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Multifunctional Natural Material-based Delivery Systems for Gene Therapy

Tang, Qiong
http://rave.ohiolink.edu/etdc/view?acc_num=akron1415382826

Abstract Details

2014, Doctor of Philosophy, University of Akron, Chemical Engineering.
Gene therapy has drawn significant interest in the past two decades since it provides promising strategies to treat both genetic disorders and acquired diseases. However, the transfer of gene therapy to clinical applications is troubled with many difficulties, since many current systems are concerned with toxicity, insufficient drug loading, inefficient targeting, low transfection efficiency and low biodegradability. To address these challenges, I developed a series of integrated and biodegradable drug delivery platforms which incorporate multiple functional moieties that are desired for successful gene drug delivery into one natural material. Firstly, an integrated peptide-based vector with desired functions for targeted gene delivery, K12H6V8SSQHWSYKLRP (KHV-LHRH), was developed for the first time. The results showed that KHV-LHRH induced significantly higher gene expression than KHV in LHRH-receptor positive MCF-7 cells with lower cytotoxicity compared with Polyethylenimine (PEI). Secondly, for our first report, a small molecule-peptide hybrid as a gene drug vector with high transfection efficiency was developed. Four amphiphilic cholesterol-peptide conjugates (Ch-R5H5, Ch-R3H3, Ch-R5 and Ch-R5) were evaluated in vitro to understand the structure-property-function relationship of this gene delivery system. Among all four, Ch-R5H5 loading drugs achieved the highest luciferase expression level which was comparable or even higher than that induced by PEI. Thirdly, we developed the first co-delivery system to simultaneously deliver an anticancer drug and a gene drug for multidrug resistant cancer chemotherapy. Having an anticancer drug camptothecin (CPT) as the hydrophobic moiety in the amphiphilic prodrug (CPTssR5H5), the drug loading content for both drugs was greatly increased. In the CPTssR5H5 system, drugs could be control-released and achieved enhanced therapeutic effect. Finally, we developed, for the first time, a dextran-peptide hybrid as a gene drug delivery vector with high transfection efficiency and low cytotoxicity. Dextran, with different molecular weight, was conjugated with a cationic peptide, R5H5, at various degrees of substitution. In vivo study showed that Dex-R5H5/DNA, with low molecular weight of dextran and at high substitution of R5H5 (40%), achieved greater gene expression than PEI/DNA at low vector/drug ratio with minimal cytotoxicity, which indicated this platform may be a promising delivery system for safe and efficient gene therapy.
Gang Cheng, Dr. (Advisor)
Liu Lingyun, Dr. (Committee Member)
Zheng Jie, Dr. (Committee Member)
Zhang Ge, Dr. (Committee Member)
John Senko, Dr. (Committee Member)
140 p.
Chemical Engineering
drug delivery; biomaterials; multifunctional; biodegradability; natural materials; gene therapy

Recommended Citations

Citations

  • Tang, Q. (2014). Multifunctional Natural Material-based Delivery Systems for Gene Therapy [Doctoral dissertation, University of Akron]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=akron1415382826

    APA Style (7th edition)

  • Tang, Qiong. Multifunctional Natural Material-based Delivery Systems for Gene Therapy. 2014. University of Akron, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=akron1415382826.

    MLA Style (8th edition)

  • Tang, Qiong. "Multifunctional Natural Material-based Delivery Systems for Gene Therapy." Doctoral dissertation, University of Akron, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=akron1415382826

    Chicago Manual of Style (17th edition)

akron1415382826
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© 2014, all rights reserved.
This open access ETD is published by University of Akron and OhioLINK.