Tumor-targeted and stimuli-responsive nanoplatform with cascade activities for multiple model tumor therapy
The contradiction between normal tissues damage caused by strong photothermal/chemo therapy and invalid tumor treatment caused by gentle photothermal/chemo therapy is still a great challenge. Therefore, development of new therapeutic system to selectively destruct tumors under gentle but effective photothermal/chemo therapy would be a promising strategy for clinical treatment. Herein, a rambutan-like nanocomplex (PDA-SNO-GA-HA-DOX, PSGHD for short) with tumor selective accumulation, pH-triggered doxorubicin (DOX) release, near infrared light (NIR) dependent nitric oxide release, NIR dependent photothermal conversion and HAase-induced gambogic acid (GA) release was fabricated for effective and accurate tumor treatment, which consists of S-nitrosothiol-functionalized polydopamine (PDA-SNO) core and gambogic acid derivatized hyaluronic acid (HA-GA) shell with doxorubicin (DOX) as cargos. The as-synthesized PSGHD nanocomplex exhibited different kinetics for the release of both DOX (agent for chemotherapy) and GA (agent for enhancing thermal damage) under different simulated physiological conditions, where the release of DOX was highly pH dependent and the release of GA could only be triggered by HAase, indicating its good responsiveness to tumor environment (Low pH and rich of HAase) as design. When the PSGHD nanocomplex was exposed under 808 nm NIR radiation, it further performed excellent photothermal conversion, which resulted in rise of local temperature over 50 oC and controllable conversion of SNO to nitric oxide (NO, agent for reducing drug-efflux). Moreover, due to the HA section, PSGHD nanocomplex could be rapidly and selectively internalized by tumor cells instead of healthy cells in 12 h co-incubation. Based on the tumor targeting, stimuli-responsive DOX/GA release, photothermal conversion and NIR triggered NO generation, the PSGHD nanocomplex simultaneously achieved both tumor specific low-drug-efflux chemotherapy and low-temperature photothermal therapy, resulting in an eight-fold apoptosis of tumor cells over normal cells under NIR radiation. In vivo data from mouse models further showed that the PSGHD nanocomplex could completely inhibit the tumor growth and significantly prolonged the survival rate of tumor bearing mice in 50 days, demonstrating the high efficiency of the PSGHD nanocomplex for tumor therapy.