| 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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| Files |
| Filename |
Size |
Approximate Download Time
(Hours:Minutes:Seconds)
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56K Modem |
ISDN (64 Kb) |
ISDN (128 Kb) |
Higher-speed Access |
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Evans.pdf |
12.59 Mb |
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