"Targeted plus controlled" - Composite nano delivery system opens the tumor vascular and microenvironment normalization window for anti-tumor therapy.

The bottleneck of traditional anti-tumor therapy is mainly limited by the abnormal microenvironment of tumors. Leaky vessels are difficult for drugs or immune cells to penetrate deep into tumors, but tumor cells can easily escape through which and metastasize to other organs. Reprogramming the tumor microenvironment is one of the main directions for anti-cancer research, among which, tumor vascular normalization has received increasing attention. However, how to control the dose and time of anti-angiogenic drugs for stable vascular normalizing effect limits it for further research. We developed a composite nano delivery system, P-V@MG, with double delivery function of pH-responsibility and sustained drug release. The PHMEMA shell improves amphiphilicity of nano delivery system and prolongs in vivo retention, and releases V@MG in the weakly acidic tumor microenvironment, which slowly release anti-angiogenic drugs, Vandetanib. We found that P-V@MG not only prolonged the normalization window of tumor vascular but also reprogram tumor microenvironment with increased perfusion, immune cells infiltration and relieved hypoxia, which further opened the pathway for other anti-cancer therapeutics. This synergy was proved by the improving anti-tumor efficiency by combination of P-V@MG with the doxorubicin hydrochloride in 4 T1 breast cancer model suggesting the desirable value of pro-vascular normalization nano delivery systems in the field of anti-tumor combination therapy.