Near-infrared photoactivatable three-in-one nanoagents to aggravate hypoxia and enable amplified photo-chemotherapy.

Solid tumors create a hypoxic microenvironment and this character can be utilized for cancer therapy, but the hypoxia levels are insufficient to achieve satisfactory therapeutic benefits. Some tactics have been used to improve hypoxia, which however will cause side effects due to the uncontrolled drug release. We herein report near-infrared (NIR) photoactivatable three-in-one nanoagents (PCT) to aggravate tumor hypoxia and enable amplified photo-combinational chemotherapy. PCT are formed based on a thermal-responsive liposome nanoparticle containing three therapeutic agents: a hypoxia responsive prodrug tirapazamine (TPZ) for chemotherapy, a vascular targeting agent combretastatin A-4 (CA4) for vascular disturbance and a semiconducting polymer for both photodynamic therapy (PDT) and photothermal therapy (PTT). With NIR laser irradiation, PCT generate heat for PTT and destructing thermal-responsive liposomes to achieve activatable releases of TPZ and CA4. Moreover, PCT produce singlet oxygen (O) for PDT via consuming tumor oxygen. CA4 can disturb the blood vessels in tumor microenvironment to aggravate the hypoxic microenvironment, which results in the activation of TPZ for amplified chemotherapy. PCT thus enable PTT, PDT and hypoxia-amplified chemotherapy to afford a high therapeutic efficacy to almost absolutely eradicate subcutaneous 4 T1 tumors and effectively inhibit tumor metastases in lung and liver. This work presents an activatable three-in-one therapeutic nanoplatform with remotely controllable and efficient therapeutic actions to treat cancer.