Ratiometric co-delivery of hydroxychloroquine and calculated low-dose paclitaxel efficiently suppresses tumor growth in hepatocellular carcinoma mouse models in vivo

Abstract

Utilizing a liposomal nanocarrier to co-encapsulate autophagy inhibitor hydroxychloroquine (HCQ) plus a calculated low-dose chemotherapeutic agent paclitaxel (PTX), we demonstrated a ratiometrically designed nanoformulation with synergistic anti-cancer efficacy in various hepatocellular carcinoma (HCC) mouse models. Using CompuSyn software to calculate drug synergy, we determined the synergistic drug ratios in cultured HCC cells, which became the reference to design ratiometric liposomes. Particle synthesis was accomplished by a film dispersion method for the calculated amount of PTX lipid incorporation and a remote loading process for HCQ import using ammonium sulfate. Ratiometric co-delivery led to synergistic killing effect and autophagy inhibition in cultured HCC cells and nude mice that were used to grow subcutaneous human HepG2 xenografts. Intravenous injection of ratiometric liposome yielded the most effective tumor shrinkage compared to various controls, including the free drug mix. A similar outcome was achieved in a HepG2 orthotopic model. We further explored the anti-cancer effect in a Hep1–6 murine HCC in immunocompetent mice, with or without co-administrated anti-PD1 antibody. Anti-PD1 antibody synergized with HCQ/PTX ratiometric liposome in the immunocompetent model.