A dual drug-loaded tumor vasculature-targeting liposome for tumor vasculature disruption and hypoxia-enhanced chemotherapy

Vascular disrupting agents (VDAs) can destroy tumor vasculature and lead to tumor ischemia and hypoxia, resulting in tumor necrosis. However, VDAs are easy to induce the upregulation of genes that are associated with drug resistance and angiogenesis in tumor cells. Hypoxia-activated chemotherapy will be an ideal supplement to VDAs therapy since it can help to fully utilize the ischemia and hypoxia induced by VDAs to realize a synergistic antitumor therapeutic outcome. Here, we design a liposome whose surface is modified with a tumor-homing peptide Cys-Arg-Glu-Lys-Ala (CREKA, which can specifically target tumor vessels and stroma) and whose inner cavity is loaded by a hypoxia-activated drug banoxantrone dihydrochloride (AQ4N) as well as a VDA combretastatin A4 (CA4). CA4 can selectively target vascular endothelial cells and destroy the tumor blood vessels, which will cause the rapid closure of blood flow in tumor and enhance the hypoxia in the tumor region. As a consequence, AQ4N can exert its boosted cytotoxicity under the enhanced hypoxic environment. The as-prepared liposome with a uniform particle size exhibits good stability and high cancer cell killing efficacy in vitro. In addition, in vivo experiments confirm the excellent tumor-targeting/accumulation, tumor vascular damaging, and tumor inhibition effects of the liposome. This work develops CA-TL which can achieve safe and effective tumor suppression without external stimulus excitation by only single injection, and is expected to benefit the future development of effective antitumor liposomal drugs.