A Mitochondria-targeted Aggregation-induced Emission Photosensitizer For Image-guided Photodynamic Therapy Of Cholangiocarcinoma

Objective:Cholangiocarcinoma is a highly aggressive tumor originated from epithelial cells of biliary tree.Surgery is the only curative treatment for cholangiocarcinoma,but most patients are in the advanced stage at the preliminary diagnosis while lose the opportunity of radical resection.Even underwent locoregional therapy and system chemotherapy,the median survival of patients with unresectable cholangiocarcinoma is only about 2 years.Photodynamic therapy is a low-invasive locoregional therapy of cancer,which can effectively extend the survival and improve the life quality of patients with cholangiocarcinoma.Photosensitizer is the crucial element of photodynamic therapy.Traditional photosensitizers are often limited by aggregation-induced quenching effect,resulting in insufficient production of reactive oxygen species.The limited range of action of reactive oxygen species in cells also affects its efficiency of photodynamic therapy.Photosensitizers with organelle targeting ability and aggregation-induced emission feature are expected to improve the efficacy of photodynamic therapy.Methods:In this study,the electron donor-π conjugation-electron acceptor structure was used as the molecular skeleton,a photosensitizer named TTVPHE was synthesized.This photosensitizer has aggregation-induced emission properties and get mitochondrial targeting ability by introducing positively charged pyridine group.In this study,the photophysical properties,cellular uptake,biocompability,photodynamic tumor killing effect in vitro and in vivo,and mitochondrial targeting damage ability of the photosensitizer were verified,and the mechanism of mitochondria-dependent cell apoptosis caused by photodynamic therapy was investigated.Results:The molecular weight of TTVPHE was 652.18,the maximum absorption and emission wavelength of TTVPHE were 482 nm and 596 nm.It had good aggregation-induced emission ability and reactive oxygen species generation capacity.TTVPHE can be effectively taken up by cholangiocarcinoma cells and have good photodynamic tumor killing effects in vitro and in vivo.Meanwhile,TTVPHE was localized to mitochondria in cells,causing mitochondrial damage morphological changes during the white lighe irradiation.Photodynamic therapy with TTVPHE can cause the decline of mitochondrial membrane potential,the leakage of cytochrome c,and then the activation of mitochondria-dependent apoptosis pathway.TTVPHE can also cause nuclear membrane damage and increased permeability of nuclear membrane.Conclusion:In this study,a new mitochondria-targeted aggregation-induced emission photosensitizer,TTVPHE,was synthesized.This photosensitizer can effectively aggregate in the mitochondria of cholangiocarcinoma cells and provide self-monitoring during the photodynamic therapy process.The photosensitizer can effectively damage mitochondria and activate the apoptosis pathway and can effectively kill cholangiocarcinoma in in vitro and in vivo experiments.This new photosensitizer has a good prospect in the photodynamic therapy of cholangiocarcinoma.