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

基于碳酸氢钠脂质体的肿瘤内乳酸中和策略增强化疗免疫治疗疗效

作　　者：Taoxing Peng Xinyue Shao Wenqin Song Weihua Xu Wei Xiong Yihao He Yang Ding Yongzhuo Huang 彭涛兴;邵欣悦;宋文沁;许玮华;熊维;何毅豪;丁杨;黄永焯

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

出　　处：《Science Bulletin》2024年第24期3936-3948,共13页科学通报(英文版)

基　　金：the National Key Research and Development Program of China(2021YFC400600,2022YFE0203600);the National Natural Science Foundation of China(81925035 and 82341232);the Future Network(083GJHZ2023012FN);Grand Challenges(083GJHZ2023021GC)of the International Partnership Program of the Chinese Academyof Sciences,CAS President’s International Fellowship Initiative(2024VBB0004);High-level Innovative Research Institute(2021B0909050003)from Department of Science;Technology of Guangdong Province;Zhongshan Municipal Bureau of Science and Technology(LJ2021001 and CXTD2022011).

摘　　要：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(NaHCO_(3)@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.NaHCO_(3)@Flip achieved deep tumor penetration,with the ability to neutralize lactic acid and normalize the acidic tumor microenvironment.NaHCO_(3)@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 NaHCO_(3)@Flip demonstrated enhanced inhibition of tumor growth.NaHCO_(3)@Flip can also synergize with PD-1 antibody therapy.NaHCO_(3)@Flip has the potential to serve as a therapeutic adjuvant for boosting chemoimmunotherapy by overcoming the ion-trapping effect and normalizing the tumor microenvironment.

关 键 词：Sodium bicarbonate Lactic acid neutralization Tumor microenvironment normalization CHEMOIMMUNOTHERAPY PD-1 antibody Ion-trapping barrier 

分 类 号：R730.51[医药卫生—肿瘤]