dc.creator | Evans, Brian Connor | |
dc.date.accessioned | 2020-08-21T21:13:38Z | |
dc.date.available | 2017-04-05 | |
dc.date.issued | 2015-04-05 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-03182015-162324 | |
dc.identifier.uri | http://hdl.handle.net/1803/10864 | |
dc.description.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. | |
dc.format.mimetype | application/pdf | |
dc.subject | intimal hyperplasia | |
dc.subject | peptide | |
dc.subject | drug delivery | |
dc.subject | endosomal escape | |
dc.subject | polyplex | |
dc.subject | nanoparticle | |
dc.title | Development of pH-responsive nano-polyplexes for intracellular delivery of therapeutic biomacromolecules | |
dc.type | dissertation | |
dc.contributor.committeeMember | Todd Giorgio | |
dc.contributor.committeeMember | Hak-Joon Sung | |
dc.contributor.committeeMember | Colleen Brophy | |
dc.contributor.committeeMember | James Goldenring | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Biomedical Engineering | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2017-04-05 | |
local.embargo.lift | 2017-04-05 | |
dc.contributor.committeeChair | Craig L. Duvall | |