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Polymeric Nano-Systems Used in Drug Delivery. Arsen Simonyan SUNY-ESF. Types of Nano-Sized Drug Delivery Vehicles. Nanosuspensions & Nanocrystals Liposomes Solid Lipid Nanoparticles Nanotubes & Nanowires Polymeric Nanoparticles. Benefits of Polymer Systems.
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Polymeric Nano-Systems Used in Drug Delivery Arsen Simonyan SUNY-ESF
Types of Nano-Sized Drug Delivery Vehicles • Nanosuspensions & Nanocrystals • Liposomes • Solid Lipid Nanoparticles • Nanotubes & Nanowires • Polymeric Nanoparticles
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
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
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
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
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
Hydrogels Benefits - 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
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
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
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
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