Skip to Main Content
Frequently Asked Questions
Submit an ETD
Global Search Box
Need Help?
Keyword Search
Participating Institutions
Advanced Search
School Logo
Files
File List
osu1127403022.pdf (5.7 MB)
ETD Abstract Container
Abstract Header
Receptor-mediated DNA-based therapeutics delivery
Author Info
Chiu, Shihjiuan
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=osu1127403022
Abstract Details
Year and Degree
2005, Doctor of Philosophy, Ohio State University, Pharmacy.
Abstract
The objective of this dissertation was to develop and evaluate receptor-mediated non-viral delivery systems for DNA-based therapeutics. Novel strategies might prove critical for the in-vivo performance of receptor-targeted vectors. Continued efforts in optimization of receptor-mediated delivery systems may lead to the development of tumor-specific vehicles for DNA-based therapeutics delivery and promote the advancement of clinical translation of cancer gene therapy. In Chapter 2, a non-viral, PEI-based, HER2-targeted gene transfer vector was developed. The anti-HER2 antibody (Herceptin®) was conjugated to PEI and polyplexes were shown to selectively deliver plasmids to HER2-overexpressing cells with high resistance to serum. Herceptin/PEI polyplexes exhibited promising HER2-receptor-specific gene transfer properties. In Chapter 3, an ethanol dilution method for the preparation of ODN was developed. This method provides a suitable platform to prepare receptor-targeted-ODN-containing liposomes. The small size, low toxicity, and, more importantly, high encapsulation efficiency of ODNs at optimized conditions are important characteristics for the development of DNA-based therapeutics delivery systems. In the next two chapters, similar method was applied to other systems including ODNs and siRNAs with high molecular weight target-ligands. The aim of Chapter 4 was to develop a targeted ODN(G3139)-containing liposome formulation that can efficiently and specifically delivery ODNs to leukemias. Transferrin receptors were overexpressed in many tumor and leukemia cells. A Tf-targeted liposomal formulation of antisense G3139 was evaluated in K562 leukemia cells, which exhibited excellent characteristics in terms of particle size, loading efficiency, colloidal stability, and vehicle toxicity. Furthermore, this formulation was very efficient in antisense delivery, showing excellent bcl2 down-regulation efficiency and TfR specificity. In Chapter 5, similar strategy was applied to siRNA delivery. Desferrioxamine(DFO) was used to up-regulate TfR in K562 cells. The data demonstrated that DFO pretreatment increased the uptake of TfR-targeted siRNA in K562 cells and exhibited higher luciferase downregulation effect. Tf-targeted siRNA formulation with DFO pretreatment was a highly efficient delivery vehicle for siRNA for leukemias that express TfR. This formulation provides the prospect of more selective targeting effect in association with increased intracellular concentrations in target cells. More future studies such as optimization and in-vivo studies are needed for this formulation to work clinically.
Committee
Robert Lee (Advisor)
Pages
181 p.
Subject Headings
Health Sciences, Pharmacy
Keywords
Gene delivery
;
antisense delivery
;
Her2
;
Herceptin
;
Folate
;
Transferrin
;
targeted delivery
Recommended Citations
Refworks
EndNote
RIS
Mendeley
Citations
Chiu, S. (2005).
Receptor-mediated DNA-based therapeutics delivery
[Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1127403022
APA Style (7th edition)
Chiu, Shihjiuan.
Receptor-mediated DNA-based therapeutics delivery.
2005. Ohio State University, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=osu1127403022.
MLA Style (8th edition)
Chiu, Shihjiuan. "Receptor-mediated DNA-based therapeutics delivery." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1127403022
Chicago Manual of Style (17th edition)
Abstract Footer
Document number:
osu1127403022
Download Count:
1,055
Copyright Info
© 2005, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.