Successful treatment of pancreatic cancer remains a challenge due to the presence of pronounced desmoplastic tumor microenvironment and emergence of chemoresistance resulting in recurrence and metastatic spread. Gemcitabine shows only limited efficacy due to its inefficient delivery to tumor because of its hydrophilicity and rapid metabolism and also due to the activity of cancer stem cells (CSCs), which are regulated by miRNAs. In our preliminary studies, gemcitabine was conjugated to poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate) (PEG- PCC) and formulated into micelles which significantly inhibited tumor growth compared to free drug when injected intravenously into pancreatic tumor bearing NSG mice. To achieve complete tumor regression, we identified miR-205 among a series of dysregulated miRNAs from the CSCs isolated from gemcitabine resistant MIA PaCa-2R cells and human pancreatic cancer tissues, to be significantly downregulated and playing a predominant role in regulating cell growth, epithelial to mesenchymal transition (EMT) and resistance. Transfection of MIA PaCa-2R cells with miR-205 mimic resulted in the restoration of chemosensitivity to gemcitabine. Then, we synthesized gemcitabine conjugated poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft- dodecanol-graft-tetraethylenepentamine) copolymer having cationic chains for polyplex formation with miR-205 mimic which showed improved stability in fetal bovine serum and efficiently transfected and reversed chemoresistance, invasion and metastasis in gemcitabine resistant cells. Therefore, we hypothesize that co-formulation of miR-205 mimic with gemcitabine may effectively treat pancreatic cancer by reversing the chemo-resistance of CSCs and simultaneously target bulk tumor cells as well. Major focus of the project is to: a) discover suitable miRNAs to target chemo-resistance and EMT (like miR205) in pancreatic cancer and b) co-deliver this miRNA with gemcitabine to the tumor using a actively targeted nanocarrier which can protect both these molecules from plasma degradation and ensure enhanced uptake.
Our specific aims are to i) identify the aberrantly expressed miRNAs and validate their role in chemoresistance, invasion and metastasis; ii) co- formulate miRNA and gemcitabine in polymeric micelles and assess their synergistic effect on the inhibition of pancreatic cancer and, iii) assess the synergistic action of micelles carrying gemcitabine and miRNA on the regression of human pancreatic tumor bearing mice. Significance of the project is to develop nanomedicines of miRNA mimic and gemcitabine that effectively increase local drug concentrations within the fibrotic stroma of these tumors and bypass the chemo-resistant mechanisms that allow tumor growth and inhibit the efficacy of current standard chemotherapies.
The combination of miRNA mimic with gemcitabine conjugated micelles will provide a novel treatment strategy for advanced pancreatic tumor whereby nano-sized micelles will enhance drug and miRNA stability in vivo and cetuximab based targeting shall increase their concentration and mean residence time within the tumor. Further, presence of miRNA mimic would sensitize the resistant cancer stem cells to gemcitabine chemotherapy.
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