Local delivery of arsenic trioxide nanoparticles for hepatocellular carcinoma treatment

Jian Hu,Zhihua Wu,Yang Dong,Yourong Duan,Li Ding,Ming Shen,Yi Dong,Wenping Wang

doi:10.1038/s41392-019-0062-9

Abstract

Hepatocellular carcinoma (HCC) is a malignancy with a poor prognosis. Surgery combined with chemotherapy has been recommended as a curative regimen for HCC. Nevertheless, the anticancer mechanisms of chemicals in hepatocellular carcinoma remain unclear. Pyroptosis is a type of programmed necrosis, and its mechanism in hepatocellular carcinoma is poorly understood. The efficacy and mechanism of arsenic trioxide nanoparticles in the treatment of HCC were explored in this research. Arsenic trioxide alone and arsenic trioxide nanoparticles were conveniently administered to mice intratumorally using a needle. Compared with As2O3, As2O3 nanoparticles (As2O3-NPs) showed better inhibition, promoted greater LDH release, and induced cell morphology indicative of pyroptosis in vitro. Compared with the free drug, As2O3-NPs increased GSDME-N expression and decreased Dnmt3a, Dnmt3b, and Dnmt1 expression in Huh7 cells. In vivo, As2O3-NPs induced a significant decrease in the expression of Dnmt3a, Dnmt3b and Dnmt1, but significantly upregulated the expression of GSDME-N (gasdermin E (GSDME) was originally found to be related to deafness; recently, it has been defined as a gasdermin family member associated with pyroptosis). As2O3-NPs inhibited tumor growth more strongly than As2O3 or control, a finding likely attributed to the downregulation of PCNA and DNMT-related proteins and the upregulation of GSDME-N.

Highlights

Hepatocellular carcinoma (HCC) is a malignancy with a poor prognosis, and an considerable medical challenge.[1]
This study aimed to investigate the nano drug delivery system mPEG-PLGA-PLL loaded with arsenic trioxide, which was delivered via intratumoral administration
The results indicated that GSDME cleavage was strongly triggered by the increase in As2O3 dose in Huh[7] cells, while GSDMD was not detected by western blotting (Fig. S3)

Summary

Introduction

Hepatocellular carcinoma (HCC) is a malignancy with a poor prognosis, and an considerable medical challenge.[1]. Arsenic trioxide has been used alone and in combination as drug therapy for acute promyelocytic leukemia.[2,3] In addition, there has been constant progress in applying arsenic trioxide treatment for solid tumors, including HCC.[4,5,6,7] As2O3 can promote the differentiation of surviving cancer cells. This characteristic allows As2O3 to reduce the malignant behavior and metastatic risk of surviving cancer cells during chemotherapy, achieving better treatment responses with lower rates of metastasis and recurrence than traditional anticancer drugs.[8] it is difficult to achieve effective As2O3 accumulation inside a solid tumor because of rapid clearance of this drug in blood circulation.[9,10] A high dose can be used to maintain the therapeutic activity but causes systemic adverse reactions. Much attention has been focused on localized chemotherapy, such as a direct intratumoral injection.[11,12] Local drug delivery systems can prolong the retention time of chemotherapeutic agents at the dosing site to obtain more continuous efficacy and reduce adverse reactions in normal organs and tissues.[13,14,15,16,17]

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Conclusion