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Ternary Regulation of Tumor Microenvironment by Heparanase‐Sensitive Micelle‐Loaded Monocytes Improves Chemo‐Immunotherapy of Metastatic Breast Cancer
Author(s) -
Lang Tianqun,
Zheng Zhong,
Huang Xin,
Liu Yiran,
Zhai Yihui,
Zhang Pengcheng,
Li Yaping,
Yin Qi
Publication year - 2021
Publication title -
advanced functional materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.069
H-Index - 322
eISSN - 1616-3028
pISSN - 1616-301X
DOI - 10.1002/adfm.202007402
Subject(s) - cancer research , tumor microenvironment , heparanase , immunotherapy , triple negative breast cancer , metastatic breast cancer , metastasis , breast cancer , medicine , immune system , docetaxel , pharmacology , cancer , immunology , tumor cells
Tumor immunotherapy approaches such as programmed cell death‐1/programmed cell death‐ligand 1 (PD‐1/PD‐L1) checkpoint blockade and indoleamine 2,3‐dioxygenase (IDO) inhibition are proven to promote immune response against tumors. Unfortunately, their positive response rates are unsatisfactory due to complicated immunosuppressive mechanisms in the tumor microenvironment, which can probably be rescued by integrating multiple immunoregulators and chemotherapeutic agents together. To improve the combination therapy of metastatic breast cancer, a ternary heparanase (Hpa)‐sensitive micelle‐loaded monocyte delivery system, termed as HDNH@MC, is designed, exploiting the capacity of Ly6C hi monocytes to be recruited to tumor sites and the overexpression of Hpa in tumors. The prodrugs of the chemotherapeutic agent docetaxel and IDO inhibitor NLG919 are synthesized by conjugating them on the substrate of Hpa, heparan sulfate. Then the PD‐1/PD‐L1 inhibitor HY19991‐encapsulating prodrug micelle@Ly6C hi monocyte system is prepared. HNDH@MC elevates drug concentrations and relieves immunosuppression in tumors of 4T1 breast carcinomas mice model, thus enhancing the infiltration and activity of CD8 + T cells and presenting significant anti‐cancer effect. The lung metastasis is suppressed and the survival of mice is prolonged. HNDH@MC will be a promising option for treating metastatic breast cancer by synergy of tumor‐targeting chemotherapy and immunotherapy.