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Receptor-mediated DNA-based therapeutics delivery.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Receptor-mediated DNA-based therapeutics delivery./
Author:	Chiu, Shih-Jiuan.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2005,
Description:	181 p.
Notes:	Source: Dissertations Abstracts International, Volume: 67-08, Section: B.
Contained By:	Dissertations Abstracts International67-08B.
Subject:	Pharmaceuticals. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3193283
ISBN:	9780542373213

Receptor-mediated DNA-based therapeutics delivery.
Chiu, Shih-Jiuan.

Receptor-mediated DNA-based therapeutics delivery. - Ann Arbor : ProQuest Dissertations & Theses, 2005 - 181 p.

Source: Dissertations Abstracts International, Volume: 67-08, Section: B.

Thesis (Ph.D.)--The Ohio State University, 2005.

This item must not be sold to any third party vendors.

The overall objective of this dissertation was to develop and evaluate receptor-mediated non-viral delivery systems for DNA-based therapeutics. Novel strategies, such as covalent vector stabilization and PEGylation of the vector, might prove critical for the in vivo performance of receptor-targeted vectors. Continued efforts in optimization of receptor-mediated delivery systems will likely 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 (trastuzumab, 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, a modified ethanol dilution method for the preparation of ODN was developed. DC-Chol was chosen as the cationic lipid due to its unique charge property in different pH. Combining with PEG-derivatives, this formulation can avoid some problems including rapid circulation elimination occurred on cationic ODN-liposomal formulations. This method provides a suitable platform to prepare ODN-containing liposomes. The small size, near-neutral charge, 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 antisense delivery systems including ODNs and siRNAs with a high molecular weight ligand. 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, especially those rapidly proliferating tumor 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 downregulation efficiency and TfR specificity. In Chapter 5, similar strategy was applied to siRNA delivery. DFO was used to upregulate 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.

ISBN: 9780542373213Subjects--Topical Terms:

3562593
Pharmaceuticals.
Subjects--Index Terms:

Gene delivery

Receptor-mediated DNA-based therapeutics delivery.
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500 $a Advisor: Lee, Robert J.
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506 $a This item must not be added to any third party search indexes.
520 $a The overall objective of this dissertation was to develop and evaluate receptor-mediated non-viral delivery systems for DNA-based therapeutics. Novel strategies, such as covalent vector stabilization and PEGylation of the vector, might prove critical for the in vivo performance of receptor-targeted vectors. Continued efforts in optimization of receptor-mediated delivery systems will likely 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 (trastuzumab, 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, a modified ethanol dilution method for the preparation of ODN was developed. DC-Chol was chosen as the cationic lipid due to its unique charge property in different pH. Combining with PEG-derivatives, this formulation can avoid some problems including rapid circulation elimination occurred on cationic ODN-liposomal formulations. This method provides a suitable platform to prepare ODN-containing liposomes. The small size, near-neutral charge, 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 antisense delivery systems including ODNs and siRNAs with a high molecular weight ligand. 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, especially those rapidly proliferating tumor 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 downregulation efficiency and TfR specificity. In Chapter 5, similar strategy was applied to siRNA delivery. DFO was used to upregulate 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.
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