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Polymeric Nano-Systems Used in Drug Delivery
Arsen Simonyan SUNY-ESF
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Types of Nano-Sized Drug Delivery Vehicles
Nanosuspensions & Nanocrystals Liposomes Solid Lipid Nanoparticles Nanotubes & Nanowires Polymeric Nanoparticles
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Benefits of Polymer Systems
Increase stability of volatile drug agents Produced relatively easily Vast source of chemistries available May have engineered specificity both to the drug and the target – difficult to achieve with other carriers Drug-release profiles and triggering dependent on polymer structure
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Qualities of Relevant Polymers
Biodegradable/Biocompatible – lactic acid, glycolic acid, ethylene glycol, glycerin, fatty acids, amino acids, sugars, etc. Structure – mostly copolymers, combining different qualities of their parent polymers – Tg, Tm, crystal structure, or exhibiting new ones - self-assembly random graft alternating block
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Most Common Types of Block Copolymers
Typical Applications as: - Micro and nano-particles (mPEO-PLA, PLA) Unimolecular drug vehicles (star blocks – PEG-PLA, PLA-PEG, dendr-PBE-PEO, etc.) Hydrogels (Pluronics, PEO-PBO, PEG-PLGA, dendr-PBE-PEO, PIPAAm-PAA, PEO-PLA) Micellar systems (PEG-PLys, PEG-PAsp, PIPAAm-PBMA,etc.) Surface modifications Drug conjugates AB diblock ABA triblock or ABC Multiblock n Star block
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Nano-particles Benefits - Fairly easy preparation
Good control over size and size distribution Good protection of the encapsulated drug Longer clearance times Drawbacks Extensive use of poly(vinyl alcohol)-PVA as a detergent - issues with toxicity - Limited targeting abilities PLA nanoparticles loaded with HAS formed by a double emulsion technique, stabilized with PVA Image taken from M. F. Zambauxa, F. Bonneauxa, *, R. Grefb, P. Maincentc, E. Dellacherieb, M. J. Alonsod, P. Labrudea and C. Vignerona, J. Controlled Release, 1998, 50, 31
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Star Block Copolymers Benefits
Smaller sizes and lower intrinsic viscosities leading to better excretion Size determined by chemical structure and uniform size distribution Long clearance times due to slow degradation Possibility for attachment of homing (targeting) device at the extremities of the arms Drawbacks Smaller loading capacity per molecule - Longer preparation and purification process Image taken from Youxin Li, Thomas Kissel, Polymer, 1998, 39, 4421
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Hydrogels Benefits Drawbacks - Closest analogue to living tissue
- Capable of binding large amounts of fluids and drugs, incl. proteins - Swelling ratio controllable by variation in structure (mostly by the hydrophobic/hydrophilic ratio) - Small changes in temperature, pH, electric/magnetic field can trigger large volume change/release of drug In many cases well defined release patterns - ~ t1/2 Drawbacks - More difficult to characterize/predict behavior - Not as well defined as stoichiometric compounds
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Micellar Systems Benefits - Unique core-shell structure
- Fairly high loading capacities depending on the chemistry of the drug - Attachment of homing device(s) possible – biotin, folic acid, antibodies - Variation of polymer composition, free charges, hydrophobic/ hydrophilic ratio, offers vast possibilities for design of unique gene/protein/drug delivery vehicles - Physical affinity targeting using stimuli-responsive polymers to pH, electro-magnetic fields, temperature - Additional crosslinking in the core/shell leads to novel nanostructures with different drug delivery properties
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Crosslinkable micelles
Drawbacks - Difficult prediction of micellar characteristics by unimer structure - Not very well studied Image taken from Roesler, A., Vandermeulen, W, Klok, H., Adv. Drug Deliv. Rev., 2001, 53, 95
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Surface Modification and Drug Conjugation, Examples
1 3 2 Images 1&2 taken from Roesler, A., Vandermeulen, W, Klok, H., Adv. Drug Deliv. Rev., 2001, 53, 95 Image 3 taken from Anil K. Patri, Jolanta F. Kukowska-Latallo, James R. Baker Jr., Adv. Drug Deliv. Rev., 2005, 57/15
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Conclusions Polymeric systems have great potential in drug delivery applications Offer closest mimicking of natural products Difficult characterization, expensive and long processes of synthesis and purification are major drawbacks Still none of the discussed systems is applied in practice to patients – FDA approval requires extensive toxicity investigations
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