Abstract B67: Stroma breaking dual targeted theranostic nanoparticles for image-guided and targeted therapy of pancreatic cancer
Authors: Zhou Hongyu , Guo Xiangxue , Qian Weiping , Uckun Fatih M. , Wang Liya , Wang Y Andrew , Chen Hongyu , Kooby David A. , Lipowska Malgorzata , Staley Charles A. , Yang Lily 
Published: December 2016

Abstract
Low efficiency in drug delivery into pancreatic cancer cells due to the presence of a dense fibrotic tumor stromal barrier has been the major unmet clinical challenge for pancreatic cancer treatment. Drug delivery stromal barriers include irregular and insufficient tumor blood vessels, extensive fibroblasts, massive infiltration of tumor associated macrophages, and enriched fibrous stromal matrix. Building upon our understanding of pancreatic cancer biology and expertise in developing theranostic nanoparticles, we have developed a stroma breaking drug delivery nanoparticle platform with dual receptor targeting ability and protease activity for overcoming the above stromal barriers. Targeting urokinase plasminogen activator receptor (uPAR) that is expressed in angiogenic tumor endothelial cells, tumor stromal fibroblasts and macrophages, and invasive tumor cells facilitates nanoparticle extravasation, retention, intratumoral distribution and internalization into tumor stromal and pancreatic cancer cells. Co-targeting IGF-IR that is uniformly expressed at a very high level in all tumor cells as well as an intermediate level in tumor stromal cells enhances nanoparticle-drug delivery into drug resistant pancreatic cancer cells. Interactions of dual receptor targeted IONPs with uPAR and IGF-1R expressing tumor fibroblasts and macrophages ensure retention of the nanoparticles in the tumor stroma while MMP14 catalytic activity of the uPAR-targeting ATFMMP14 ligand breaks down the extracellular matrix and facilitates the migration of IONPs through the tumor stroma to reach cancer cells. Additionally, internalization of theranostic IONPs into tumor stromal cells leads to the stromal collapse and further enhances nanoparticle delivery into tumor cells. This dual targeted and protease activate IONP was produced by conjugation of the recombinant amino terminal fragment (ATF) of uPA and catalytic domain of MMP14 fusion ligand and human insulin-like growth factor 1 (IGF-1) to the polymer coating of the same IONP. We found that systemic delivery of the targeted and protease active theranostic IONPs led to the accumulation of significant higher levels of the theranostic IONPs into pancreatic tumors, and marked improvement of intratumoral distribution and tumor cell uptake of the nanoparticle-drug carriers in orthotopic human pancreatic cancer tissue derived xenografts (PDX) models in nude mice. Enhanced intratumoral delivery of theranostic nanoparticles could be detected by non-invasive MRI and optical imaging. Multiphoton microscopy showed the ability of the targeted and MMP14 active theranostic nanoparticles penetrating through the stromal barrier that enriched in collagen fibers and entering into the tumor center following intravenous delivery in mice bearing PDX tumors. As the result of improved nanoparticle-drug delivery, systemic administrations of the dual receptor targeted and MMP14 active theranostic IONPs carrying chemotherapy drug, doxorubicin, produced the strongest anti-tumor growth effect compared to single receptor targeted, uPAR-targeted without MMP14 or non-targeted theranostic IONPs in orthotopic pancreatic cancer PDX models in nude mice. Histological analysis revealed that PDX tumors obtained from the mice that received repeated administrations of the dual receptor targeted MMP14-IONPs-Dox had higher levels of tumor cell death and inhibition of cell proliferation compared to those treated with other targeted and non-targeted theranostic IONPs. Therefore, uPAR and IGF-1R dual targeted and MMP14 active theranostic IONPs provide promising nanoparticle-drug delivery carriers for the development of novel targeted and image-guided therapy for applications of precision oncology for effective treatment of pancreatic cancer.
Citation Format: Hongyu Zhou, Xiangxue Guo, Weiping Qian, Fatih M. Uckun, Liya Wang, Y Andrew Wang, Hongyu Chen, David A. Kooby, Malgorzata Lipowska, Charles A. Staley, Lily Yang.{Authors}. Stroma breaking dual targeted theranostic nanoparticles for image-guided and targeted therapy of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B67.