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

• Published in: Asian journal of pharmceutical sciences Vol. 19; no. 2; p. 100905
• Main Authors: Guo, Xiaoju, Chen, Xiaoxiao, Ding, Jiayi, Zhang, Feng, Chen, Shunyang, Hu, Xin, Fang, Shiji, Shen, Lin, Lu, Chenying, Zhao, Zhongwei, Tu, Jianfei, Shu, Gaofeng, Chen, Minjiang, Ji, Jiansong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2024; Shenyang Pharmaceutical University; Elsevier
• Subjects: Acidity neutralization; CaCO3-based nanoparticles; Enhanced chemo-immunotherapy; Hypoxia attenuation; Reversal of chemotherapy resistance; CaCO3-based nanoparticles; Enhanced chemo-immunotherapy; Reversal of chemotherapy resistance; Hypoxia attenuation; Acidity neutralization
• ISSN: 1818-0876; 2221-285X
• DOI: 10.1016/j.ajps.2024.100905

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. Schematic illustration of DHCaNPs for amplified chemo-immunotherapy of TNBC. After treatment with DHCaNPs, it would lead to an excellent capability of simultaneously alleviating tumor acidity and hypoxia, thereby greatly enhancing the therapeutic efficacy of chemotherapy against breast cancer. Meanwhile, DHCaNPs could effectively elicit systemic antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cell. Consequently, DHCaNPs could synergize with αPD-L1 to effectively suppress the growth of primary and metastatic tumors [Display omitted] .