NIR laser-activated multifunctional nanocomposites for cascade low-temperature photothermal and oxygen-irrelevant thermodynamic therapy

Osteosarcoma, occurring most frequently in adolescents, are highly malignant bone tumor and prone to develop local recurrence and long-distance metastasis. Therefore, new comprehensive therapeutic strategies for osteosarcoma are urgently needed. Different from traditional photothermal therapy (PTT), low temperature PTT (LTPTT) not only brings less heat damages to the surrounding normal tissues but also prevent tumor metastasis. Nevertheless, its therapeutic effects are severely attenuated due to the tumor thermo-resistance induced by the overexpression of heat shock protein (HSP). In our work, an acid-responsive core–shell nanocomposite was fabricated for cancer therapy. The nanoplatform can independently encapsulate alkyl radical initiator 2,2-azobis[2-(2-imidazolin-2-yl) propane]-dihydroch-loride (AIPH) in the mesoporous polydopamine (MPDA) core and HSP inhibitor (gambogic acid, GA) in the zeolite imidazolate framework-8 (ZIF-8) microporous shell, called MPDA/AIPH@ZIF-8/GA (MAZG), which could achieve the combined functions of LTPTT and thermodynamic therapy (TDT). After endocytosing by tumor cells, the pH-responsive degradation of the ZIF-8 coating stimulates the rapid release of GA, which can effectively inhibit HSP expression in advance, and then simultaneously enhanced the therapeutic efficacy of LTPTT. Further, both in vitro and in vivo experiments have demonstrated that the as-synthesized MAZG nanocomposite exhibited favorable biosafety and remarkable tumor growth inhibition.