Access Type

Open Access Dissertation

Date of Award

January 2017

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmaceutical Sciences

First Advisor

Olivia Merkel

Abstract

Gene therapy is thought to be a solution for various difficult to treat diseases such as cancer. Small interfering RNA (siRNA) as a promising anti-sense molecule can specifically silence disease related gene have been exploit in different diseases. However, lack of safe and efficient siRNA delivery systems limits the application of siRNA therapy in clinic. Transferrin receptor (TfR) is an essential transmembrane receptor involved in iron uptake. TfR universally express in most cells/ tissues but upregulated in certain cells, for example, many cancer cells and activated T cells (ATCs). To overcome the biological barriers and increase siRNA delivery efficiency, in this dissertation, various TfR targeted siRNA delivery systems have been developed. Holo-Tf and TfR binding peptide were conjugated to polyethylenimine (PEI), an efficient gene delivery polymer, via different crosslinkers. Tf-PEI was evaluated in asthma model and breast cancer model. Tf-PEI polyplexes demonstrated satisfactory physicochemical properties and selectivity to cells overexpressing TfR (e.g. basal like breast cancer cells and ATCs). Tf-PEI can achieve efficient gene knockdown ex vivo and targeted delivery to ATCs in asthma model via pulmonary delivery. Peptide-PEI was evaluated in lung cancer model. Peptide-PEI can selectively deliver siRNA to lung cancer cells overexpressing TfR and achieve efficient GAPDH gene knockdown. In conclusion, the present study described the feasibility to efficiently deliver siRNA to ATCs in asthma and cancer cells in various cancer model via targeting TfR. This results could help to develop an efficient delivery system of siRNA for asthma therapy and cancer therapy.

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