Targeted low-dose TNFα delivered by TCP-1 peptide exerts differential synergistic effects on anti-cancer actions of chemotherapeutic drugs

Abstract Minute amounts of tumor vasculature-targeted TNFα was reported to increase endothelial permeability, thereby accelerating drug penetration and increasing the therapeutic index of chemotherapeutic agents. This study aimed at assessing the synergistic anti-cancer effects of three chemotherapeutic drugs and tumor vasculature-targeted TNFα in a murine orthotopic colorectal cancer model. TNFα was firstly coupled with a vascular-homing peptide TCP-1 to form a TNFα derivative (TCP-1/TNFα). After pretreated with 1 ng TCP-1/TNFα, the three chemotherapeutic drugs exerted differential synergistic effects on anti-cancer actions and presented different intratumoral accumulation statuses. To further assess transvascular transport efficiency of these drugs, an in vitro system was carried out to mimic the endothelial cell monolayer. Results showed that 5-fluorouracil which exerted the best anti-cancer action and intratumoral accumulation status with preadministration of 1 ng TCP-1/TNFα had the highest transvascular transportation efficiency. This work would provide important information for designing clinical studies with vasculature-targeted TNFα in combination with chemotherapeutic drugs for optimal synergism.