Utility of two distinct macromolecular carriers for nucleic acid delivery Public Deposited

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Last Modified
  • March 21, 2019
Creator
  • An, John Sunghoon
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics
Abstract
  • The major crux of nucleic acid-based therapy is that nucleic acids are not naturally occurring outside the cell. The systems biology of humans has evolved to detect exogenous nucleic acids as a part of foreign pathogens with efficient mechanisms to destroy and eliminate the threat. Therefore, exogenous naked or unmodified nucleic acids are restricted to the site of their administration and hence are of limited clinical value. A means of delivering therapeutic concentrations of these macromolecules to the target site for a desirable period of time is, thus, an essential component in their development as medicines. This dissertation describes the origination of two differing approaches to achieve one specific goal, deliver nucleic acid based medicine to cancer cells. The first approach is a gold nanoparticle-based delivery carrier to actively target human derived nasopharyngeal carcinoma specifically over-expressing the folate receptor. Two derivatives were studied which led to the successful synthesis and characterization of the gold nanoparticle-based carrier. A new modular strategy was also developed utilizing some of the therapeutic oligonucleotide as a linker to attach folic acid targeting ligands for increased efficiency. Preliminary in vitro experiments failed to elicit a pharmacologic response. Further in vitro studies focusing on time-dependant uptake and cellular localization may identify the lack of efficacy. The second approach utilized endogenous albumin as a carrier for therapeutic oligonucleotides. Unlike exogenous macromolecular carriers that must undergo stringent testing to ensure human safety, binding to albumin using its natural ligand, fatty acid, ensures that the carrier is inert and nontoxic. It was proposed that preservation of both ionic and hydrophobic interactions of fatty acids is necessary to bind with high affinity to albumin. An amino (palmitic) acid analog was designed and synthesized in order to produce a handle to attach the therapeutic oligomer while preserving the ionic charge. Initial binding studies reveal a loss of affinity compared to the free palmitic acid, but superior to the currently marketed fatty acylated delivery system. Currently, studies are focusing on the affect of charge interactions in binding to albumin in order to develop a fatty acid analog with enhanced binding properties.
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  • In Copyright
Advisor
  • Cho, Moo J.
Degree granting institution
  • University of North Carolina at Chapel Hill
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  • Open access
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