Mitochondria-targeted pentacyclic triterpene NIR-AIE derivatives for enhanced chemotherapeutic and chemo-photodynamic combined therapy

Complexes formed by combining pentacyclic triterpenes (PTs) with Aggregation-Induced Emission luminogens (AIEgens), termed pentacyclic triterpene-aggregation induced emission (PT-AIEgen) complexes, merge the chemotherapeutic properties of PTs with the photocytotoxicity of AIEgens. In this study, we synthesized de-rivatives by connecting three types of triphenylamine (TPA) pyridinium derivatives with three common penta-cyclic triterpenes. Altering the connecting group between the electron donor TPA and the electron acceptor pyridinium resulted in increased production of reactive oxygen species (ROS) by PT-AIEgens and a red-shift in their fluorescence emission spectra. Importantly, the fluorescence emission spectra of BA-3, OA-3, and UA-3 extended into the near-infrared (NIR) range, enabling NIR-AIE imaging of the sites where the derivatives aggregated. The incorporation of the pyridinium structure improved the mitochondrial targeting of PT-AIEgens, enhancing mitochondrial pathway-mediated cell apoptosis and improving the efficiency of chemotherapy (CT) and chemo-photodynamic combined therapy (CPCT) both in vivo and in vitro. Cellular fluorescence imaging demonstrated rapid cellular uptake and mitochondrial accumulation of BA-1 (-2,-3). Cell viability experiments revealed that BA-1 (-2), OA-1 (-2), and UA-1 (-2) exhibited superior CT cytotoxicity compared to their parent drugs, with BA-1 showing the most potent inhibitory effect on HeLa cells (IC50 = 1.19 mu M). Furthermore, HeLa cells treated with BA-1 (1 mu M), BA-2 (1.25 mu M), and BA-3 (1 mu M) exhibited survival rates of 2.99 % +/- 0.05 % mu M, 5.92 % +/- 2.04 % mu M, and 2.53 % +/- 0.73 % mu M, respectively, under white light irradiation. Mechanistic ex-periments revealed that derivatives induced cell apoptosis via the mitochondrial apoptosis pathway during both CT and CPCT. Remarkably, BA-1 and BA-3 in CPCT inhibited cancer cell proliferation in an in vivo melanoma mouse xenograft model. These results collectively encourage further research of PT-AIEgens as potential anti-cancer agents.