Hypoxia-Triggered Nanoscale Metal-Organic Frameworks for Enhanced Anticancer Activity

The oxygen-dependent feature of most photosensitizers (PSs) and the aggravated hypoxia tumor microenvironment seriously impede the photodynamic therapy (PDT) effectiveness. However, this undesirable impediment can be utilized to further trigger the activation of hypoxia-sensitive prodrugs. Moreover, a combined therapy can be used by associating PDT with hypoxia-activated chemotherapy. Herein, a multifunctional Hf-porphyrin nanoscale metal-organic framework (NMOF) platform [Hf/tetra(4-carboxyphenyl)porphine (TCPP)] has been synthesized, with a high porphyrin loading capacity and a well-ordered coordination array preventing porphyrin self-quenching, thus greatly improving the generation efficiency of reactive oxygen species (ROS), which is helpful for PDT. As-synthesized Hf-TCPP nanoparticles possess more than 50 wt % of TCPP PS content, good crystallization, and a large Brunauer-Emmett-Teller surface for further loading the hypoxia-activated prodrug [tirapazamine (TPZ)] in a high-loading content. Additionally, subsequent surface modification with a dopamine-derived polymer (DOPA-PIMA-mPEG) significantly improves their dispersibility and structural stability, and the controlled release kinetics of TPZ. Such a nanoplatform can efficiently produce ROS for PDT upon irradiation, and also the depletion of the oxygen could further aggravate the hypoxic environment of tumors to induce the activation of TPZ for achieving an enhanced treatment efficacy. This work demonstrates the great advantages of an NMOF-based platform in antitumor therapies for combined PDT and hypoxia-activated chemotherapy.