Starvation-Sensitized and Oxygenation-Promoted Tumor Sonodynamic Therapy by a Cascade Enzymatic Approach.

Wencheng Wu,Jianlin Shi,Heliang Yao,Yinying Pu,Han Lin

doi:10.34133/2021/9769867

Abstract

The therapeutic outcomes of noninvasive sonodynamic therapy (SDT) are always compromised by tumor hypoxia, as well as inherent protective mechanisms of tumor. Herein, we report a simple cascade enzymatic approach of the concurrent glucose depletion and intratumoral oxygenation for starvation-sensitized and oxygenation-amplified sonodynamic therapy using a dual enzyme and sonosensitizer-loaded nanomedicine designated as GOD/CAT@ZPF-Lips. In particular, glucose oxidase- (GOD-) catalyzed glycolysis would cut off glucose supply within the tumor, resulting in the production of tumor hydrogen peroxide (H2O2) while causing tumor cells starvation. The generated H2O2 could subsequently be decomposed by catalase (CAT) to generate oxygen, which acts as reactants for the abundant singlet oxygen (1O2) production by loaded sonosensitizer hematoporphyrin monomethyl ether (HMME) upon the US irradiation, performing largely elevated therapeutic outcomes of SDT. In the meantime, the severe energy deprivation enabled by GOD-catalyzed glucose depletion would prevent tumor cells from executing protective mechanisms to defend themselves and make the tumor cells sensitized and succumbed to the cytotoxicity of 1O2. Eventually, GOD/CAT@ZPF-Lips demonstrate the excellent tumoral therapeutic effect of SDT in vivo without significant side effect through the cascade enzymatic starvation and oxygenation, and encouragingly, the tumor xenografts have been found completely eradicated in around 4 days by the intravenous injection of the nanomedicine without reoccurrence for as long as 20 days.

Highlights

Great progress has been achieved on oncology over the decades, cancer remains one of the major threats to human health due to its high risk and mortality [1,2,3]
This result is further confirmed by the changes of zeta potential of nanoparticles during the modification process, in which the surface charge of glucose oxidase (GOD)/CAT@ZPF-Lips was measured to be -9.56 mV (Table S1)
To verify whether GOD and CAT were successfully immobilized in ZPF or not, we previously labeled the GOD and CAT with fluorescein isothiocyanate (FITC) and Rhodamine B (RB), respectively, for the subsequent synthesis

Summary

Introduction

Great progress has been achieved on oncology over the decades, cancer remains one of the major threats to human health due to its high risk and mortality [1,2,3]. Given that traditional protocols (such as surgical excision, radiation therapy, and chemotherapy) would cause severe side effects and painful experiences on patients, noninvasive and safe sonodynamic therapy (SDT) shows promising prospects in cancer treatments [4,5,6,7]. Even as one of the most promising noninvasive cancer treatment modalities, there are still two major obstacles that deteriorate the effectiveness of SDT in solid tumor therapy. The toxic effect of 1O2 on tumor cells would be compromised by their diverse intrinsic protective mechanisms [14, 15]. If the two major drawbacks can be overcome concurrently using a facile strategy, undoubtedly, the therapeutic effect of SDT can be greatly enhanced

Methods

Results

Conclusion