An Injectable Hydrogel for Enhanced FeGA-Based Chemodynamic Therapy by Increasing Intracellular Acidity.

Wen Zeng,Zeming Liu,Ziqi Wang,Weilong Suo,Dazhen Jiang,Daoming Zhu,Qinqin Huang

doi:10.3389/fonc.2021.750855

Abstract

Hydroxyl radical (•OH)-mediated chemodynamic therapy (CDT) is an emerging antitumor strategy, however, acid deficiency in the tumor microenvironment (TME) hampers its efficacy. In this study, a new injectable hydrogel was developed as an acid-enhanced CDT system (AES) for improving tumor therapy. The AES contains iron–gallic acid nanoparticles (FeGA) and α-cyano-4-hydroxycinnamic acid (α-CHCA). FeGA converts near-infrared laser into heat, which results in agarose degradation and consequent α-CHCA release. Then, as a monocarboxylic acid transporter inhibitor, α-CHCA can raise the acidity in TME, thus contributing to an increase in ·OH-production in FeGA-based CDT. This approach was found effective for killing tumor cells both in vitro and in vivo, demonstrating good therapeutic efficacy. In vivo investigations also revealed that AES had outstanding biocompatibility and stability. This is the first study to improve FeGA-based CDT by increasing intracellular acidity. The AES system developed here opens new opportunities for effective tumor treatment.

Highlights

Cancer, as one of the primary diseases affecting human health, has a profound impact on human life, and the patient’s condition becomes due to the rapid propagation and diffusion of cancer cells, and the lower efficacy of the currently used chemotherapeutic agents [1,2,3,4,5]
The applicability of FeGA can be greatly improved through the hydrogel delivery system
The results revealed that, despite the presence of a-cyano-4-hydroxycinnamic acid (a-CHCA) in the acid-enhanced CDT system (AES) group, a-CHCA was unable to affect the cells due to the hydrogel’s encapsulation, but the AES + NIR group had increased lactic acid concentration. a-CHCA can be released after laser irradiation, changing the lactic acid ecological microenvironment of tumor cells

Summary

Introduction

As one of the primary diseases affecting human health, has a profound impact on human life, and the patient’s condition becomes due to the rapid propagation and diffusion of cancer cells, and the lower efficacy of the currently used chemotherapeutic agents [1,2,3,4,5]. FeGA turns light energy into heat energy upon irradiating the AES system with an 808 nm near-infrared (NIR) laser, causing the temperature rise of the agarose hydrogel, as a result, reversible hydrolysis and softening occur. This demonstrates that our AES system has a strong ability to control drug release, which inhibits lactic acid efflux, strengthens the tumor’s acidic environment, and keeps the cells in an acidic environment, which is likely to promote FeGA-mediated CDT.

Results

Conclusion