Design of poly (alkylene oxide) graft copolymer chemistries for improved antisense drug delivery
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Peddada, Lavanya Y..
Design of poly (alkylene oxide) graft copolymer chemistries for improved antisense drug delivery. Retrieved from
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TitleDesign of poly (alkylene oxide) graft copolymer chemistries for improved antisense drug delivery
Date Created2012
Other Date2012-01 (degree)
Extentxvi, 100 p. : ill.
DescriptionGene-based therapies hold tremendous promise to treat conditions such as cancer, muscular dystrophy, and cardiovascular disease. Non-viral carriers consisting of synthetic and natural cationic polymers, liposomes, and non-ionic copolymer micelles have demonstrated moderate success in overcoming some of the delivery challenges. At the systemic level, the issues of drug degradation in the bloodstream and poor pharmacological distribution to target disease site exist. At the cellular level, the key barrier involves escape of the carrier and therapeutic cargo from the degradative endolysosomal pathway. Efforts have been made to understand and to design carrier chemistries based on physical properties including particle size, particle surface charge, degree of carrier hydrophilicity/hydrophobicity, polymer conformation, etc. To date, clear design rules based on physicochemical properties have not emerged. Previously, our group has formulated a multi-component liposome-based carrier system that efficiently delivers antisense oligonucleotide in the absence of serum, but which is considerably less active in the presence of serum. This motivated us to improve the existing carrier chemistry for improved delivery in the presence of extracellular nucleases and serum proteins, while maintaining the function of evading intracellular barriers. In this dissertation, we provide a comprehensive evaluation of graft copolymers consisting of poly (propylacrylic acid) and poly (alkylene oxide) chemistries with varying degrees of hydrophobicity to hydrophilicity, and describe the influence of this parameter on liposome-mediated antisense gene delivery. First, various steps involved in the antisense gene delivery process including serum-stability, membrane penetration, and endosome membrane lysis was evaluated in vitro. Secondly, we address the hypothesis that liposomes stabilized with poly (alkylene oxide) graft copolymers can improve biodistribution by using a tumor xenograft model that allows us to relate biodistribution profiles to nanoparticle size, surface charge, and polymer architecture. Our findings indicate that the balance of polymer hydrophobicity to hydrophilicity plays a key role in dictating serum-stability and cellular entry in vitro, as well as fate of antisense in vivo.
NotePh.D.
NoteIncludes bibliographical references
NoteIncludes vita
Noteby Lavanya Y. Peddada
Genretheses, ETD doctoral
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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