Porous silicon nanocarriers for dual targeting tumor associated endothelial cells and macrophages in stroma of orthotopic human pancreatic cancers

Pancreatic cancer is a highly fatal disease characterized by a dominant stroma formation. Exploring new biological targets, specifically those overexpressed in stroma cells, holds significant potential for the design of specific nanocarriers to attain homing of therapeutic and imaging agents to the tumor. In clinical specimens of pancreatic cancer, we found increased expression of CD59 in tumor associated endothelial cells as well as infiltrating cells in the stroma as compared to uninvolved pancreas. We explored this dual targeting effect using orthotopic human pancreatic cancer in nude mice. By immunofluorescence analysis, we confirmed the increased expression of Ly6C, mouse homolog of CD59, in tumor associated endothelial cells as well as in macrophages within the stroma. We decorated the surface of porous silicon nanocarriers with Ly6C antibody. Targeted nanocarriers injected intravenously accumulated to tumor associated endothelial cells within 15 min. At 4 h after administration, 9.8 ± 2.3% of injected dose/g tumor of the Ly6C targeting nanocarriers accumulated in the pancreatic tumors as opposed to 0.5 ± 1.8% with non-targeted nanocarriers. These results suggest that Ly6C (or CD59) can serve as a novel dual target to deliver therapeutic agents to the stroma of pancreatic tumors.

• We propose a new targeting strategy to enable accumulation of drug carriers in the stroma of pancreatic tumors.
• We demonstrate that CD59 and its murine analogue Ly6C are over-expressed by tumor associated stroma cells in clinical specimens and in vivo orthotopic models of human pancreatic cancer, respectively.
• Several subpopulations of storma cells, including tumor associated macrophages and endothelial cells have pronounceable over-expression of the biomarker.
• We further use Ly6C as a new target to enhance accumulation of nanocarriers to the stroma in the orthotopic pancreatic tumors in mice.