Abstract 379: Target delivery of multistage nanovectors to tumor-associated macrophages and endothelial cells in orthotopic model of human pancreatic cancer

Abstract

Abstract Pancreatic cancer is one of the most aggressive malignancies in humans with a 1-year survival rate of 18%, and a 5-year survival rate of less than 3%. Clearly, there is an urgent need to develop novel therapies for this disease. In patients, the tumor microenviroments consist of 70 to 90% stroma tissue supporting growth, invasion and metastasis of cancer. Therefore stroma is a potential target for therapy. The stroma consists of various cellular elements, including tumor associated macrophages and endothelial cells. Identification of molecular targets overexpressed in stroma cells holds great potential for design of specific nanocarriers to attain homing of therapeutic and imaging agents to the tumor. Physico-chemical characteristics of the nanovectors greatly affect their in vivo behavior and we have recently shown that carrier geometry plays an important role in its biodistribution. In this study, we found increased expression of CD59 in tumor associated endothelial cells as well as infiltrating cells in the stroma as compared to uninvolved pancreas in clinical specimen of pancreatic cancer patients. We explored this dual targeting effect using L3.6pl human pancreatic cancer cells implanted into the pancreas of nude mice. To produce a chronic disease with high proportion of stroma, we injected only 5 × 104 viable cells that produced visible tumors after three months (chronic disease model). Increased stroma formation was found only in the chronic disease model, but not when 1 × 106 cells were injected (acute model). In the chronic model, immunofluorescence analysis of tumor confirmed the increased expression of Ly6C, mouse homolog of CD59, in tumor associated endothelial cells as well as in macrophages in stroma. In the next experiment, we decorated the surface of porous silicon nanovectors with Ly6C antibody. Targeted nanovectors injected intravenously accumulated to tumor associated endothelial cells expressing Ly6C 15 minute after injection. At 4 hours after administration, 9.8 ± 2.3 % of injected dose/g tumor of the Ly6C targeting nanovectors accumulated in the pancreatic tumors as opposed to 0.5 ± 1.8 % of control nanovectors with non targeting antibody. Immunofluorescence analysis of tumor revealed that Ly6C targeting nanovectors were engulfed by tumor associated macrophages which also express Ly6C in stroma. Collectively, these results suggest that Ly6C (or CD59) expressed on tumor associated endothelial cells and macrophages can serve as a novel dual target for pancreatic cancer. These experiments are on going. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 379. doi:10.1158/1538-7445.AM2011-379