Therapeutic Effects Of Arsenic Trioxide Nano-Prodrug On Hepatocellular Carcinoma Model

Currently,arsenic trioxide（As₂O₃,ATO）is the first-line chemotherapy drug for acute promyelocytic leukemia（APL）,but its inappropriate pharmacokinetics and systemic toxicity make it difficult for clinical treatment of solid tumors.Here,we designed a gadolinium arsenite colloid（GdAsO₃）based on endogenous inorganic phosphorus（Pi）triggered release of ATO,namely arsenic trioxide nano-prodrug（ATONP）.A series of work was carried out around the pharmacology and toxicology at cellular and animal levels,and we also compared the efficacy of ATO nano-prodrug with traditional drugs such as ATO,sorafenib for the treatment of hepatocellular carcinoma.For the cytotoxicity test of SMMC-7721,ATONP was more active than ATO,killing cancer cells more effectively,and cell viability was Pi concentration dependent.Except for higher delivery efficiency（ID%.g=5%of ATONP vs 0.5%of ATO）,ATONP can change TME（tumor microenvironment）because it lowered the Pi concentration and increases the pH.On the basis,We used a clinically relevant Tet-Off MYC-inducible transgenic hepatocellular carcinoma model to assess treatment efficiency.Firstly,tumor volume was reduced by more than 50%after multiple administrations.Besides,ATONP significantly prolonged survival compared to other groups.Compared to the same dose of ATO,ATONP caused more cancer cells apoptotic due to higher delivery efficiency.The median lethal dose（LD50）was7.59 mg（As）/kg,slightly lower than ATO（10.7 mg（As）/kg）,showing systemic toxicity.But we found the toxicity reversibility of ATONP,because the main organs returned to normal after three weeks by stopping the injection of ATONP.These results indicated ATONP had significant results in the treatment of preclinical hepatocellular carcinoma model and toxicity was tolerable,showing ATONP had great potential in the clinical transformation of hepatocellular carcinoma.