical

applications are, • first, that they can be manipulated by an external magnetic field – this feature is useful for

separation, immunoassay and drug targeting, and • second, hysteresis and other losses occur in alternating magnetic fields – this is useful in

hyperthermia applications.

• In biology, bees and pigeons of magnetic materials as biological compasses for navigation. Some magnetotactic bacteria are known to respond to a magnetic field.• The earliest known biomedical use of naturally occurring magnetic materials involves

magnetite (Fe3O4) or lodestone which was used by the Indian surgeon Sucruta around 2,600 years ago.

• Biomagnetism - In the human body, there is a constant movement of ions within and outside the cells as well as across cellular membranes. This electrical activity is responsible for magnetic fields, called biomagnetic fields, which we can measure using sensitive instruments placed outside the body.

Fig. Schematic depicting the spin magnetic moments for Fe3+ and Fe2+in Fe3O4

Magnetism and Magnetic MaterialsCategories of Magnetic MaterialsThe Influence of Temperature

The main advantages of magnetic (organic or inorganic) NPs are that they can be: (i) visualized (superparamagnetic NPs are used in MRI); (ii) guided or held in place by means of a magnetic field; and(iii) heated in a magnetic field to trigger drug release or to producehyperthermia/ablation of tissue.

Fig: Schematic illustration of MNP-

based cancer therapies.

Magnetic properties of such materials enable their applications in numerous areas

• Magnetically responsive nano- and microparticles and other relevant materials can be selectively separated (removed) from the complex samples using an external magnetic field (e.g. using an appropriate magnetic separator, permanent magnet, or electromagnet) – Magnetic separation• This process is very important for bioapplications due to the fact that absolute

majority of biological materials have diamagnetic properties which enable efficient selective separation of magnetic materials.• Magnetic particles can be targeted to the desired place and kept there using an

external magnetic field. These properties can be used e.g. for sealing the rotating objects or in the course of magnetic drug targeting.• Magnetic particles can generate heat when subjected to high frequency

alternating magnetic field; this phenomenon is employed especially during magnetic fluid hyperthermia (e.g., for cancer treatment).

• Magnetic iron oxides nanoparticles generate a negative T2 contrast during magnetic resonance imaging thus serving as efficient contrast agents.

• Magnetorheological fluids exhibit great increase of apparent viscosity when subjected to a magnetic field.

• Magnetic nano- and microparticles can be used for magnetic modification of diamagnetic biological materials (e.g. cells or plant-derived materials), organic polymers and inorganic materials, and for magnetic labeling of biologically active compounds (e.g. antibodies, enzymes, aptamers etc.).

• Magnetic Particles: Exhibiting magnétisation on exposure to magnetic Field.

• Magnetic Twisting: Twisting the magnetically tagging Biomolecules under magnetic field.

• Magnetic Tweezer: Fetching the magnetically tagged Biomelecules under magnetic field

• Magnetuc clustering: Clustering the Magnetically tagged Biomeolecule under Magnetic field.

Types of BioMagnetic ApplicationSize Dependent Magnetism

Fig. Magnetic properties are affected by the particle size (DM = diamagnetic, PM = paramagnetic, SPM = superparamagnetic, FM = ferromagnetic)

e) The interaction (exchange coupling; linked red dots) at the interface between a ferromagnet and an antiferromagnet produces the exchange bias effect. In an exchange-biased system, the hysteresis is shifted along the field axis (exchange bias field (Heb))and the coercivity increases substantially. f) Pure antiferromagnetic nanoparticles could exhibit superparamagnetic relaxation as well as a net magnetization arising from uncompensated surface spins (blue arrows in (b)). This Figure, is a rather simplistic view of some phenomena present in small magnetic particles. In reality, a competition between the various effects will establish the overall magnetic behavior.

Figure 1. The different magnetic effects occurring in magnetic nanoparticles. The spin arrangement in a) a ferromagnet (FM) and b) an antiferromagnet (AFM); D=diameter, Dc=critical diameter. c) A combination of two different ferromagnetic phases (magenta arrows and black arrows in (a)) may be used for the creation of novel functional nanomaterials, for example, permanent magnets, which are materials with high remanence magnetization (Mr) and high coercivity (HC), as shown schematically in the magnetization curve (c), d) An illustration of the magnetic moments in a superparamagnet (SPM). A superparamagnet is defined as an assembly of giant magnetic moments which are not interacting, and which can fluctuate when the thermal energy, kBT, is larger than the anisotropy energy. Superparamagnetic particles exhibit no remanence or coercivity, that is, there is no hysteresis in the magnetization curve (d).

Special Features of Magnetic Nanoparticles

Modified Nanoparticle and tissue interaction

Examples and Property Requirements of Magnetic Biomaterials

• Magnetite is found in many biological entities, from bacteria to people. It is an example of cubic ferrites which have an inverse spinel structure. It is ferrimagnetic with a Curie temperatureof 578 ◦C and a saturation magnetization of 4.76 × 105 A/m. • Another example is maghemite (gamma Fe2O3), which is formed when

magnetite is oxidized. It has a structure similar to that of magnetite, the difference being that all or most of the iron is trivalent, the saturation magnetization is 4.26 × 105 A/m.• Ferritin is a protein that stores iron in humans. It contains typically 4,500 iron

atoms in an approximately spherical 12 nm diameter molecule. It has a 12 subunit protein shell containing a ferrihydrite core and an antiferromagnetic core. • Gadolinium(III) chelates are commonly used in MRI applications. • Iron coated with activated carbon has recently been tried for magnetic drug

targeting for the treatment of hepatocellular carcinomas.

• The magnetic biomaterial can, in principle, also be Ni, Co, b.c.c. Fe, magnetic alloys of Fe, Co, Ni, Nd–Fe–B or samarium–cobalt materials. • In all cases, however, issues of biocompatibility and toxicity limit the choice of

materials; however, the use of coatings may make the use of these materials feasible. • The hard magnetic materials Nd–Fe–B and samarium–cobalt have the

disadvantage that large external fields are required to influence these materials. • Materials with high magnetization and high susceptibility are preferred for

applications such as drug targeting and magnetic separation. • Most of the examples of useful magnetic biomaterials are in powder form, and

usually the particles are suitably coated before use. • Ideally, the magnetic material should be non-toxic and non-immunogenic.

• In the case of drug delivery, the particle sizes should be small enough to be injected into the bloodstream and then to pass through the required capillary systems.• In many cases, it is required to coat the magnetic particles; this is usually done

by coating with a biocompatible polymer or with other coatings such as gold, activated carbon or silica. • The coating reduces aggregation and prevents the magnetic particle from

being exposed directly to the body.• In addition, the polymer can be used as a matrix in which drugs, radionuclides

or genetic material can be dissolved or as a site for binding of drugs; thus the magnet-coating system can act as “carrier” to deliver useful material to the targeted region. • Some examples of common coatings are derivatives of dextran, polyethylene

glycol (PEG) and polyethylene oxide (PEO), phospholipids and polyvinyl alcohol

Synthesis of Magnetic

Nanoparticle and biofunctionalisation

Fig. Magnetic carrier for drug targeting and drug delivery

Fig: Interaction within the functionalized Nanoparticle

Size Dependence On Particle removal and particle delivery

Magnetic separation

• Cell labelling and magnetic separation- It is a two-step process, involving

(i) the tagging or labelling of the desired biological entity with magnetic material, and

(ii) the separating out of these tagged entities via a fluid-based magnetic separation device.

• Tagging is made possible through chemical modification of the surface of the magnetic nanoparticles, usually by coating with biocompatible molecules such as dextran, polyvinyl alcohol (PVA) and phosopholipids—all of which have been used on iron oxide nanoparticles.

• As well as providing a link between the particle and the target site on a cell or molecule, coating has the advantage of increasing the colloidal stability of the magnetic fluid.

• Specific binding sites on the surface of cells are targeted by antibodies or other biological macromolecules such as hormones or folic acid.

• As antibodies specifically bind to their matching antigen this provides a highly accurate way to label cells.

• For example, magnetic particles coated with immunospecific agents have been successfully bound to red blood cells, lung cancer cells, bacteria, urological cancer cells and Golgi vesicles.

• For larger entities such as the cells, both magnetic nanoparticles and larger particles can be used: for example, some applications use magnetic ‘microspheres’— micron sized agglomerations of sub-micron sized magnetic particles incorporated in a polymeric binder

• This force needs to overcome the hydrodynamic drag force acting on the magnetic particle in the flowing solution, Fd = 6πηRm

∆v,where η is the viscosity of the medium surrounding the cell (e.g. water), Rm is the radius of the magnetic particle, andv = vm −vw is the difference in velocities of the cell and the water

Magnetic drug carriers

• The major disadvantage of most chemotherapies is that they are relatively non-specific. • The therapeutic drugs are

administered intravenously leading to general systemic distribution, resulting in deleterious side-effects as the drug attacks normal, healthy cells in addition to the target tumour cells.

• The objectives are two-fold: (i) to reduce the amount of

systemic distribution of the cytotoxic drug, thus reducing the associated side-effects; and

(ii) to reduce the dosage required by more efficient, localized targeting of the drug

Hyperthermia

• The amount of heat generated per unit volume is given by the frequency multiplied by the area of the hysteresis loop:PFM = μ0f ∫H dM.

MECHANISM OF HYPERTHERMIA

Conclusion• Advancements in our ability to fabricate MNPs with greater control over physicochemical and

bioactive properties have led to new NP candidates for imaging and therapeutic use. • These formulations offer• (1) disease diagnosis at their earliest stages and improved preoperative staging, • (2) delivery of therapeutics specifically to diseased tissue, limiting unwanted side effects, and • (3) non-invasive monitoring capabilities of new therapeutics. Size, shape, and surface chemistry dictate in vivo

behavior, including biodistribution, biocompatibility, and pharmacokinetics.

• As such, these parameters can be tuned to achieve enhanced targeting via passive, active, and magnetic targeting mechanisms.

• Active targeting, in particular, offers high sensitivity due to the ability to direct MNP localization, but requires added attention be paid to the targeting agent used, and the method of MNP attachment employed.

• A number of bioconjugation strategies including physical methods, covalent strategies, and click chemistries are available, each having distinct advantages.

• In addition to assisting in disease imaging, cell targeting by MNPs can also assist in disease treatment if a therapeutic payload is integrated into the MNP.

• This requires additional design considerations, though, including type of therapeutic, method of release, and intracellular activity.

Reference• Chapter 17, Magnetic Particles for Biomedical Applications by Raju V. Ramanujan.

• O. Veiseh, et al., Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging, Advanced Drug Delivery Reviews (2009).

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• Chapter 7, Magnetic Nanoparticles: Synthesis, Surface Modifications and Application in Drug Delivery by Seyda Bucak, Banu Yavuztürk and Ali Demir Sezer.

• Article in Nanotoday, Magnetic nanoparticles for drug delivery, JUNE 2007 | VOLUME 2 | NUMBER 3

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