Dendrimers and its applications

DENDRIMERSPRESENTED BY: SAMIKSHA SAWANT M.PHARM(IP), 1st SEM GUIDED BY : SHRUTI SHRIKHANDE1

WHY DENDRIMERS? They act as a carrier for :Targeted drug delivery.Controlled release of drug 2

WHAT ARE DENDRIMERS?The name comes from Greek word dendron which means tree.Also called as arborols/ cascade molecules

They are family of nanosized, highly branched three dimensional molecules.

Synthesis of polyamidoamine(PAMAM) dendrimer in 1985 was a turning point.

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STRUCTURE OF DENDRIMERAn interior coreInterior layers composed of repeating units radically attached to cores.Exterior layer (terminal functionality) attached to interior generations.

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3D STRUCTURE OF DENDRIMER

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PROPERTIES OF DENDRIMERSMonodispersityNanoscale size and shapeViscosityHigh aqueous solubilityHigh solubility in non polar solutionsNon crystalline and have low glass temperatureLow compressibility6

CHARACTRIZATION OF DENDRITIC POLYMERSSpectroscopy and spectroscopy methods.Scattering techniques.Electrical techniques.Chromatographic techniques.Microscopy.Rheology, physical properties.7

SYNTHESIS OF DENDRIMERS There are two methods of synthesizing dendrimers:Divergent methodConvergent method

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DIVERGENT METHODDendrimer grows from core to periphery.The core molecule reacts with the monomer molecule having two dormant and one reactive group.

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DIVERGENT METHODCan cause trailing generations.

Difficult to purify the product.

Because the relative size differences between perfect and imperfect dendrimers is very small.

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CONVERGENT METHODDendrimer grows starting from end groups and progresses inward.

Method makes impurity removal easier monodisperse dendrimers are obtained.

But stearic effects along the core limits the size.11

CONVERGENT METHODSmall molecules come together and reaction proceeds inward.Eventually the molecules become attached to the core.

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OVERVIEW

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TYPES OF DENDRIMERSPAMAM dendrimers-They are synthesized by divergent method starting with ammonia or ethylene diamine initiator core reagent.

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USES OF PAMAM DENDRIMERSSimple PAMAM-drug complexes would affect a broad spectrum of cells upon introduction to a living system

PAMAM derivatized with folic acid is preferentially taken up bycancer cell, which are known toover express thefolate receptor on their surfaces.

Attaching additional treatment methods along with the folic acid, such asboron isotopes, cisplatin andmethotrexate have proven quite effective.15

In gene therapy

Surface amine residues on PAMAM dendrimers bind to the phosphate backbone of nucleic acids through charged interactions. Typically, G6-7 PAMAM dendrimers are used for gene tranfection; these dendrimers are typically 6-10nm in length.16

Pamamos dendrimer-radially layered poly(amidoamine-organosilicon)dendrimers consist of hydrophilic,nucleophilic polyamidoamine interiors and hydrophobic organosilicon exterior.

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SYNTHESIS OF PAMAMOS

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DIFFERENT GENERATIONS OF SILICON DENDRIMER

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PPI DENDRIMERSPPI dendrimers-poly-Propylene Imine having primary amines as end groups, the dendrimer interior consist of tertiary tris-propylene amines. PPI dendrimers are commercially available upto G5 generation.Also called as POPAM or DAB dendrimers.

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TECTO DENDRIMERSComposed of core dendrimer, surrounded by dendrimers of several steps to work as a smart nanodevice.Perfoms disease cell recognition, diagnosis of disease, drug delivery etc.

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FRECHET TYPE DENDRIMERIt is based on poly-benzyl ether hyper branched skeleton. They have carboxylic acid groups as surface groups.These groups serve as good anchoring points for further surface functionalisation. Also act as polar groups to increase the solubility of this hydrophobic dendrimer.

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AMPHIPHILIC DENDRIMERSThey have hydrophobic interior core and hydrophilic exterior.Hence are good carriers for drugs with poor solubility.

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MECHANISMS OF DRUG LOADINGSimple encapsulation

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MECHANISMS OF DRUG LOADING2. Electrostatic interaction-The high density of functional groups like amine or carboxyl on surface of dendrimer have potential application in enhancing the solubility of hydrophobic drugs by electrostatic attractions.3. Covalent conjugation:The presence of large functional groups on the surface of dendrimers make them suitable for covalent conjugation of numerous drugs with relevant functional groups. 25

MECHANISM OF DRUG DELIVERY THROUGH DENDRIMERSIn-vivo degradation of drug dendrimer

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MECHANISM OF DRUG DELIVERY THROUGH DENDRIMERS 2) Drug release due to change in physical environment.

Due to change in temperature27

MECHANISM OF DRUG DELIVERY THROUGH DENDRIMERS

Due to change in pH28

APPLICATIONS OF DENDRIMERSBlood substitution: The stearic bulk surrounding a hememimetic centre significantly slows degradation compared to free heme.

Sensors: Cadmium-sulfide/polypropylenimine tetrahexacontamine dendrimer composites to detect fluorescence signal quenching.

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APPLICATIONS OF DENDRIMERS3. Solubility enhancers: Dendrimers have hydrophobic core and hydrophilic outer surface. This enhances solubility of poorly soluble drugs by forming cascade and nonskid-chain like synthesis of covalent, non covalent complexes with drug molecules.

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APPLICATIONS OF DENDRIMERS 4.Gene transfection: Dendrimers are non-viral gene transfer agents, enhancing transfection by endocytosis.

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APPLICATIONS OF DENDRIMERS 5. Dendrimers as nanoparticles: Poly(amidoamine) dendrimers have tertiary amine group at the branching point. Metal ions are introduced into aqueous solution of dendrimer and metal ions form complex with lone pair of electrons present at the tertiary amines. The ions are then reduced to zerovalent state to form nanoparticles that is encapsulated within the dendrimer.32

APPLICATIONS OF DENDRIMERS 6. Dendrimers as nano-drugs:Polylysine dendrimers with sulfonated naphthyl group are antiviral.

PPI dendrimers with tertiary alkyl ammonium groups attached to the surface are antibacterial

Chitosan- Dendrimers hybrids have been used as antibacterial agents.33

APPLICATIONS OF DENDRIMERS7. Dendrimer hydrogel for ocular drug delivery:Cross linked networks in dendrimers increase in volume in aqueous solution.Adding PEG groups to dendrimers extends their application to cartilage tissue production and for sealing ophthalmic injuries.Drug attached to the dendrimers efficiently deliver the drug to the eyes.34

APPLICATIONS OF DENDRIMERS8. Dendrimers in pulmonary drug delivery:Dendrimers have been used for pulmonary delivery of Enoxaparin.G2 and G3 positively charged PAMAM dendrimers increased bioavailability of drug.Positively charged dendrimer forms complex with enoxaparin.

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APPLICATIONS OF DENDRIMERS9. Dendrimers in transdermal drug delivery:Dendrimers improve solubility and plasma circulation via transdermal formulation.

PAMAM dendrimers complex with NSAIDS improve drug permeation through the skin as penetration enhancers.PAMAM-Indomethacin complex as model drug was reported to be effective.36

APPLICATIONS OF DENDRIMERS10. Dendrimers for targeted drug delivery:

37Active and passive targeting of cancer cells

APPLICATIONS OF DENDRIMERS11. Dendrimers mimicking in angiogenesis:Angiogenesis is an important process for tumor growth initiated by angiogenic factors.These factors bind to receptors on endothelial cells with dependence on heparin.Endostatin binds to heparin and prevents angiogenesis.Dendrimers which mimic structure of endostatin exhibit antiangiogenic activity.Eg: TX-1943 AND TX-1944

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APPLICATIONS OF DENDRIMERS 12. Dendrimers as carriers or scaffolds for diagnosis and therapy:Medium size dendrimers(5nm) are used for MRI contrast agents.The highly branched dendrimers are used for tissue engineering applications, cross linking agents, modulators of surface charge and surface chemistry and in scaffolds that mimic natural extracellular matrices.39

APPLICATIONS OF DENDRIMERS Dendrimers in boron neutron capture therapy:The cancer patient is injected with boron attach to dendrimer.It migrates to cancerous cells.Then irradiate with neutral beam of low energy neutrons.This generates alpha particles which destroy tumour cells.40

APPLICATIONS OF DENDRIMERS Dendrimers in vaccine development:Dendrimers are used as carriers for small antigens, making it possible to prepare multimeric antigenic conjugates. 41

CASE STUDYPEGylated nanoparticles accumulate in the tumor tissues due to the EPR effect. On the surface of a variety of cancer cells, folate receptors are over expressed. Folate-modified dendrimers target these cells via ligand receptor recognition. Folic acid targeted dendrimers which are covalently conjugated with methotrexate specifically kill receptor-expressing cells after the intracellular delivery of the drug through receptor-mediated endocyctosis. In a study, reseachers synthesized an ethylenediamine core PAMAM dendrimer of generation 3 which was covalently attached to folic acid, fluorescein, and methotrexate. This complex provided targeting, imaging and intracellular drug delivery capabilities with 100-fold decreased cytotoxicity over free methotrexate.42

CASE STUDY In a study, the pH-activated dendrimer was demonstrated to be a successful drug delivery vehicle system, whereas the photochemical internalization (PCI) was invented for site-specific delivery of membrane impermeable macromolecules from endocytic vesicles into the cytosol. In this study, doxorubicin (DOX) was conjugated to polyamidoamine (PAMAM) dendrimers via pH-sensitive linkers and was combined with different PCI strategies to evaluate the cytotoxic effects. The results showed that both PCI strategies significantly improved the cytotoxicity of free DOX on Cancer cells at higher concentrations. The 'light after' PCI treatment was efficient in releasing DOX from the PAMAM-hyd-DOX conjugates, resulted in more nuclear accumulation of DOX and more cell death through. The results provide invaluable information in the future design of drug-polymer complexes for multi-modality cancer treatments.43

MARKETED PRODUCTS AVAILABLESeveral dendrimer based products have been approved by the FDA. For example, Stratus CS Acute Care TM(Dade Behring) was launched for cardiac diagnostic testing , SuperFect TM(Qiagen) is a famous gene transfection agent applicable to a broad range of cell lines. In addition Starpharma has already taken a dendrimer-based drug into clinical trials conducted to US FDA requirements

VivaGel(R) microbicide and has anti HIV property is currently in Phase 3 clinical trial

Poly (propylene imine) dendrimers are available under name Astramol TM.

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CONCLUSION Among the nanoparticulate carriers, dendrimers have tremendous potential in the applications involving multifunctional nanoparticulate systems combining targeting, imaging, diagnostics and therapy. Thus, this multifunctional, unique nanoparticulate carrier has the potential to detect diseases, deliver medications, and monitor the ability to change the current scenario of cancer research and diagnosis in real time.45

REFERENCES Article on Dendrimers: A tool for drug delivery by Anirudh Malik, Sudhir Chaudhary, Garima Garg and Avnika TomarArticle in Dendrimers as carriers for delivery of Chemotherapeutic Agents by Scott H. Medina and Mohamed E. HL- SayedDendrimers: properties and applications by Barbara Klajnert and Maria Bryszewska (http://www.actabp.pl/pdf/1_2001/199.pdf)Dendrimers- Nanomaterials (http://www.sigmaaldrich.com/materials-science/material-science-products.html)Dendrimers by Paul holister and im Harper (http://www.sps.aero/Key_ComSpace_Articles/TSA-001_Dendrimers_White%20Paper.pdf)46

REFERENCESDendrimers Introduction (www. nano.med.umich.edu/Platforms/Dendrimers-Introduction.html)Dendrimers as nanocarrier for drug delivery-Sciencedirect.com(www.sciencedirect.com/science/article/pii/S007960013000853)PDF on Dendrimers: A tool for drug delivery- Idosi (www. idosi.org/abr/6(4)12/6.pdf)Dendrimers for drug delivery- Journal of Materials Chemistry (pubs.rsc.org/en/journals/journal/tb)PDF on Dendrimers and their applications as Novel Drug Delivery by S Tripathy47

REFERENCESDendrimers- An Overview (http://www.pharmainfo.net/reviews/dendrimer-overview)Nanoparticles and cancer therapy: A concise overview with emphasis on dendrimers(http://www.ncbi.nlm.nih.gov/pmcPMC2720735//articles/ )PDF on Dendrimers: Design, Synthesis and Chemical

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THANKYOU!49