Delivery of MutT homolog 1 inhibitor by functionalized graphene oxide nanoparticles for enhanced chemo-photodynamic therapy triggers cell death in osteosarcoma

Abstract

Photodynamic therapy (PDT) generates highly toxic reactive oxygen species (ROS) during noninvasive cancer treatment. MutT homolog 1 (MTH1) protein is a DNA oxidative damage repair protease and suppressing its function may provide a strategy to enhance PDT efficacy by improving cellular sensitivity to ROS. A nanoparticle, composed of functional graphene oxide (GO) conjugated with polyethylene glycol (PEG), folic acid (FA) and photosensitizer indocyanine green (ICG), was constructed to deliver MTH1 inhibitor (TH287) and doxorubicin. The effects of this nanoparticle on biological properties and cell death of osteosarcoma cells were investigated. We further examined the endoplasmic reticulum (ER) stress and apoptosis in osteosarcoma. A xenograft tumor model was used to validate the results in vivo. This drug-carrying PEG-GO-FA/ICG nanoparticle showed combined chemo-photodynamic therapy (Chemo-PDT) to inhibit the proliferation and migration of osteosarcoma cells. Enhanced Chemo-PDT promoted both apoptosis and autophagy by suppressing the MTH1 protein and promoting the accumulation of ROS. In this study, autophagy served as a rescue pathway against cell death, and suppressing autophagy enhanced the anti-cancer effects of Chemo-PDT. However, Chemo-PDT induced apoptosis was related to the occurrence of ER stress. ROS might contribute to ER stress and further induce apoptosis via the JNK/p53/p21 pathway. These findings provide a mechanistic understanding of nanoparticle-induced cell death in osteosarcoma. The combination of Chemo-PDT with other therapies is promising as a new strategy to treat osteosarcoma. Statement of significanceAdministration of chemotherapeutic drugs by traditional methods still has many problems. We designed a functionalized graphene oxide drug delivery system to deliver the photosensitizer indocyanine green, doxorubicin, and MTH1 inhibitor TH287. This nano delivery system showed combined chemo-photodynamic effects to inhibit osteosarcoma. Suppressing MTH1 protein might induce “phenotypic lethality” and enhance chemo-photodynamic therapy efficacy by improving cellular sensitivity to reactive oxygen species.