A biothiol-reactive and mitochondria-targeting photosensitizer for dual-modal antitumor treatment combining photodynamic and nitric oxide therapies

Abstract

Photodynamic therapy (PDT) is an effective approach for tumor treatment but its in vivo efficacy is limited by the tumor microenvironment and intrinsic factors. Novel multimodal synergistic PDT therapies may address the challenges. Combining PDT and nitric oxide (NO) gas therapy for tumor treatment simultaneously may provide synergistic advantages, such as controllable in situ tumor-site treatments and minimizing side effects. In this study, a new glutathione-activating photosensitizer, Cyl-ASRG-NO is developed, allowing effective PDT and NO synergistic dual-modal therapy. Hemicyanine is utilized as the backbone and incorporate a NO-releasing phenylsulfonyl furoxan functional group into the photosensitizer. Cyl-ASRG-NO is selectively activated by the high concentration of glutathione in tumor microenvironment, triggering the release of NO at the tumor site. The released NO further reacts with reactive oxygen species (ROS) generated in situ by PDT, forming highly toxic peroxynitrite (ONOO−) to kill tumor cells. This process depletes glutathione at the tumor, reducing its intracellular levels and impairing the cellular redox balance in tumor cells. Consequently, the induced oxidative stress promotes tumor cell death. The in vivo results demonstrate that, Cyl-ASRG-NO under NIR laser irradiation, the synergistic effect of ROS and reactive nitrogen species provides superior antitumor activity compared to the single-modal treatment.