Vascular-targeted TNFα improves tumor blood vessel function and enhances antitumor immunity and chemotherapy in colorectal cancer

Delivery and penetration of chemotherapeutic drugs into neoplasm through the tumor vasculature are essential mechanisms to enhance the efficiency of chemotherapy. Vascular targeting strategy focuses on promoting the infiltration of chemotherapeutic drugs into neoplastic tissues. In this study, we achieved a targeted therapy by coupling tumor necrosis factor a (TNF alpha) with TCP-1, a novel vascular-targeting peptide, in an orthotopic colorectal cancer model in mice. High dose of TCP-1-conjugated TNF alpha (TCP-1/TNF alpha: 5 mu g/mouse) displayed potent antitumor activity by inducing apoptosis and reducingmicrovessel number in tumors than unconjugated TNF alpha, with no evidence of increased toxicity. In the combined therapy, the antitumor action of 5-fluorouracil (5-FU) was potentiated when the mice were pretreated with a low dose of TNF alpha (1 ng/mouse) and to a greater extent by the same concentration of TCP-1/TNF alpha. In this regard, TCP-1/TNF alpha combined with 5-FU synergistically inhibited the tumor growth, induced apoptosis and reduced cell proliferation. More importantly, TCP-1/TNF alpha normalized the tumor vasculature and facilitated the infiltration of immune cells to neoplasm as well as attenuated the immunosuppressing effects of TNFa in bone marrow and spleen. At the same time, TCP-1/TNF alpha significantly improved 5-FU absorption into the tumor mass. Taken together, these findings underscore the therapeutic potential of TCP-1 as a drug carrier in cancer therapy. TCP-1 is a novel vascular-targeting peptide and appears to be a promising agent for drug delivery. TCP-1 fused with TNF alpha holds great promise for colorectal cancer therapy. (C) 2015 Elsevier B.V. All rights reserved.