Hypoxia and acidic microenvironments are characteristic features of solid tumors, driving tumor growth, drug resistance, and metastasis. To address these issues, we combined hyperbaric oxygen therapy with rational designed hydroxyethyl starch-doxorubicin-copper nanoparticles to modulate the acidic microenvironment of tumors while enhancing the efficacy of chemotherapy and chemodynamic therapy to effectively kill hypoxic solid tumors. Our work reveals that alleviating hypoxia and modulating the tumor pH environment are effective for tumor therapy and expected to enhance the efficacy of multiple therapies in the treatment of solid tumors.
Abstract:
An extracellular acidic environment and an intracellular mildly alkaline environment induced by carbonic anhydrase 9 (CA9) play a critical role in self-renewal, invasion, migration, and drug resistance of cancer stem cells (CSCs) within hypoxic solid tumors. Here, we report an antitumor strategy leveraging hyperbaric oxygen therapy (HBO) to regulate tumor pH and boost hydroxyethyl starch-doxorubicin-copper nanoparticles (HHD-Cu NPs) against CSCs. HBO overcomes tumor hypoxia, downregulates pH-regulatory proteins such as CA9, and leads to intracellular accumulation of acidic metabolites. As a result, HBO promotes intracellular acidification of both tumor cells and CSCs, triggering efficient doxorubicin release and the potent copper-mediated chemical dynamic effect of subsequently administered dual-acid-responsive HHD-Cu NPs. The combination of HBO with HHD-Cu NPs not only eliminates tumor cells but also inhibits CSCs, altogether leading to potent tumor inhibition. This study explores a new function of clinical-widely used HBO and establishes a novel combination therapy for treating CSCs abundant hypoxic solid tumors.
Author list:
Qingyuan Deng†, Ao Hua†, Shiyou Li, Zhijie Zhang, Xiang Chen, Qiang Wang, Xing Wang, Zhiqin Chu, Xiangliang Yang*, Zifu Li*
How to cite:
Q. Deng, A. Hua, S. Li, Z. Zhang, X. Chen, Q. Wang, X. Wang, Z. Chu, X. Yang, Z. Li, Exploration 2025, 20240080.
https://doi.org/10.1002/EXP.20240080