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Title page for ETD etd-03182015-162324


Type of Document Dissertation
Author Evans, Brian Connor
Author's Email Address brian.c.evans@vanderbilt.edu
URN etd-03182015-162324
Title Development of pH-responsive nano-polyplexes for intracellular delivery of therapeutic biomacromolecules
Degree PhD
Department Biomedical Engineering
Advisory Committee
Advisor Name Title
Craig L. Duvall Committee Chair
Colleen Brophy Committee Member
Hak-Joon Sung Committee Member
James Goldenring Committee Member
Todd Giorgio Committee Member
Keywords
  • intimal hyperplasia
  • peptide
  • drug delivery
  • endosomal escape
  • polyplex
  • nanoparticle
Date of Defense 2015-03-16
Availability unrestricted
Abstract
Peptide-based therapeutics hold significant therapeutic potential for use in a variety of clinical applications ranging from cancer to cardiovascular disease. However, the potential of peptide-based therapeutics is limited due to poor cellular uptake and peptide sequestration within endo-lysomal vesicles that are trafficked for exocytosis or lysosomal degradation resulting in an attenuated therapeutic half-life. The drug delivery platform described herein provides a means to overcome these barriers through the use of cell-permeant, pH-responsive nanoparticles that significantly enhance cell internalization and facilitate endosomal escape of cationic, therapeutic peptides. A reproducible method to synthesize electrostatically complexed nanoparticles, or nano-polyplexes, containing a therapeutic peptide and a pH-responsive polymer has been developed and optimized with several therapeutic peptides. The translatability of this peptide delivery technology was demonstrated through the enhanced uptake, retention, and therapeutic efficacy of nano-polyplexes formulated with a MAPKAP Kinase 2 inhibitory peptide applied as prophylactic treatment to prevent vein bypass graft intimal hyperplasia ex vivo in human saphenous vein and in vivo in a rabbit vein graft interposition model. The modular nature of this intracellular peptide delivery platform was subsequently demonstrated through the enhanced therapeutic efficacy of two vasoactive peptides formulated into nano-polyplexes and applied to prevent pathological vasoconstriction, or vasospasm, in human vascular tissue. This nano-polyplex technology provides a simple, translational method to effectively enhance intracellular delivery of cytosolically-active peptides and demonstrates a potentially high-impact therapeutic approach to preventing vasospasm and improving graft patency in vascular bypass grafting applications.
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