Abstract 4593: Targeted therapy of pancreatic cancer by intraperitoneal delivery of uPAR-targeted theranostic nanoparticles

Abstract

Abstract The leading challenge in pancreatic cancer treatment is inability to deliver sufficient amounts of therapeutic agents into cancer cells due to the presence of extensive tumor stroma. Increasing evidence shows that pancreatic tumor microenvironment promotes proliferation, metastasis, and chemoresistance of the cancer cells. Urokinase plasminogen activator receptor (uPAR) is highly expressed in pancreatic tumor cells and tumor stroma but is not found in the normal pancreas. Therapeutic agents targeting to uPAR may offer a means to break down the tumor stromal barrier and enhance drug delivery into cancer cells. In this study, we engineered a near infrared dye NIR-830 labeled amino-terminal fragment (ATF) of mouse uPA conjugated magnetic iron oxide nanoparticles (IONP) carrying chemotherapy drug cisplatin (Cis) without or with PEG-coating (ATF-IONP-Cis ATF-PEG-IONP-Cis). To determine the effect of PEG-coating on non-specific uptake of the IONPs by enriched macrophages in the peritoneal cavity and its consequent effect on targeted delivery of the theranostic IONPs, we established a mouse pancreatic tumor model derived from the PANC02 cell line with simultaneous carrying a subcutaneous and an orthotopic tumor. First, we examined the best delivery method for this animal tumor model and found that the i.p. delivery of mouse uPAR targeted ATF-PEG-IONPs resulted in stronger optical signal in the orthotopic cancers with much lesser signals in the liver compared that of the i.v. delivery. Next, the effects of the i.p. delivery of the ATF-IONP-Cis, ATF-PEG-IONP-Cis, and non-targeted ATF-IONP-Cis were evaluated in the mouse pancreatic cancer model. We found that i.p. delivery of 5 mg/kg of Cisplatin equivalent ATF-IONP-Cis or ATF-PEG IONP-Cis every 3 day for 4 injections significantly inhibited tumor growth (Control vs ATF-PEG-IONP-cis: p=0.008; ATF-IONP-Cis: p=0.016). It seemed that PEG-coating didn't affect the inhibitory effects of ATF-IONP-Cis nanoparticles on tumor growth. However, free cisplatin and non-targeted-IONP-Cis treated groups didn't show significant anti-tumor effects. We also observed that the mice treated with ATF-IONP-Cis had much less amounts of ascites (average 0.5ml/mouse) compared to the mice treated with free cisplatin (an average of 5 ml/mouse). Additionally, markedly systemic toxicity effect was seen in the mice treated conventional cisplatin but this was not observed in the mice treated with ATF-IONP-cis. We further confirmed targeted delivery of ATF-IONP-cis into the tumor using Prussian blue staining on frozen tissue sections and chemical analysis to quantify amount of IONPs in tumor tissues. Taken together, the ATF-PEG-IONP-Cis theranostic nanoparticles and the i.p. delivery approach developed in this study have great potential for the development of novel targeted and image-guided treatment of pancreatic cancer Citation Format: Ning Gao, Erica Bozeman, Weiping Qian, Charles Staley, Andrew Wang, Hui Mao, Lily Yang. Targeted therapy of pancreatic cancer by intraperitoneal delivery of uPAR-targeted theranostic nanoparticles. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4593. doi:10.1158/1538-7445.AM2014-4593