Development of Nanomedicine to Simultaneously Target Pancreatic Cancer Cells and Stroma

Abstract

Dense desmoplastic stroma is a fundamental characteristic of pancreatic ductal adenocarcinoma (PDAC) and comprises up to 80% of the tumor mass, which acts as a barrier that impedes the delivery of antitumor drugs into the tumor microenvironment and reduces the therapeutic efficacy. The objective of this dissertation is to develop combination therapies for pancreatic cancer by simultaneously targeting pancreatic cancer cells and the stroma. In Chapter 1, we briefly introduce the background of the dissertation research and present the Statement of the Problems and Objectives. In Chapter 2, we review the epidemiology of pancreatic cancer and the widely used diagnoses and treatments. Also, the role of desmoplasia in pancreatic cancer progression and the therapeutics targeting the desmoplastic stroma are discussed. In Chapter 3, we report a novel biodegradable copolymer to co-deliver LY2109761 (a TGF-β receptor I/II inhibitor) and CPI-613 (a novel chemotherapy agent) to desmoplastic stroma and tumor cells, respectively, in the pancreatic tumor microenvironment. Hydrophobic CPI-613 is conjugated to the hydrophilic copolymer via a newly designed MMP-2-responsive linker to form a tumor-responsive nanopolyplex. LY2109761 is hydrophobic and encapsulated into the hydrophobic core of the nanopolyplex. The resulting nanopolyplex is modified with a plectin-1-targeting peptide to enhance the accumulation of the nanopolyplex in pancreatic tumors. The nanopolyplex aims to normalize the stroma by blocking the interaction between tumor cells and pancreatic stellate cells to inhibit the activation of pancreatic stellate cells and subsequently reduce the dense extracellular matrix. Normalized stroma increases the penetration of the nanopolyplex into the tumor. The nanopolyplex shows enhanced accumulation in xenograft pancreatic tumors in a biodistribution study. Moreover, the targeted nanopolyplex markedly inhibits tumor growth in an orthotopic pancreatic cancer mouse model by dual-targeting tumor cells and stroma. Overall, the multifunctional nanopolyplex is a promising platform for pancreatic cancer therapy. In Chapter 4, we provide a strategy to allow chemotherapy to kill the tumor cells in “nest” after normalization of the stroma. We first demonstrate that silencing the poly (rC)-binding protein (PCBP2) gene using an siRNA reverses the accumulation of type I collagen in human pancreatic stellate cells (PSCs) and NIH 3T3 fibroblasts. A micro-flow mixing method is developed to fabricate a core-stabilized PCBP2 siRNA nanocomplex to reverse the accumulation of type I collagen in pancreatic cancer tumor stroma. The siRNA nanocomplex significantly reduces ECM production and enhances drug penetration through desmoplastic tumor stroma. The combination of gemcitabine with the PCBP2 siRNA nanocomplex markedly suppresses the tumor progression in a desmoplastic pancreatic orthotopic mouse model. This work provides a new therapeutic avenue to improve the antitumor efficacy of pancreatic cancer therapies by normalizing the tumor stroma using the PCBP2 siRNA nanocomplex.