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In situ injectable hydrogel encapsulating Mn/NO-based immune nano-activator for prevention of postoperative tumor recurrence

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Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 102-119页

作者： Shengnan Huang Chenyang Zhou Chengzhi Song Xiali Zhu Mingsan Miao Chunming Li Shaofeng Duan Yurong Hu Academy of Chinese Medical Sciences Henan University of Chinese MedicineZhengzhou 450046China School of Pharmaceutical Sciences Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical DiseasesZhengzhou UniversityZhengzhou 450001China Center for Quantitative Biology Peking UniversityBeijing 100871China School of Pharmaceutical Sciences Henan University of Chinese MedicineZhengzhou 450046China Department of Pharmacy Chongqing University Cancer HospitalChongqing 400030China School of Pharmaceutical Sciences Henan UniversityZhengzhou 450046China

Postoperative tumor recurrence remains a predominant cause of treatment failure. In this study, we developed an in situ injectable hydrogel, termed MPB-NO@DOX + ATRA gel, which was locally formed within the tumor resection cavity. The MPB-NO@DOX + ATRA gel was fabricated by mixing a thrombin solution, a fibrinogen solution containing all-trans retinoic acid (ATRA), and a Mn/NO-based immune nano-activator termed MPB-NO@DOX. ATRA promoted the differentiation of cancer stem cells, inhibited cancer cell migration, and affected the polarization of tumor-associated macrophages. The outer MnO2 shell disintegrated due to its reaction with glutathione and hydrogen peroxide in the cytoplasm to release Mn2+ and produce O2, resulting in the release of doxorubicin (DOX). The released DOX entered the nucleus and destroyed DNA, and the fragmented DNA cooperated with Mn2+ to activate the cGAS-STING pathway and stimulate an anti-tumor immune response. In addition, when MPB-NO@DOX was exposed to 808 nm laser irradiation, the Fe-NO bond was broken to release NO, which downregulated the expression of PD-L1 on the surface of tumor cells and reversed the immunosuppressive tumor microenvironment. In conclusion, the MPB-NO@DOX + ATRA gel exhibited excellent anti-tumor efficacy. The results of this study demonstrated the great potential of in situ injectable hydrogels in preventing postoperative tumor recurrence.

关键词： Post-sur gical tumor recurrence In situl hydrogel Immunotherapy Tumor micr oenvir onment Manganese(Ⅱ) Nitic oxide

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In situ injectable hydrogel encapsulating Mn/NO-based immune nano-activator for prevention of postoperative tumor recurrence

引用

Asian Journal of Pharmaceutical Sciences 2024年第02期 104-121页

作者： Shengnan Huang Chenyang Zhou Chengzhi Song Xiali Zhu Mingsan Miao Chunming Li Shaofeng Duan Yurong Hu Academy of Chinese Medical Sciences Henan University of Chinese Medicine School of Pharmaceutical Sciences Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases Zhengzhou University Center for Quantitative Biology Peking University School of Pharmaceutical Sciences Henan University of Chinese Medicine Department of Pharmacy Chongqing University Cancer Hospital School of Pharmaceutical Sciences Henan University

Postoperative tumor recurrence remains a predominant cause of treatment failure. In this study, we developed an in situ injectable hydrogel, termed MPB-NO@DOX + ATRA gel,which was locally formed within the tumor resection cavity. The MPB-NO@DOX + ATRA gel was fabricated by mixing a thrombin solution, a fibrinogen solution containing all-trans retinoic acid（ATRA）, and a Mn/NO-based immune nano-activator termed MPB-NO@*** promoted the differentiation of cancer stem cells, inhibited cancer cell migration,and affected the polarization of tumor-associated macrophages. The outer MnO2shell disintegrated due to its reaction with glutathione and hydrogen peroxide in the cytoplasm to release Mn2+and produce O2, resulting in the release of doxorubicin（DOX）. The released DOX entered the nucleus and destroyed DNA, and the fragmented DNA cooperated with Mn2+to activate the cGAS-STING pathway and stimulate an anti-tumor immune *** addition, when MPB-NO@DOX was exposed to 808 nm laser irradiation, the Fe-NO bond was broken to release NO, which downregulated the expression of PD-L1 on the surface of tumor cells and reversed the immunosuppressive tumor *** conclusion, the MPB-NO@DOX + ATRA gel exhibited excellent anti-tumor efficacy. The results of this study demonstrated the great potential of in situ injectable hydrogels in preventing postoperative tumor recurrence.

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