Abstract 3899: Nanoparticle reduces hepatotoxicity of cancer treatment by controlled release and Kupffer cell uptake

Abstract

Background: One of the major concerns in cancer treatment and clinical translation of many anti-cancer compounds has been their potential toxicities, especially hepatotoxicity. Nanoparticle (NP) holds great potential to solve the problem, as many clinical studies have not shown increased hepatotoxicity for nanotherapeutics with higher accumulation in the liver. However, there are few studies investigating how nanoparticle assists in reducing hepatotoxicity. Herein, we demonstrated that nanoformulation of known hepatotoxic anti-cancer compounds showed lower hepatotoxicity than their small molecule counterparts. Importantly, we demonstrated that slower drug release is associated with reduced hepatotoxicity. We also showed that that Kupffer cell uptake in the liver reduce nanotherapeutics’ hepatotoxicity. Methods: Two different antineoplastic drugs with high hepatotoxicity, SN-38 and wortmannin (Wtmn), were encapsulated into lipid shell-PLGA core nanoparticles separately. NP release kinetics were controlled by adjusting lipids/polymer ratio for fast (Fast-NPs), medium (Medium-NPs) and slow drug release profile (Slow-NPs), respectively. Hepatotoxicity of NPs or free drugs was analyzed by assessing serum ALT and AST levels post intravenous injection at ½ MTD in CD-1 mice. IHC staining of HO-1 and Mn-SOD was also used to show liver damage. In vitro hepatotoxicity of primary hepatocytes after Kupffer cell uptake was assessed by MTS assay and LDH assay. In vivo macrophage depletion was achieved using clodrosome. Results: Nanoformulations of SN-38 and Wtmn showed lower ALT and AST levels than their small molecule counterparts 12 h and 24 h post treatment. The liver damage was further confirmed with IHC staining of Mn-SOD and HO-1. To address the effect of drug release kinetics on hepatotoxicity, we showed that over 90% of drugs were released within 24 h in Fast-NP. While the release rate of Slow-NPs was 66.8% for SN-38 and 67.5% for Wtmn. We showed that Slow-NPs of Wtmn resulted in minimal increase of ALT and AST levels. Compared to the baseline in untreated mice, the ALT level was 2.3-fold for Slow-NPs, 4.4-fold for Medium-NPs and 6-fold for fast-NPs; meanwhile, the AST level was 1.6-fold, 2.5-fold and 3.6-fold, respectively. To assess the effect of Kupffer cell uptake in hepatotoxicity, we found that the toxicity of the nanotherapeutics for primary hepatocytes significantly reduced after Kupffer cell uptake in vitro . We further confirmed it in vivo by depleting Kupffer cells in CD-1 mice. We demonstrated that ALT and AST levels of nanotherapeutics significantly increased to the levels comparable to free drugs after Kupffer cell depletion. Conclusions: We demonstrate that nanoparticle reduces hepatotoxicity of cancer treatment by controlled release and Kupffer cell uptake. Our work bridges an important knowledge in nanoparticle drug delivery and clinical translation of nanomedicine. Citation Format: Yu Mi, Feifei Yang, Andrew Z. Wang. Nanoparticle reduces hepatotoxicity of cancer treatment by controlled release and Kupffer cell uptake [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3899.