Targeted Low-Dose Tnf Alpha Delivered By Tcp-1 Peptide Exerts Differential Synergistic Effects On Anti-Cancer Actions Of Chemotherapeutic Drugs

Minute amounts of tumor vasculature-targeted TNF alpha 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 TNF alpha in a murine orthotopic colorectal cancer model. TNF alpha was firstly coupled with a vascular-homing peptide TCP-1 to form a TNF alpha derivative (TCP-1/TNF alpha). After pretreated with 1 ng TCP-1/TNF alpha, 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/TNF alpha had the highest transvascular transportation efficiency. This work would provide important information for designing clinical studies with vasculature-targeted TNF alpha in combination with chemotherapeutic drugs for optimal synergism.