Augmented EPR effect post IRFA to enhance the therapeutic efficacy of arsenic loaded ZIF-8 nanoparticles on residual HCC progression

Xuehua Chen,Zhongzhen Su,Yongquan Huang,Hao Wang,Dan Li,Ziman Chen,Hui Chen,Jiaxin Chen

doi:10.1186/s12951-021-01161-3

Abstract

BackgroundInsufficient radiofrequency ablation (IRFA) can promote the local recurrence and distal metastasis of residual hepatocellular carcinoma (HCC), which makes clinical treatment extremely challenging. In this study, the malignant transition of residual tumors after IRFA was explored. Then, arsenic-loaded zeolitic imidazolate framework-8 nanoparticles (As@ZIF-8 NPs) were constructed, and their therapeutic effect on residual tumors was studied.ResultsOur data showed that IRFA can dramatically promote the proliferation, induce the metastasis, activate the epithelial–mesenchymal transition (EMT) and accelerate the angiogenesis of residual tumors. Interestingly, we found, for the first time, that extensive angiogenesis after IRFA can augment the enhanced permeability and retention (EPR) effect and enhance the enrichment of ZIF-8 nanocarriers in residual tumors. Encouraged by this unique finding, we successfully prepared As@ZIF-8 NPs with good biocompatibility and confirmed that they were more effective than free arsenic trioxide (ATO) in sublethal heat-induced cell proliferation suppression, apoptosis induction, cell migration and invasion inhibition, and EMT reversal in vitro. Furthermore, compared with free ATO, As@ZIF-8 NPs exhibited remarkably increased therapeutic effects by repressing residual tumor growth and metastasis in vivo.ConclusionsThis work provides a new paradigm for the treatment of residual HCC after IRFA.Graphical

Highlights

Hepatocellular carcinoma (HCC) is the sixth most common cancer, and its mortality rate is third among cancerrelated deaths worldwide [1]
The results showed that heat treatment increased the levels of N-cadherin and vimentin and decreased the level of E-cadherin, which suggested that heat stress can promote the epithelial–mesenchymal transition (EMT) process (Fig. 1D)
Power Doppler revealed that the percentage of blood vessels (PV) in residual tumors after Insufficient radiofrequency ablation (IRFA) was 2.47 ± 0.45-fold greater than that before ablation, but the PV in the control group did not change significantly (Fig. 1F)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common cancer, and its mortality rate is third among cancerrelated deaths worldwide [1]. The local recurrence rate of HCC after RFA ranges from 2 to 36% [6]. Recurrent tumors tend to have a high malignant grade and show low sensitivity to traditional chemotherapy, which leads to a worse patient prognosis [5]. These findings may be primarily attributed to the residual tumor that remains after insufficient radiofrequency ablation (IRFA). Insufficient radiofrequency ablation (IRFA) can promote the local recurrence and distal metastasis of residual hepatocellular carcinoma (HCC), which makes clinical treatment extremely challenging. The malignant transition of residual tumors after IRFA was explored. Arsenic-loaded zeolitic imidazolate framework-8 nanoparticles (As@ZIF-8 NPs) were constructed, and their therapeutic effect on residual tumors was studied

Methods

Results

Conclusion