Graduation Date

Spring 5-9-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Ram I. Mahato

Abstract

The ineffective delivery of genes and drugs have become a big obstacle for the treatment of cancer, due to either poor stability or low aqueous solubility. In the first part, A ROS responsive polymer named poly(ethylene glycol)–poly[aspartamidoethyl(p-boronobenzyl)diethylammonium bromide] (PEG-B-PAEBEA) was developed for codelivery miR-34a mimic and small molecule PLK1 inhibitor volasertib (BI6727) for the treatment of pancreatic ductal adenocarcinoma (PDAC), since tumor suppressor microRNA-34a (miR-34a), which targets many oncogenes related to proliferation, apoptosis, and invasion is significant downregulated while Polo-like kinase 1 (PLK1) closely associated with short survival rates of pancreatic cancer patients is remarkably upregulated . In part 2, due to increased number of cancer stem cells (CSCs), a pH and glutathione (GSH) sensitive delivery system, fabricated by DTX and a pH responsive diisopropylamino ethanol and GSH responsive RUB prodrug conjugated polycarbonate DTX loaded P-RUBs (DTX/P-RUBs), was developed to overcome the chemoresistance by targeting both of tumor bulk cells and CSCs. Rubone (RUB) is a miR-34a activator which is downregulated in CSCs. Fast release of DTX and RUB in the cytoplasm after endocytosis could upregulate the intracellular miR-34a, which then affected the expression of proteins involved in chemoresistance, thus sensitizing the tumor cells towards DTX and further leading to significant inhibition of TXR tumor progression. Thus, DTX/P-RUBs has the potential to treat TXR prostate cancer. By taking advantage of this dual responsive strategy, the successful delivery of many other hydrophobic drugs can be achieved for cancer treatment.

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