Synergism of Ca2+ overload with mitochondria-targeted ursolic acid to enhance hepatocellular carcinoma therapy via endoplasmic reticulum stress and mitochondrial dysfunction

The mitochondrial targeting UT was synthesized by modifying ursolic acid (UA) with TPP-NH 2 . • A CaO 2 -based nanosystem loaded UT and surface coated with hyaluronic acid (HA) was successfully constructed for selective accumulation in hepatocellular carcinoma (HCC). • The combination of Ca 2+ overload and mitochondrion localized UT effectively promotes cancer cell apoptosis via induced mitochondrial dysfunction. • CUTP@HA significantly reduced the IC 50 for Hepa 1–6 cells to 14.6 μmol·L −1 and suppressed orthotopic liver tumor growth by 93.65%. Mitochondria not only act as the central regulator in cell apoptosis, but also highly determine the death of cancerous cells. The triggering of endoplasmic reticulum (ER) stress and mitochondrial dysfunction pose as potential strategies for advanced hepatocellular carcinoma (HCC) therapies of chemotherapeutic agents. Herein, we firstly reported the synthesis of mitochondrial targeted ursolic acid (UT) by modification of ursolic acid with [2-(triphenylphosphonio)ethyl]amine bromide (TPP-NH 2 ). Then, UT was loaded during the preparation of CaO 2 via crosslinking of Ca 2+ with dendritic polyacrylic acid in H 2 O 2 , and finally surface-coated with tumor-targeting hyaluronic acid (HA), termed CUTP@HA. CUTP@HA selectively accumulated in HCC and was destructed in the acidic tumor environment, which provoked the generation of abundant exogenous Ca 2+ , H 2 O 2 , and O 2 in situ. They effectively trigger calcium influx to jointly stimulate ER stress, and synergized with mitochondria-located UT to enhance Ca 2+ overload-induced mitochondrial dysfunction in cancer therapy, ultimately promoting cell apoptosis. Consequently, the amplified Ca 2+ overload-induced mitochondrial dysfunction’ methodology remarkably reduced the IC 50 of CUTP@HA for Hepa 1–6 cells to 14.6 μmol·L −1 , thereby suppressing orthotopic liver tumor growth by 93.65%. CUTP@HA provides perspectives on the modification and enhanced antitumor efficacy of active Chinese novel herbal chemotherapeutic ingredients. Synergism of Ca 2+ overload with mitochondria-targeted ursolic acid to enhance hepatocellular carcinoma therapy via endoplasmic reticulum stress and mitochondrial dysfunction. Download: Download high-res image (134KB) Download: Download full-size image