Novel curcumin nanocarrier for targeting drug delivery of mitochondria proves efficacy in in vivo experiments on hepatocellular carcinoma mice models

Hepatocellular carcinoma (HCC) remains difficult to treat due to systemic toxicity of non-selective therapies. To address this, we hypothesized that targeting the highly active mitochondria of cancer cells, which have considerably increased membrane potential compared with normal cells, could be a promising approach to induce a stronger anticancer effect. Here, we report a curcumin nanocarrier (TDC) synthesized by modifying PAMAM G4 dendrimers with triphenylphosphonium (TPP). This design enables mitochondrial targeting, leveraging the elevated membrane potential of cancer cells to enhance curcumin's anticancer activity. According to the results, the TDC influences the secreted levels of INF-γ and IL-4 on tumor lysis-stimulated splenocytes. In tumor-positive groups, TDC also increased cell population (sub G1 phase) 3.5 times, which was remarkable compared to healthy groups. Consistent with this, in tumor-positive mice, the amount of ROS and the overall rate of TDC-induced apoptosis were increased by approximately 40-50%. In addition, TDC upregulates pro-apoptotic genes (bax, p53) and downregulates oncogenic genes (bcl2, p21, xiap) in the cancerous liver tissues, reflecting the anti-cancer effect of TDC as a mitochondria-targeted delivery system. Investigations conducted ex vivo on mitochondria isolated from liver and brain tissues revealed elevated levels of ATP, malonaldehyde (MDA), and reactive oxygen species (ROS), along with reduced glutathione (GSH) levels, all of which were linked to the process of apoptosis. Finally, the biodistribution findings indicate that the accumulation of TDC in the tumor and liver was considerably greater than that of free curcumin (FC), likely due to the rapid elimination of FC at the concentration tested.