Graduate Thesis Or Dissertation
 

Development of Micellar and Nanoparticle Structures based on Polyester Diblock Copolymer Platform for the Treatment of Metastatic Tumors

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/hd76s3616

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  • Poor aqueous solubility of a large number of newly discovered chemical entities is posing a significant challenge for the formulation industry and is delaying their drug development. The number of formulation techniques available to solubilize these poorly soluble molecules is very limited. In addition to that, traditional formulation methods involve the use of surfactants such as Cremophor EL and polysorbate 80 that trigger unwanted toxicities and the lack of proper targeting moieties is further hampering their in vivo efficacy. The search for alternate drug delivery systems that overcome these limitations and toxicity issues has therefore led to the use of polyester based diblock copolymers. Polyester based diblock copolymers have garnered tremendous interest in the past two decades for their applications in drug delivery. These block copolymers comprise of a hydrophilic and hydrophobic segments and they readily self-assemble into micellar and nanoparticle structures in aqueous solvents. The ability to modify their surface properties by mixing different copolymers along with their capability to load multiple poorly soluble drug entities into their hydrophobic cores have made them highly sought after in the formulation industry. The polyesters are biodegradable and are approved by the FDA for use in drug delivery purposes. This work encompasses the development of a micellar and a nanoparticle formulation using polyester based diblock copolymers for the delivery of multiple chemotherapeutic agents and imaging applications. The lack of a delivery system that can achieve substantial lymphatic accumulation has motivated us in developing a poly (ethylene glycol)-block-poly (ε-caprolactone) [PEG-b-PCL] nanoparticle system that can simultaneously load three drugs at therapeutically relevant concentrations and also achieve significant lymphatic accumulation, courtesy of its modified surface properties. The efficacy of the developed nanoparticle system was evaluated in its ability to reduce the proliferation of melanocytes in metastatic melanoma mice models. We were able to develop locally acting and centrally acting drug loaded nanoparticles that effectively reduced melanocyte proliferation. We then wanted to demonstrate the diagnostic applications of these nanostructures and therefore developed a methoxy poly (ethylene glycol)-block-poly (lactic acid) mPEG-b-PLA micelle formulation that encapsulates a nerve specific fluorophore BMB. The micellar formulation of BMB achieved significantly higher nerve specific accumulation and fluorescence intensity when compared to its traditional formulation in DMSO and also prevented the unwanted side effects occurring from the formulation excipients. The micellar BMB formulation was a first of its kind as no previous nerve visualization techniques were clinically approved. Finally, we also developed a mPEG-b-PLA micellar formulation that encapsulates two drugs that target the major pathways involved in ovarian cancer and prevent tumor progression by exhibiting synergistic effects. The combination therapy proved more beneficial in reducing the tumor burden in animal models compared to the individual drugs and also reduced the development of drug resistance by inhibiting multiple pathways. We have thus effectively demonstrated the therapeutic and diagnostic applications of micellar and nanoparticle platforms developed from polyester based diblock copolymers in treating metastatic diseased states
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file details DoddapaneniBhuvanaS2016.pdf 2017-08-22 Público Baixar