RESUMO
Multi-drug resistance (MDR) is a major cause of cancer therapy failure. Photodynamic therapy (PDT) is a promising modality that can circumvent MDR and synergize with chemotherapies, based on the generation of reactive oxygen species (ROS) by photosensitizers. However, overproduction of glutathione (GSH) by cancer cells scavenges ROS and restricts the efficacy of PDT. Additionally, side effects on normal tissues are unavoidable after PDT treatment. Here, to develop organic systems that deliver effective anticancer PDT and chemotherapy simultaneously with very little side effects, three GSH-sensitive photosensitizer-drug conjugates (CyR-SS-L) are designed and synthesized. CyR-SS-L localized in the mitochondria then is cleaved into CyR-SG and SG-L parts by reacting with and consuming high levels of intracellular GSH. Notably, CyR-SG generates high levels of ROS in tumor cells instead of normal cells and be exploited for PDT and the SG-L part is used for chemotherapy. CyR-SS-L inhibits better MDR cancer tumor inhibitory activity than indocyanine green, a photosensitizer (PS) used for PDT in clinical applications. The results appear to be the first to show that CyR-SS-L may be used as an alternative PDT agent to be more effective against MDR cancers without obvious damaging normal cells by the combination of PDT, GSH depletion, and chemotherapy.
Assuntos
Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Glutationa , Mitocôndrias , Fotoquimioterapia , Fármacos Fotossensibilizantes , Fármacos Fotossensibilizantes/farmacologia , Glutationa/metabolismo , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fotoquimioterapia/métodos , Animais , Camundongos , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Modelos Animais de Doenças , Antineoplásicos/farmacologiaRESUMO
Herein, we designed a new nanoplatform for combined PDT/PTT/CDT through simultaneously self-supplying H2O2 and depleting GSH using one single laser irradiation. The nanoplatform was capable of generating multiple reactive oxygen species (ROS), such as 1O2, O2-Ë and ËOH, resulting in cell death. Moreover, the nanoplatform demonstrated low dark toxicity, high phototoxicity and better biosafety. In vivo animal experiments showed that the tumor growth was efficiently inhibited.