Intratumoral lactic acid neutralization strategy for boosting chemoimmunotherapy using liposomal sodium bicarbonate

Taoxing Peng; Xinyue Shao; Wenqin Song; Weihua Xu; Wei Xiong; Yihao He; Yang Ding; Yongzhuo Huang

doi:10.1016/j.scib.2024.08.042

Intratumoral lactic acid neutralization strategy for boosting chemoimmunotherapy using liposomal sodium bicarbonate

Sci Bull (Beijing). 2024 Nov 6:S2095-9273(24)00800-4. doi: 10.1016/j.scib.2024.08.042. Online ahead of print.

Authors

Taoxing Peng¹, Xinyue Shao², Wenqin Song³, Weihua Xu⁴, Wei Xiong⁵, Yihao He⁴, Yang Ding⁶, Yongzhuo Huang⁷

Affiliations

¹ State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
³ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁵ Zhongshan Institute for Drug Discovery, Shanghai Institutes of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
⁶ State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
⁷ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Zhongshan Institute for Drug Discovery, Shanghai Institutes of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China; NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, Shanghai 201203, China. Electronic address: [email protected].

PMID: 39547906
DOI: 10.1016/j.scib.2024.08.042

Abstract

Glycolysis-related lactic acid overproduction creates an "ion-trapping" barrier and immunosuppressive tumor microenvironment that compromise effective intratumoral drug delivery and therapy. Therefore, normalization of tumor microenvironment via lactic acid neutralization can be a promising avenue for overcoming this therapeutic hurdle. In this study, the flexible liposomes loaded with sodium bicarbonate (NaHCO₃@Flip) were used as a nano-adjuvant to boost chemoimmunotherapy. Their effects on assisting DOXIL and anti-programmed cell death protein 1 (PD-1) therapy were investigated. NaHCO₃@Flip achieved deep tumor penetration, with the ability to neutralize lactic acid and normalize the acidic tumor microenvironment. NaHCO₃@Flip is biosafe and can enhance cellular uptake efficiency of doxorubicin (DOX) by overcoming the ion-trapping barrier and amplify immunogenic cell death induced by DOX. The combination therapy of liposomal DOX and NaHCO₃@Flip demonstrated enhanced inhibition of tumor growth. NaHCO₃@Flip can also synergize with PD-1 antibody therapy. NaHCO₃@Flip has the potential to serve as a therapeutic adjuvant for boosting chemoimmunotherapy by overcoming the ion-trapping effect and normalizing the tumor microenvironment.

Keywords: Chemoimmunotherapy; Ion-trapping barrier; Lactic acid neutralization; PD-1 antibody; Sodium bicarbonate; Tumor microenvironment normalization.