Graduation Date

Spring 5-6-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Ram I. Mahato

Abstract

The aim of this thesis is to develop combination therapy using a small molecule and RNA including siRNA, shRNA, or miRNA inhibitor for the treatment of type 1 diabetes and prostate cancer. New amphiphilic biodegradable polymers capable of co-delivering small hydrophobic molecules and RNAs or human bone marrow-derived mesenchymal stem cell (hBMSC) for co-delivery of an shRNA and a miRNA inhibitor were used as drug delivery platform. The drug delivery properties were evaluated in vitro and in vivo islet transplantation, subcutaneous and orthotopic prostate cancer models.

In Chapter 1, an overview of prostate cancer, the role of miRNA and the way for regulating miRNA as well as the design of delivery systems is given. I also introduce a brief background of type 1 diabetes and the treatment methods. Chapter 2 discussed the treatment of early stage or advanced prostate cancer using a luteinizing hormone release hormone (LHRH) conjugated micelles for target delivery of CBDIV17 (a bicalutamide analog) or combination therapy using CBDIV17 and embelin (a XIAP inhibitor). In Chapter 2, subcutaneous model was used to prove our concept. Our results indicated that LHRH conjugated micelles carrying CBDIV17 or both CBDIV17 and embelin inhibited tumor cell growth in vitro and in vivo.

Chapter 3 reports the newly screened small molecule named rubone as a miR-34a modulator for combination therapy with paclitaxel to treat chemoresistant prostate cancer. This compound was first characterized for miR-34a modulation efficacy in paclitaxel resistant prostate cancer cell lines including DU145-TXR and PC3-TXR. The miR-34a downstream protein level and combination therapy efficacy were also evaluated. The biodegradable copolymer poly (ethylene glycol)-block-poly (2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol) (PEG-PCD) were used to co-deliver both drugs in an orthotopic prostate tumor model after characterizing the drug delivery properties. This combination therapy using rubone as a miR-34a modulator reversed the chemoresistance of prostate cancer and significantly inhibited paclitaxel-resistant tumor growth in vivo. Finally, we summarized the results for prostate cancer treatment and gives suggestions for further research.

Chapter 4 provided the background information about islet transplantation for treating type 1 diabetes. In Chapter 4, we constructed plasmid encoding shRNA against Fas receptor and miRNA inhibitor for downregulating miR-375. This plasmid was transfected to hBMSCs as an RNA delivery vehicle and hBMSC transferred these two small RNAs to human islet by direct touch and exosome. This stem cell-based gene therapy and cell therapy suppressed islet apoptosis and promoted islet function in vitro and in a humanized NOD scid gamma (NSG) mouse model. The immune reaction after islet transplantation was suppressed by intravenous injection of hBMSC and peripheral blood mononuclear cells (PBMC) co-cultured exosomes. We obtained a 100% insulin independence after humanization by intraperitoneal injection of PBMC.

Chapter 5 summarizes the results of this thesis and gives suggestions to further research.

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