Long-Circulating Drug-Dye-Based Micelles with Ultrahigh pH-Sensitivity for Deep Tumor Penetration and Superior Chemo-Photothermal Therapy

摘要

Nanocarriers for chemo-photothermal therapy suffer from insufficient retention at the tumor site and poor penetration into tumor parenchyma. A smart drug-dye-based micelle is designed by making the best of the structural features of small-molecule drugs. P-DOX is synthesized by conjugating doxorubicin (DOX) with poly(4-formylphenyl methacrylate-co-2-(diethylamino) ethyl methacrylate)-b-polyoligoethyleneglycol methacrylate (P(FPMA-co-DEA)-b-POEGMA) via imine linkage. Through the pi-pi stacking interaction, IR780, a near-infrared fluorescence dye as well as a photothermal agent, is integrated into the micelles (IR780-PDMs) with the P-DOX. The IR780-PDMs show remarkably long blood circulation (t(1/2 beta) = 22.6 h). As a result, a progressive tumor accumulation and retention are presented, which is significant to the sequential drug release. Moreover, when entering into a moderate acidic tumor microenvironment, IR780-PDMs can dissociate into small-size conjugates and IR780, which obviously increases the penetration depth of drugs, and then improves the lethality to deep-seated tumor cells. Owing to the high delivery efficiency and superior chemo-photothermal therapeutic efficacy of IR780-PDMs, 97.6% tumor growth in the A549 tumor-bearing mice is suppressed with a low dose of intravenous injection (DOX, 1.5 mg kg(-1); IR780, 0.8 mg kg(-1)). This work presents a brand-new strategy for long-acting intensive cancer therapy.