Intracellular Reduction-Responsive Molecular Targeted Nanomedicine for Hepatocellular Carcinoma Therapy.

Lei Ding,Xingkai Liu,Xu Huang,Zhenxiang Yu,Ping Zhang,Kunmeng Yang

doi:10.3389/fphar.2021.809125

Abstract

The stimuli-responsive polymer-based platform for controlled drug delivery has gained increasing attention in treating hepatocellular carcinoma (HCC) owing to the fascinating biocompatibility and biodegradability, improved antitumor efficacy, and negligible side effects recently. Herein, a disulfide bond-contained polypeptide nanogel, methoxy poly(ethylene glycol)−poly(l-phenylalanine-co-l-cystine) [mPEG−P(LP-co-LC)] nanogel, which could be responsive to the intracellular reduction microenvironments, was developed to deliver lenvatinib (LEN), an inhibitor of multiple receptor tyrosine kinases, for HCC therapy. The lenvatinib-loaded nanogel (NG/LEN) displayed concise drug delivery under the stimulus of glutathione in the cancer cells. Furthermore, the intracellular reduction-responsive nanomedicine NG/LEN showed excellent antitumor effect and almost no side effects toward both subcutaneous and orthotopic HCC tumor-allografted mice in comparison to free drug. The excellent tumor-inhibition efficacy with negligible side effects demonstrated the potential of NG/LEN for clinical molecular targeted therapy of gastrointestinal carcinoma in the future.

Highlights

Hepatocellular carcinoma (HCC), the most commonly diagnosed liver cancer, is the third most lethal malignancy in China, causing 4,221,000 deaths in 2015 (Chen et al, 2016)
The S−S-crosslinked mPEG−polypeptide nanogel was constructed by a hydrophobic reduction-responsive S−Scontained core of P(LP-co-LC) and a hydrophilic shell of mPEG
The results showed that LEN could effectively inhibit the hepatocellular carcinoma (HCC) progression, and the encapsulation by mPEG−polypeptide nanogel could improve the efficacy of LEN further

Summary

INTRODUCTION

Hepatocellular carcinoma (HCC), the most commonly diagnosed liver cancer, is the third most lethal malignancy in China, causing 4,221,000 deaths in 2015 (Chen et al, 2016). Due to its hydrophobicity, oral administration as the only option induces short half-life (Xu et al, 2021) Besides these side effects, the high cost and ease to generate resistance further limit the extensive use of molecular targeted drugs (Liu et al, 2021; Sun et al, 2021). Smart nanoparticles decorated with moderate radical groups exhibited tumor microenvironment-responsive characteristics, which could achieve precise delivery and release of antitumor agents (Huo et al, 2017; Chen et al, 2019; Zhang et al, 2020). The high GSH concentration in the tumor cells provides the possibility for the effectively disulfide bond (S−S)contained nanogel for reduction-responsive delivery of therapeutic agents in HCC treatment. The results confirmed that the reductionresponsive polypeptide nanogel was proven to be a good design to deliver molecular targeted drugs with enhanced effect for inhibition of tumor progression

MATERIALS AND METHODS

RESULTS AND DISCUSSION

CONCLUSION

ETHICS STATEMENT