Pre-clinical Research Of Arsenic Trioxide Nano-Prodrug In Interventional Therapy For VX2 Liver Cancer Model

Background:Arsenic trioxide(ATO)has remarkably therapeutic efficacy in treating both newly diagnosed and relapsed patients with acute promyelocytic leukemia(APL).However,it didn't benefit treatment of solid tumor,whether as a single agent,or combined with interventional therapy/radiotherapy as a chemosensitizer or radiosensitizer.The failure was attributed to severe systemic toxicity(such as cardiac toxicity,acute renal failure and gastrointestinal toxicity,etc.)and inappropriate pharmacokinetic including low delivery efficiency and rapid renal elimination.Nanomedicine aims to improve pharmaceuticals as well as reducing adverse effects by moderation of its absorption,distribution,metabolism,and excretion.However,even nano-ATO has improved its pharmacokinetic and takes higher chance to penetrate into tumor tissue it is still far from "bedside”,and the mystery need to be explored.The benefit of chemotherapy as a constituent of transcatheter arterial chemoembolization(TACE)is still in debate.Recently we have developed arsenic trioxide nanoparticle prodrug(ATONP)as a new anticancer drug,but its systemic toxicity is a big issue.Methods:We synthesized and characterized the nano prodrug-ATONP and determined its dosage in next TACE operation by vivo and vitro toxicity experiments.Blood samples were collected for blood drug concentration measurement after TACE administration to analyzed the pharmacokinetics of ATONP.The accumulation,distribution and excretion were explored by collecting tumor,normal liver tissues,feces and urine samples at designated intervals after procedure.Finally,we evaluated the efficacy and toxicity of ATONP as a TACE intraoperative drug through pathological,immunohistochemical and biochemical analysis methodsResults:In this preclinical TACE study,ATONP emulsified in lipiodol behaved as drug-eluting bead manner.Sustained release of arsenic from ATONP within occluded tumor caused very low arsenic level in plasma(Cmax=3.89 ± 0.38 ?g/L and 24.71 ± 2.96 ?g/L),avoiding the "rushing out”effect as ATO did.Correspondingly,intratumoral arsenic accumulation and inorganic phosphate deprivation were simultaneously observed,and arsenic concentration was much higher as ATONP was transarterially administered than ATO,or intravenously injected(15.32±1.41 ?g/g vs 4.90±0.93 ?g/g vs 0.89±0.53?g/g,P<0.01).Tumor necrosis and apoptosis(grade of apoptosis)were remarkably more severe in ATONP group than ATO(66.5±7.1%vs 44.3±3.7%,P<0.05 and 2.62±0.16 vs 2.25±0.14,P<0.01),but no significant hepatic and renal toxicity was perceived.Conclusion:In brief,ATONP alleviated arsenic toxicity and boosted the therapeutic effect of TACE via Pi-activated drug sustainable release.