Nano-Reprogrammed Pitavastatin Cubosomes for Hepatocellular Carcinoma: Boosted Cytotoxicity, In Vivo Pharmacokinetics, and Multitarget Anticancer Action

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality, and current treatments remain restricted by limited efficacy and systemic toxicity. This study's objective was to assess the feasibility of developing a targeted platform based on cubosomal nanoparticles loaded with pitavastatin (PTV) for HCC therapy. A total of 15 formulations were created and optimized using a 33 Box-Behnken design to study the influence of glyceryl monooleate (GMO) concentration, GMO: Pluronic F127 (F127) ratio (GMO: F127), and homogenization time on formulation characteristics. The optimized cubosomes (10% GMO, 100:5 GMO: F127, 5 min homogenization) exhibited a nanoscale size (165 ± 0.6 nm), low polydispersity (0.27), high entrapment efficiency (95 ± 0.6%), and a stable zeta potential (–24.7 mV). Nanoparticle size, uniformity, and successful drug encapsulation were confirmed by morphological inspection. The optimized biphasic PTV-cubosomes showed 94.8% drug release within 24 hours, a significant increase compared to the pure drug suspension. The formulation achieved the highest cytotoxicity against HepG2 and Huh7 cells. Cyto- and drug release behavior showed in silico evidence of strong binding to EGFR with favorable pharmacokinetics. Collectively, PTV-loaded cubosomes offer a promising nanotechnological approach to enhance pitavastatin's therapeutic potential in the management of hepatocellular carcinoma.