Triphenylphosphonium-functionalised cubosomes for mitochondrial-targeted delivery of 5-fluorouracil and lycopene in skin cancer therapy

The importance of mitochondria in cancer is undeniable, as they serve as a vital centre for energy metabolism and regulating apoptosis. Herein, we engineered cubosomes as a nanocarrier with encapsulation of the chemotherapeutic agent 5-fluorouracil and an antioxidant with reported antitumor activity, lycopene. The formulation was fabricated by utilising glyceryl monooleate, oleic acid, and polaxamer-407, facilitating simultaneous encapsulation of hydrophobic lycopene and hydrophilic 5-fluorouracil. To target mitochondria, the nanoparticle surface was decorated with triphenylphosphine, a lipophilic cation known to gather within the negatively charged mitochondrial membrane. Physicochemical evaluation verified nanoscale particle size (158.7 nm), uniform distribution (0.2482 PDI), and high encapsulation efficiency (79 <b>±</b> 5.2% for 5-FU and 85 <b>±</b> 7.1% for lycopene). The synergistic impact of 5-FU-induced DNA synthesis suppression and lycopene-mediated mitochondrial oxidative stress was augmented by TPP-driven mitochondrial accumulation, resulting in significant apoptotic activity in cancer cells, as confirmed in <i>in vitro</i> cytotoxicity assays and <i>in vivo</i> animal studies. These findings highlight the potential of synergism of 5-FU and lycopene in skin cancer and also the potential of TPP-functionalised entrapped dual-drug-loaded cubosomes in mitochondrial targeting of skin cancerous cells.