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Title page for ETD etd-11172016-131552


Type of Document Master's Thesis
Author Jackson, Meredith Allyn
URN etd-11172016-131552
Title Exploring Zwitterionic Coronas as Alternatives to Traditional PEG Architectures for Improved siRNA Polyplex Pharmacokinetics and Tumor Delivery
Degree Master of Science
Department Biomedical Engineering
Advisory Committee
Advisor Name Title
Craig L. Duvall, Ph.D. Committee Member
Todd D. Giorgio, Ph.D. Committee Member
Keywords
  • siRNA
  • pharmacokinetics
  • zwitterionic materials
  • polyplexes
  • drug delivery
Date of Defense 2016-11-15
Availability unrestricted
Abstract
Although siRNA-based therapeutics hold great promise for systemic cancer treatment, polyplex nanocarrier systems face many intravenous challenges that limit their pharmacokinetic potential and therefore reduce tumor accumulation. While PEGylation has been traditionally applied to improve in vivo polyplex stability, alternative “stealth” coronas have recently emerged, including zwitterionic coronas and brush-like PEG architectures. We are the first to compare zwitterionic phosphorylcholine-based surface chemistries to linear and brush-like PEG architectures in the context of in vivo pharmacokinetics and tumor delivery of siRNA polyplexes. A library of six polymers was created, all containing the same pH-responsive, endosomolytic core block but different corona blocks including 5kDa and 20kDa linear PEG, 10kDa and 20kDa brush-like PEG (POEGMA), and 10kDa and 20kDa zwitterionic phosphorylcholine-based polymers (MPC). In vitro, it was found that 20kDa PEG and 20kDa MPC had superior stability properties and reduced protein adsorption compared to other polymers. In vivo, 20kDa PEG and 20kDa MPC both extended average early-phase polyplex half-lives to ~25 minutes, but zwitterionic MPC-based polyplexes exhibited significantly better in vivo luciferase knockdown and tumor uptake. Thus, our results show that zwitterionic polyplex coronas significantly improve siRNA delivery to tumors over traditional PEG architectures.
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