Cubosome-based co-delivery of doxorubicin and polydatin for targeted cancer therapy

Liver cancer is one of the most prevalent and deadly malignancies worldwide, with limited effective therapeutic strategies. Although doxorubicin (DOX) is widely used as a frontline chemotherapeutic agent, its severe cardiotoxicity and lack of tumor selectivity significantly limited its clinical applications. Polydatin (PLD), a natural antioxidant and anticancer compound, has shown promise as an adjuvant for reducing DOX-induced cardiotoxicity, yet its poor bioavailability hinders its therapeutic potential. To improve the therapeutic efficacy of DOX while reducing systemic toxicity, we developed a hyaluronic acid (HA)-functionalized cubosome-based nanosystem co-loaded with DOX and PLD (1:3 ratio), i.e. HA 3% -D/P-CUBS + , to specifically target tumor sites with enhanced antitumor efficiency and alleviated DOX-induced cardiotoxicity. HA 3% -D/P-CUBS + significantly improved drug internalization and induced apoptosis in hepatocellular carcinoma cells (HepG-2 and HUH-7). Meanwhile, HA 3% -D/P-CUBS + protected normal hepatocytes (HL-7702 and AML-12) and reduced oxidative stress in cardiomyocytes (H9C2 cells). Notably, HA 3% -D/P-CUBS + inhibited in vivo tumor growth of 94 % without causing damage to vital organs, leading to improved survival rates. Moreover, it also mitigated DOX-induced oxidative stress by restoring the balance between oxidative and antioxidant systems. These findings highlight HA 3% -D/P-CUBS + as a promising and synergistic nanomedicine for targeted live cancer therapy, providing new insights into combination chemotherapy with enhanced safety and efficacy.