A hybrid metal-organic framework nanomedicine-mediated photodynamic therapy and hypoxia-activated cancer chemotherapy.

The hypoxic tumor microenvironment and photodynamic therapy (PDT)-aggravated hypoxia compromise the anticancer efficacy of chemotherapy, immunotherapy, and PDT. Thus, sophisticated nanomedicines that can activate their anticancer capability in situ in response to specific stimuli need to be developed. This study aimed to construct a hybrid nanomedicine that activated chemotherapy by inducing hypoxia, which synergized with PDT to promote antitumor outcomes, contrary to the strategies focusing on reversing tumor hypoxia. The hybridization of a porphyrin metal-organic framework (MOF) and gold nanoparticles (AuNPs) enhanced the stability of the hybrid nanomedicine against the phosphate in blood, thereby preventing the premature drug release during blood circulation. The surface modification with polyethylene glycol (PEG) markedly increased the tumor accumulation of the hybrid MOF nanomedicine, which encapsulated a hypoxia-activated prodrug (tirapazamine, TPZ), by enhancing its colloidal stability and pharmacokinetics. The loaded TPZ was rapidly released from the nanomedicine in response to the concentrated intracellular phosphate after cellular uptake, and was then converted into a potent anticancer drug in a hypoxic microenvironment exacerbated by continuous O consumption during PDT. In vitro and in vivo experiments demonstrated that the synergistic PDT and hypoxia-activated chemotherapy exhibited enhanced antitumor therapeutic efficiency and superior antimetastatic effect, and effectively ablated the tumor without recurrence. Therefore, the sophisticated nanomedicine reported here, which eliminated cancer cells by inducing a hypoxic tumor microenvironment, showed translational potential in future therapeutic development.