Synthesis and Characterization of Environmentally Responsive Lipid-Nucleic Acid Complexes for Applications in Gene Delivery and Biomaterials
- Degree Grantor:
- University of California, Santa Barbara. Chemistry
- Degree Supervisor:
- Kevin Plaxco and Cyrus R. Safinya
- Place of Publication:
- [Santa Barbara, Calif.]
- Publisher:
- University of California, Santa Barbara
- Creation Date:
- 2012
- Issued Date:
- 2012
- Topics:
- Engineering, Materials Science and Chemistry, Biochemistry
- Genres:
- Online resources and Dissertations, Academic
- Dissertation:
- Ph.D.--University of California, Santa Barbara, 2012
- Description:
Environmentally responsive materials, i.e., materials that are designed to react to changes in their environment with a modification in their properties or structure, draw growing interests especially for synthetic materials for gene therapy and biomaterials applications. In this work, environmentally responsive lipid materials are designed to be responsive to (i) reducing milieu of the cytoplasm and (ii) low pH of late endosome. (i) The cleavable multivalent lipids (CMVLs) are designed with a disulfide bond in the linker between cationic headgroup and hydrophobic tails. CMVLs are designed to show the effect of lipid-nucleic acid complexes degradation in cytoplasm on nucleic acid delivery and cytotoxicity (ii) An acid-labile PEG-lipid (HPEG2K-lipid) capable of losing PEG chains at the pH of late endosomes is tailored for optimum circulation lifetime of liposomes as well as efficient endosomal release. Here, the efficient synthesis is presented as well as extensive characterization of the series of tailored cleavable multivalent lipids (CMVLn, with n = 2 to 5 the number of positive headgroup charges at full protonation). The self-assembled complexes of the CMVLs and DNA are a prototypical environmentally responsive material, undergoing extensive structural rearrangement when exposed to reducing agents. CMVL-DNA complexes are employed as carriers for nucleic acids in DNA transfection as well as small interfering RNA silencing experiments. The employment of CMVLs in complexes with nucleic acids presents the effect of CMVLs degradation on cytotoxicity, DNA transfection as well as siRNA silencing efficiency. The investigation of structural evolution of CMVL-DNA complexes at varied complex composition, temperature and incubation time was assessed employing small-angle X-ray scattering (SAXS) and wide-angle X-ray scattering (WAXS).
- Physical Description:
- 1 online resource (278 pages)
- Format:
- Text
- Collection(s):
- UCSB electronic theses and dissertations
- Other Versions:
- http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3545093
- ARK:
- ark:/48907/f3dn4318
- ISBN:
- 9781267767929
- Catalog System Number:
- 990039148200203776
- Copyright:
- Rahau Shirazi, 2012
- Rights:
- In Copyright
- Copyright Holder:
- Rahau Shirazi
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