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Title Biodegradable polymeric delivery systems for protein subunit vaccines
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Publication Date
Date Accessioned
Degree PhD
Discipline/Department Biomedical Engineering
Degree Level doctoral
University/Publisher Georgia Tech
Abstract The prevention and treatment of cancer and infectious diseases requires vaccines that can mediate cytotoxic T lymphocyte-based immunity. A promising strategy is protein subunit vaccines composed of purified protein antigens and immunostimulatory adjuvants, such as Toll-like receptor (TLR) agonists. In this research, we developed two new biodegradable polymeric delivery vehicles for protein antigens and TLR agonists, as model vaccine delivery systems. This work was guided by the central hypothesis that an effective vaccine delivery system would have stimulus-responsive degradation and release, biodegradability into excretable non-acidic degradation products, and the ability to incorporate various TLR-inducing adjuvants. The first vaccine delivery system is a cross-linked polyion complex micelle which efficiently encapsulates proteins, DNA, and RNA. The micelle-based delivery system consists of a block copolymer of poly(ethylene glycol) (PEG) and poly(L-lysine), cross-linked by dithiopyridyl side groups to provide transport stability and intracellular release. The second delivery system consists of solid biodegradable microparticles encapsulating proteins, nucleic acids, and hydrophobic compounds. The microparticles are composed of pH-sensitive polyketals, which are a new family of hydrophobic, linear polymers containing backbone ketal linkages. Polyketals are synthesized via a new polymerization method based on the acetal exchange reaction and degrade into non-acidic, excretable degradation products. In addition, the technique of hydrophobic ion pairing was utilized to enhance the encapsulation of ovalbumin, DNA, and RNA in polyketal microparticles via a single emulsion method. Using in vitro and in vivo immunological models, we demonstrated that the micelle- and polyketal-based vaccine delivery systems enhanced the cross-priming of cytotoxic T lymphocytes. The model vaccines were composed of ovalbumin antigen and various TLR-inducing adjuvants including CpG-DNA, monophosphoryl lipid A, and dsRNA. The results demonstrate that the cross-linked micelles and polyketal microparticles have considerable potential as delivery systems for protein-based vaccines.
Subjects/Keywords Vaccine delivery; Drug delivery; Microencapsulation; Nanospheres; Microspheres; Nanoparticles; Polyacetal; PH-responsive; TLR ligands; Poly(I)-poly(C); Acid-degradable; Vaccines; Polymeric drug delivery systems; Biodegradable plastics
Contributors Dr. Niren Murthy (Committee Chair); Dr. Carson Meredith (Committee Member); Dr. Julia Babensee (Committee Member); Dr. Mark Prausnitz (Committee Member); Dr. Ravi Bellamkonda (Committee Member)
Country of Publication us
Record ID handle:1853/24787
Repository gatech
Date Indexed 2020-05-13
Issued Date 2008-06-17 00:00:00
Note [degree] Ph.D.; [advisor] Committee Chair: Dr. Niren Murthy; Committee Member: Dr. Carson Meredith; Committee Member: Dr. Julia Babensee; Committee Member: Dr. Mark Prausnitz; Committee Member: Dr. Ravi Bellamkonda;

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