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 ± 5.2% for 5-FU and 85 ± 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 in vitro cytotoxicity assays and in vivo 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.