Tumor acidity/redox hierarchical-activable nanoparticles for precise combination of X-ray-induced photodynamic therapy and hypoxia-activated chemotherapy.

With the advantages of deep tissue penetration and controllability, external X-ray-induced photodynamic therapy (X-PDT) is highly promising for combined cancer therapy. In addition to the low efficiency of photosensitizer (PS) delivery to tumor sites, however, the radiation- and drug-resistance of hypoxic cells inside the tumor after X-PDT also limit its benefits. Herein, we develop a combined therapeutic modality based on an intelligent nanosized platform (TAT-NP) with tumor acidity-activated TAT presenting and redox-boosted release of tirapazamine (TPZ) for more precise and synchronous X-PDT and selective hypoxia-motivated chemotherapy. After TAT-NP has accumulated in tumor tissues decreased blood clearance by masking of the TAT ligand, its targeting ability is reactivated by tumor pH (∼6.8), which enhances tumoral cellular uptake. Upon low-dose X-ray irradiation, the encapsulated verteporfin (VP) generates reactive oxygen species (ROS) to carry out X-PDT against MDA-MB-231 breast tumors. As a result of the abundant GSH-triggered degradation of ditelluride bridged bonds, the cascaded TPZ release and activation in the hypoxic environment following X-PDT would produce highly cytotoxic radicals to serve as antitumor agents to kill the remaining hypoxic tumor cells. This concept provides new avenues for the design of hierarchical-responsive drug delivery systems and represents a proof-of-concept combinatorial tumor treatment.