Reshaping Tumor Blood Vessels to Enhance Drug Penetration with a Multistrategy Synergistic Nanosystem.

Due to the abnormal tumor vasculature and dense stroma, there is limited tumor perfusion in the immunosuppressive tumor microenvironment (TME). In order to reshape tumor blood vessels and enhance the penetration of anticancer drugs into the tumor tissue, an anionic liposome nanosystem with a "sandwich" structure was prepared. The chemotherapeutic agent topotecan (TPT) was encapsulated in the lipid hydrophilic layer, and the sensitizer indocyanine green (ICG) was loaded into the hydrophobic layer. In addition, the positively charged vascular normalization drug erlotinib (ERL) was adsorbed to the outermost layer of the microenvironment. The nanosystem showed superior tumor permeability invitro/in vivo experiments compared with the ERL-treated group. The nanosystem entered the tumor through normalization of blood vessels after the action of ERL. Ultrasound treatment improves the vascular permeability, allowing the nanoparticles to penetrate blood vessels and reach tumor cells. Finally, in addition to cytotoxic effects, TPT can also down-regulate the expression of HIF-1α and so prolong the vascular normalization time. These experimental results showed that the nanosystem effectively improves the tumor microenvironment. This work indicates the great potential of vascular normalization combined with sonodynamic therapy and chemotherapy to enhance efficiency.