Positioning Remodeling Nanogels Mediated Codelivery of Antivascular Drug and Autophagy Inhibitor for Cooperative Tumor Therapy

Tumor vasculature and enhanced autophagy collectively provide the source of nutrients for tumor growth, invasion, and metastasis. Blocking the source of nutrients will be a novel and promising antitumor approach. Herein, we exploited an intelligent nanogel (CA4-FeAlg/HCQ) with a positioning remodeling feature to precisely kill A549 cancer cells in all directions based on frontal and rear attack strategies. CA4-FeAlg/HCQ nanogels could remain stable during blood circulation. When they reached the tumor vascular site, the vascular blocker combretastatin A4 (CA4) would be released at first to exert an antiangiogenic effect. Thereafter, FeAlg/HCQ disintegrated into small nanogels (<30 nm) for tumor deep penetration. Once small nanogels entered tumor cells, FeAlg/HCQ would undergo phase remodeling (gel to sol) to release the autophagy inhibitor hydroxychloroquine (HCQ) quickly. The autophagy induced by CA4 can be effectively inhibited by HCQ to achieve synergistic treatment of tumors. In addition, after Fe3+ in FeAlg being reduced to Fe2+, it catalyzed intratumoral hydrogen peroxide (H2O2) to generate cytotoxic hydroxyl radicals (·OH), which further strengthened the antitumor effect. The in vivo pharmacodynamic result revealed that CA4-FeAlg/HCQ showed the greatest therapeutic effect, with the final V/V0 of 0.40 ± 0.10. Our study provided a hopeful platform for rational and precise tumor treatment, which may be of great significance in the combined pharmacotherapy.