Engineering PLGA particles for advanced drug delivery Public Deposited

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Last Modified
  • March 20, 2019
Creator
  • Enlow, Elizabeth
    • Affiliation: College of Arts and Sciences, Department of Chemistry
Abstract
  • Many effective therapeutics fail to meet their full potential in vivo due to toxic side effects, degradation under physiological conditions, poor bioavailability, and/or poor accumulation at the site of disease which has led to the development of particulate drug carriers. Of particular interest are biodegradable polymer particles which can be tailored to meet a wide range of needs, are biocompatible and leave no residuals in vivo. Herein the fabrication of engineered poly(lactic acid-co-glycolic acid) (PLGA) nanoparticles via the PRINT (Particle Replication In Non-wetting Templates) process is reported. Complete control of size, shape, and composition was demonstrated. Biodistribution characterization of PLGA PRINT nanoparticles showed 10-15% tumor accumulation, suggesting these particles would make excellent drug delivery vehicles for advanced cancer therapy. Two approaches to cancer therapy were investigated: RNAi therapy and chemotherapy. These two therapies have different modes of action, different delivery requirements, and different cargo sensitivities. By exploring these dissimilar systems the true versatility of the PRINT process is demonstrated. To demonstrate gene delivery, nanoparticles were loaded with siRNA and knockdown was measured in vitro. Particles with poly(ethyleneimine) (PEI) as a complexing agent achieve knockdown with an EC50 of 184 nM, while particles coated with lipid achieve knockdown with an EC50 of 7 nM, rivaling the best systems reported. To illustrate chemotherapeutic efficacy, nanoparticles were fabricated with high and efficient loadings of docetaxel, up to 40% (w/w) with encapsulation efficiencies >90%. These particles display cellular toxicity at sub-femtomolar docetaxel concentrations, displaying better in vitro efficacy than the standard of care, Taxotere. In vivo these particles were shown to delay tumor progression in a xenograft mouse model. Fabrication of PLGA particles via the PRINT process enables independent control of particle properties (size, shape, cargo, polymer molecular weight, polymer lactic acid to glycolic acid ratio, and stabilizer) leading to a higher degree of tailorability than traditional methods and is versatile enough to be applied to dissimilar therapeutics. This system therefore shows great promise as a platform drug delivery technology.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry."
Advisor
  • DeSimone, Joseph M.
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  • Chapel Hill, NC
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  • Open access
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