Acidic/hypoxia dual-alleviated nanoregulators for enhanced treatment of tumor chemo-immunotherapy  

作　　者：Xiaoju Guo Xiaoxiao Chen Jiayi Ding Feng Zhang Shunyang Chen Xin Hu Shiji Fang Lin Shen Chenying Lu Zhongwei Zhao Jianfei Tu Gaofeng Shu Minjiang Chen Jiansong Ji 

机构地区：[1]Lishui Central Hospital,Shaoxing University,Shaoxing 312000,China [2]Zhejiang Key Laboratory of Imaging and Interventional Medicine,Imaging Diagnosis and Interventional Minimally Invasive Institute,The Fifth Affiliated Hospital of Wenzhou Medical University,Lishui 323000,China [3]Clinical College of The Affiliated Central Hospital,School of Medicine,Lishui University,Lishui 323000,China [4]Key Laboratory of Precision Medicine of Lishui,Lishui 323000,China

出　　处：《Asian Journal of Pharmaceutical Sciences》2024年第2期136-152,共17页亚洲药物制剂科学（英文）

基　　金：supported by the Key R&D Program of Lishui City(2021ZDYF12,2022ZDYF07,2023zdyf14);Natural Science Foundation of China(82072026,82072025 and 82272090);Zhejiang Provincial Natural Science Foundation(LY23H180003,LQ22H180010);Provincial and Ministerial Joint Construction of Key Projects(WKJ-ZJ-2317).

摘　　要：Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.

关 键 词：CaCO3-based nanoparticles Hypoxia attenuation Acidity neutralization Reversal of chemotherapy resistance Enhanced chemo-immunotherapy 

分 类 号：R943[医药卫生—药剂学]