Dendrimers for cancer therapy

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Dendrimers for cancer therapy

  1. 1. Dendrimers for cancer therapy Presented by V.Vijayalakshmi M.Tech
  2. 2. Dendrimers for cancer therapy Dendrimers Synthesis method Properties Structure- drug delivery Dendrimers- requirements for cancer targeting Dendrimers applications in cancer treatment conclusion Outline
  3. 3. Dendrimers A synthetic polymer with a branching, tree-like structure The name comes from the Greek word δένδρον (dendron), which translates to "tree" Dendrimers are highly branched, star-shaped macromolecules with nanometer-scale dimensions. Dendrimers are defined by three components: •a central core •an interior dendritic structure (the branches) •an exterior surface with functional surface groups The varied combination of these components yields products of different shapes and sizes with shielded interior cores that are ideal candidates for applications in both biological and materials sciences.
  4. 4. Dendrimer structure Figure 1: Schematic representation of dendrimer – G2 generation. Dendrimers are formed by three components a central core ,an interior dendritic structure (the branches), an exterior surface with functional surface groups, an internal cavity for drug loading http://www.sigmaaldrich.com/materials-science/nanomaterials/dendrimers/dendrons.html
  5. 5. Dendrimer- Synthesis method Figure 2.2: Schematic of convergent synthesis of dendrimers. Dendrimers are built from small molecules that end up at the surface of the sphere, and reactions proceed inward building inward and are eventually attached to a core. Figure 2.1: Schematic of divergent synthesis of dendrimers. The dendrimer is assembled from a multifunctional core, which is extended outward by a series of reactions, commonly a Michael reaction. http://en.wikipedia.org/wiki/Dendrimer
  6. 6. Dendrimers- Properties monodisperse macromolecules. size and molecular mass of dendrimers can be specifically controlled during synthesis. Molecular mass increases - viscosity decreases. Dendrimers’ solubility is strongly influenced by the nature of surface groups. Dendrimers terminated in hydrophilic groups are soluble in polar solvents, while dendrimers having hydrophobic end groups are soluble in nonpolar solvents. Dendrimers have some unique properties because of their globular shape and the presence of internal cavities. The most important one is the possibility to encapsulate guest molecules in the macromolecule interior.
  7. 7. dendrimers can play the role of photoswitchable hosts. Photochemical modifications of the dendritic surface cause encapsulation and release of guest molecules Hydrolysing the outer shell could liberate the guest molecules dendrimers which can act as extremely efficient light-harvesting antennae Subha sankar Ghosh “ Dendrimers new hope for cancer” science reporter, August 2010
  8. 8. Figure 3. Structural options for dendrimer based drug delivery. Dendrimers can be synthesized with neutral surfaces (1) and positive (2) or negative (3) charges at the periphery; moreover, dendritic macromolecules, generally when larger than G3, can harbor non covalently encapsulated guest/drug molecules (4). An alternative strategy for drug delivery is through covalent conjugation of ligands to the surface of the dendrimer.(5) The versatility of dendrimers for drug delivery is illustrated by considering that ‘‘A’’ could be a targeting ligand and the active drug could be encapsulated within the same macromolecule (6). Synthetic strategies are now available for providing dendritic clusters with extremely high densities of surface ligands (7) and for providing more than one type of surface ligand, either in a random orientation (8), or in blocks (9). The latter dendrimers are now being exploited in sophisticated cancer cell targeting and drug release strategies where A, B, and C can be any combination of targeting agents, drugs, contrast agents, or functional groups that improve pharmacological properties. Srinivasa-Gopalan Sampathkumar, and Kevin J. Yarema-” Dendrimers in Cancer Treatment and Diagnosis”. Dendrimers- drug delivery
  9. 9. Figure 4: Requirements for dendrimer-based,cancer-targeted drug delivery. (a) Dendrimers with multiple surface functional groups can be directed to cancer cells by tumor-targeting entities that include folate or antibodies specific for tumor-associated antigens (TAAs). (b) The next step is intake into the cell, which in the case of folate targeting occurs by membrane receptor mediated Endocytosis. (c) Once inside the cell, the drug generally must be released from the dendrimer, which, for the self- immolative method results in the simultaneous disintegration of the dendritic scaffold (d). Srinivasa-Gopalan Sampathkumar, and Kevin J. Yarema-” Dendrimers in Cancer Treatment and Diagnosis”. Dendrimers targeting cancer- Requirements
  10. 10. • Cancer imaging • Photodynamic therapy • Boron Neutron capture therapy • DNA- Dendrimer conjugate • Tectodendrimer- Nanodevice • Gene therapy
  11. 11. 1) Dendrimers- cancer imaging Dendrimers conjugated to fluorochromes and shown to enter cells - imaging Possible to characterize •cell tergeting, surface binding •uptake and internalization •even sub cellular localization Gadolinium, a contrasting agent conjugated to folate receptor or TAA dendrimer to target cancer cells Gd- macromolecular system, limited success Eg: PAMAM-based MR contrast agents was their long residence time in the body; this problem, however, can be met by modifying both the surface properties and basic chemical composition of the dendrimer Diaminobutane (DAB) dendrimer-based chelators were more rapidly excreted from the body, illustrating that the development of clinically-acceptable dendrimer MR platforms.
  12. 12. 2) Photodynamic therapy PDT- drug- Photosensitizer or photosensiting agent and particular type of light. When photosensitizer exposed to specific wavelength of light they produce form of oxygen which kills cancer cells Problem: Long rentention time, radiation exposed after a gap period 24-72 hours, to left normal cells – drugs Dendrimers in PDT- designed to deliver the agent only to affected tissues by recognizing the specific molecules on cancer cells Fasten the rate of treatment No need to wait for elimination of photo sensitizer from normal cells
  13. 13. 3) Boron Neutron capture therapy BNCT- require selective delivery of sufficient number of stable non radioactive isotope of boron – successful treatment Beam of low energy neutrons is given to a stable isotope of boron(boron-10) after they have accumulated in tumour cells Boron present in or adjacent to the tumour cells disintegrates after capturing neutrons produce high energy heavy charged particles that destroy only cells in close proximity to it leaving adjacent normal cells Problem: Conventional BNCT- polymer like polylysine were used which can deposit 1700 boron derivatives to the targeted site Lesser number of boron depositions Eg: Dendrimers like PAMAM – transfer 5000 Boron derivatives
  14. 14. Figure 5:DNA–dendrimer conjugates as potential cancer targeting imaging agents or therapeutics. Differentially functionalized dendrimers covalently conjugated to complementary deoxyoligonucleotides can readily form duplex combinatorial nanoclusters that possess cancer cell-specific ligands hybridized to an imaging agent or drug. Cell- specific targeting ligands (e.g., folic acid in one study) are appended to Dendrimer A, and Dendrimer B is conjugated with an imaging agent or drug. 4) DNA – Dendrimer conjugate for cancer targeting Srinivasa-Gopalan Sampathkumar, and Kevin J. Yarema-” Dendrimers in Cancer Treatment and Diagnosis”.
  15. 15. 5) Multifunctional nanodevice- Tectodendrimers Figure6.1:Tectodendrimers. Tectodendrimers are multifunctional devices built from a core dendrimer, surrounded by shell dendrimers. Each shell dendrimer performs one function. Figure 6.2: Nanodevice tergetting. To target the nanodevice specifically to the cancer cells and not to other cells, we make use of the fact that cells have on their surfaces receptors for specific molecules. By attaching the proper moiety (target of active receptor), the specificity can be precisely controlled. http://www.nano.med.umich.edu/Platforms/Dendrimers-Introduction.html 3/
  16. 16. 6) Dendrimers based gene therapy- cancer treatment Dendrimers offer many advantage over viruses as vehicles of genes Less toxic, cost, ease of production, ability to transfer long genes Eg: Polypropyleneimine dendrimer nanoparticles – capacity for tumour transfection- the process of introducing nucleic acids into cells by non viral methods in tumour bearing mice. once inside the cell gene enclosed in the particle recognises the cancer cells and kills them Human trial- not yet
  17. 17. Conclusion Dendrimers, chemically-defined entities with tunable biological properties, have advanced over the past two decades to the point where they stand on the cusp of major contributions to the treatment of cancer in a meaningful way. Dendrimers – improve the therapeutic index of cytotoxic drugs by direct delivery of drugs to cancer drugs
  18. 18. References Srinivasa-Gopalan Sampathkumar, and Kevin J. Yarema-” Dendrimers in Cancer Treatment and Diagnosis”. Subha sankar Ghosh “ Dendrimers new hope for cancer” science reporter, August 2010. James R. Baker Jr. Dendrimer-based nanoparticles for cancer Therapy American Society of Hematology,2009. Barbara Klajnert and Maria Bryszewska, Dendrimers: properties and applications Acta biochimica Polanica ;2001(48):199-208. http://www.sigmaaldrich.com/materialsscience/nanomaterials/dendrimers/den drons.html http://www.nano.med.umich.edu/Platforms/Dendrimers-Introduction.html 3/ http://en.wikipedia.org/wiki/Dendrimer

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