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ATUFA KAWAN 08-ARID-1773 Ph.D (ZOOLOGY) Dendrimers are polymeric molecules ,chemically synthesized with well defined shape, size and nanoscopic physiochemical properties reminiscent of the proteins. These polymers are almost spherical shape tree having diameters generally between 2 and 10 nm. Dendrimers possess three distinguished architectural components namely, An initiator core an interior of shells (generation) an exterior (outermost layer), which often has terminal functional groups (Figure.1). This unique architecture makes dendrimers monodispersed macromolecules compared to classical linear polymers. Fig.1: Dendritic Structure Monodispersity: Homogenous, well defined molecular structure, without individual large variations Polyvalency: Quantity of reaction sites on outer side of dendrimers have potential to form connection with various molecules of interest Nanoscale Dimensions and Shapes: Nanoscale dimensions due to their well organized synthesis strategy and size controllable Properties. Within PAMAM dendrimer family when grown from generations 1-10 the diameter of dendrimers with an ethylenediamine core increases from 1.1 to 12.4nm.The shape of dendrimers may vary with their generations PAMAM dendrimers of low generation (G0-G3) and high generation (G4-G10) have ellipsoidal and spherical shape. Solubility: Surface end groups→ hydrophobic→non polar solvent →hydrophilic→polar solvent PAMAM (Poly Amidoamine) Dendrimer PAMAMOS (Polyamidoamine organosilicon) Dendrimer PPI Dendrimer(Poly Propylene Imine) Tecto Dendrimer Chiral Dendrimer Hybrid Dendrimers Amphiphilic Dendrimers Peptide Dendrimer DIFFERENCES BETWEEN DENDRIMER AND LINEAR POLYMER Property Dendrimers Linear polymers Structure Compact, Globular Not compact Architecture Regular Irregular Size Certain Uncertain Shape Spherical Random coil Aqueous solubility High Low 1. Divergent Synthesis In this method dendrimer grow from inside(co re molecule) to outside through Michael addition. Starting from a reactive core, a generation is grown and then the new periphery of the molecule is activated for reaction with more monomers. Michael Addition: (Go) with four Alkylation of amine functional core with methyl acrylate ethylene diamine terminal amine groups Esters Produce branched (G0) with four OH surface groups Reaction with ethanolamine In this way the dendrimer size. weight and no of end group increased. Divergent Synthesis 2. Convergent Synthesis In this method the dendrimer grow from outside to inward. Ist Step: The surface unit links together to form a large wedge 2nd Step: The large surface units attached to the multifunctional core unit Convergent Synthesis INTERACTIONS BETWEEN DENDRIMERS AND DRUG MOLECULES Simple Encapsulation The ellipsoidal or spheroidal shape, empty internal cavities (hydrophobic properties, nitrogen or oxygen atoms) and open nature of the architecture of dendrimers make it possible to directly encapsulate guest molecules into macromolecules interior. Electrostatic Interaction Dendrimers have functional groups on surface(such as such as amine groups and carboxyl groups which are involved in enhancing the solubility of hydrophobic drugs by electrostatic interaction(Fig. 2). Covalent Conjugation The presence of large numbers of functional groups on the surface of dendrimers make them suitable for covalent conjugation of numerous drugs with relevant functional groups. Dendrimers have been conjugated to various biologically active molecules such as drugs, antibodies, sugar moieties and lipids. Figure 2. Potential strategies for interactions between dendrimers and drug molecules (A) electrostatic interactions or covalent conjugate, and (B) simple encapsulation. Inflow & outflow of lacrimal fluids 2. Efficient naso-lacrimal drainage 3. Dilution with tears 4. Corneal barriers 1. Non-corneal absorption: Penetration across sclera & conjunctiva into intra ocular tissues. Non productive: because penetrated drug is absorbed by general circulation. Corneal absorption: Outer epithelium: rate limiting barrier for lipophilic and hydrophilic molecules. Trans cellular transport: transport between corneal epithelium and stroma Robinson et al., 2011 suggested the use of bioadhesive polymers, such as poly (acrylic) acids, to improve drug delivery and release by optimizing contact with the absorbing area in order to prolong residence time and decrease dosage frequency. Dendrimers like poly (amido amine) (PAMAM) are used, which are liquid or semi-solid polymers and have several amine carboxylic and hydroxyl surface groups which increases with the generation number(G0, G1, G2, and so on). Because of this unique architecture, PAMAM dendrimers, are able to solubilize strongly and poorly water-soluble drugs into their inner zones containing cascading tiers of branch cells with radial connectivity to the initiator core and an exterior or surface region of terminal moieties. So, greater possibilities can be explored by using dendrimers as ophthalmic drug delivery vehicles. Vandamme and Brobeck, 2005 have reported the development of using PAMAM dendrimers as ophthalmic vehicles in ocular delivery systems. Pilocarpine nitrate and tropicamide were employed as model drugs, respectively. The eye drops containing PAMAM dendrimers were also found to have a prolongation of miotic activity. The authors explained that the increased availability of Pilocarpine nitrate and tropicamide might be due to: 1) The host–guest relationship between dendrimers and drug molecules, which induced slower release of these drugs encapsulated in dendrimers’ interior cavities 2) And the bioadhesive properties of PAMAM dendrimers, which can be explained by the structure, shape, and surface functional groups of dendrimers. Ocular neovascularization is essential for normal eye development but another main cause of blindness when it is not well controlled. The most effective angiogenic factor involved in ocular neovascularization is vascular endothelial growth factor (VEGF). A sense oligonucleotide named ODN1 was reported to have potent anti-VEGF activity. Wimmer et al., 2002 designed and synthesized lipid– lysine dendrimers in an attempt to improve the delivery of ODN-1 into the nuclei of retinal cells. TDDS can provide a steady drug blood concentration and thus avoid peaks and valleys in the drug plasma levels, which occur with traditional dosing, such as oral administration. However, transdermal delivery of drugs is limited due to the slow rate of transdermal delivery, chiefly attributable to the barrier functions of skin. The outer layer of the skin which is served as the first line of defense, is composed of closely packed dead cells formed by epidermal differentiation and cornification. The most common method to improve drug penetration through the skin is to use transdermal enhancers. Barry and coworkers describe the mechanisms by which enhancers effect skin permeability: 1. Hydration Water content of the stratum corneum is around 15 to 20%. Additional water within stratum corneum could alter the permeant solubility by swelling and opening of sratum corneum.Hydration can be increased by occlusion with plastic films.oils,waxes as components of ointments and water-in-oil emulsions that prevent transepidermal water loss and oil-inwater emulsions that donate water. 2. Lipid Disruption by Chemical Enhancers Azone,alcohols, dimethyl sulfoxide (DMSO) and fatty acids have been shown to increase permeability by forming permeable pores within lipids domains that provide less resistance to polar molecules. These enhancer compounds consist of a polar head group with a long alkyl chain and are more effective for hydrophilic and lipophilic permeants. 3. Interaction with keratin Urea, dimethyl sulfoxide interact with keratin in the corneocytes. Barry suggested that these molecules may also modify Peptide/ Protein material in the lipid bilayer domain to enhance permeability. 4. Electrical Methods Iontophoresis Driving charge molecules into skin by a small direct current approximately 0.5 mA/cm2). Electroporation Application of short micro to milli second electrical pulses of approximately 100-1000 v/cm to create transient aqueous pores. 1. Numerous reports have been published describing the use of aminoterminated PAMAM or PPI dendrimers as non-viral gene transfer agents, enhancing the transfection of DNA by endocytosis and, ultimately reach into the cell nucleus by endosomal escape mechanisms proton sponge effect The proton sponge effect is mediated by agents with a high buffering capacity and the flexibility to swell when protonated. Protonation, induces an extensive inflow of ions and water into the endosomal environment which subsequently leads to rupture of the endosomal membrane and release of the entrapped components. Tertiary amine groups that contain a hydrophobic chain, have been shown to accumulate in endosomes which have an acidic pH and become detergents upon protonation resulting in disruption of the membrane. Fig.3.Dendrimers in GeneTransfection Fig. 4. An artistic representation depicting the proton sponge hypothesis. The low pH in endosomal environment leads to protonation of the entrapped agents with a high buffering capacity. Protonation leads to inflow of H+ and Cl− and water into the endosomes, resulting in osmotic swelling and endosome rupture. 3. Fusion in the endosomal membrane Destabilization of the endosomal membrane by fusogenic peptides. Haemagluttinin which is a peptide of Influenza virus coat act as fusogenic agent that is converted from anionic hydrophilic coat at PH 7.4 to a hydrophobic helical confirmation at acidic endosomal PH. This α- helical lead to fusion of viral membrane into cellular membrane. 4.Dendrimers as Nano- Drugs Sulfonated naphthyl group Poly lysine Useful antiviral drug against Herpes Simplex virus Prevent and reduce transmission of HIV and STD PAMAM Dendrimers nanocarriers Inhibit cell adsorption Viral replication By interfering with reverse transcriptase Silva JR, N.P., Menachof F.P., Chorilli, M. 2012. Dendrimers as potential platform in nanotechnology-based drug delivery systems.IOSR Journal of Pharmacy, 2:23-30. Garg T, Singh O, Arora S and Murthy RSR.Dendrimer a novel scaffold for drug delivery. IJPSR. 2011;7:211-220. Jain A, Dubey S, Kaushik A and Kumar AT. Dendrimer: a complete drug carrier. IJPSR 2010;1(4):38-52. Biricova V and Laznickova A.Dendrimers: Analytical characterization and applications. Bioorg Chem. 2009;37:185–192. Heather A.E. Benson. 2005. Trasndermal Drug Delivery: Penetration Enhancement Techniques. 2:22-33. Heather A.E. Benson. 2005. Trasndermal Drug Delivery: Penetration Enhancement Techniques. 2:22-33. Vandamme, TH.F. and L. Brobeck, 2005. Poly(amidoamine) dendrimers as ophthalmic vehicles for ocular delivery of pilocarpine nitrate and tropicamide. Journal of Controlled Release, 102: 23-38. Sonke, S. and D.A. Tomalia, 2005. Dendrimers in biomedical application reflection on the field. Advanced Drug Delivery Reviews, 57: 2106-2129. JPVC, Li H. 2003. Efficacy of dendrimer-mediated angiostatin and TIMP-2 gene delivery on inhibition of tumor growth and angiogenesis: In vitro and in vivo studies. Int J Cancer 105:419–429. Barbara K and Maria B: Review Dendrimers: properties and applications. Acta Biochimica Polonica 2001; 48:199–208.