Augment of Oxidative Damage with Enhanced Photodynamic Process and MTH1 Inhibition for Tumor Therapy.

Abstract

Tumor cells adapt to reactive oxygen species (ROS) attacking by launching DNA damage repairing mechanisms such as nucleotide pool sanitizing enzyme mutt homologue 1 (MTH1) to mitigate the oxidatively induced DNA lesions, which could greatly limit the therapeutic efficiency of current oxidation therapy. Here, an amplified oxidative damage strategy for tumor therapy was proposed that was focused not only on the enhancement of ROS generation but also the inhibition of subsequent MTH1 enzyme activity simultaneously. In our formulation, mesoporous silica-coated Prussian blue nanoplatforms (PB@MSN) with excellent catalase-like activity and drug loading capability were employed to encapsulate MTH1 inhibitor TH287, followed by the modification of tetraphenylporphrin zinc (Zn-Por) via metallo-supramolecular coordination (PMPT), where Zn-Por behaved as photodynamic and fluorescence imaging agents, as well as acid-responsive gatekeepers. The intelligent PMPT nanosystems could induce the decomposition of H2O2 to relieve the hypoxic tumor environment, thus elevating the generation of singlet oxygen for improved oxidative damage. In the meantime, controllable-released TH287 from pores could hinder MTH1-mediated damage repairing process and aggravate oxidative damage, thereby resulting in cellular toxicity as well as tumor growth inhibition.