Injectable Hydrogel Encapsulating Mn/NO-based Immune Nano-activator for Prevention of Postoperative Tumor Recurrence

Overview

Journal Asian J Pharm Sci

Date 2024 Apr 22

PMID 38645467

Authors

Shengnan Huang

Chenyang Zhou

Chengzhi Song

Xiali Zhu

Mingsan Miao

Chunming Li

Shaofeng Duan

Yurong Hu

Affiliations

Soon will be listed here.

Abstract

Postoperative tumor recurrence remains a predominant cause of treatment failure. In this study, we developed an 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 MnO shell disintegrated due to its reaction with glutathione and hydrogen peroxide in the cytoplasm to release Mn and produce O, resulting in the release of doxorubicin (DOX). The released DOX entered the nucleus and destroyed DNA, and the fragmented DNA cooperated with Mn 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 injectable hydrogels in preventing postoperative tumor recurrence.

Citing Articles

Recent advances of injectable in situ-forming hydrogels for preventing postoperative tumor recurrence.

Wang Z, Zhai B, Sun J, Zhang X, Zou J, Shi Y Drug Deliv. 2024; 31(1):2400476.

PMID: 39252545 PMC: 11389645. DOI: 10.1080/10717544.2024.2400476.

References

Chen Q, Wang C, Zhang X, Chen G, Hu Q, Li H . In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment. Nat Nanotechnol. 2018; 14(1):89-97. DOI: 10.1038/s41565-018-0319-4. View

Kubli S, Berger T, Araujo D, Siu L, Mak T . Beyond immune checkpoint blockade: emerging immunological strategies. Nat Rev Drug Discov. 2021; 20(12):899-919. DOI: 10.1038/s41573-021-00155-y. View

Park C, Hartl C, Schmid D, Carmona E, Kim H, Goldberg M . Extended release of perioperative immunotherapy prevents tumor recurrence and eliminates metastases. Sci Transl Med. 2018; 10(433). DOI: 10.1126/scitranslmed.aar1916. View

Zhang K, Qi C, Cai K . Manganese-Based Tumor Immunotherapy. Adv Mater. 2022; 35(19):e2205409. DOI: 10.1002/adma.202205409. View

Xu J, Lv J, Zhuang Q, Yang Z, Cao Z, Xu L . A general strategy towards personalized nanovaccines based on fluoropolymers for post-surgical cancer immunotherapy. Nat Nanotechnol. 2020; 15(12):1043-1052. DOI: 10.1038/s41565-020-00781-4. View

Kim J, Francis D, Sestito L, Archer P, Manspeaker M, OMelia M . Thermosensitive hydrogel releasing nitric oxide donor and anti-CTLA-4 micelles for anti-tumor immunotherapy. Nat Commun. 2022; 13(1):1479. PMC: 8933465. DOI: 10.1038/s41467-022-29121-x. View

Wang C, Guan Y, Lv M, Zhang R, Guo Z, Wei X . Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses. Immunity. 2018; 48(4):675-687.e7. DOI: 10.1016/j.immuni.2018.03.017. View

Lv M, Chen M, Zhang R, Zhang W, Wang C, Zhang Y . Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy. Cell Res. 2020; 30(11):966-979. PMC: 7785004. DOI: 10.1038/s41422-020-00395-4. View

Wang C, Sun Z, Zhao C, Zhang Z, Wang H, Liu Y . Maintaining manganese in tumor to activate cGAS-STING pathway evokes a robust abscopal anti-tumor effect. J Control Release. 2021; 331:480-490. DOI: 10.1016/j.jconrel.2021.01.036. View

10.

Tohme S, Yazdani H, Al-Khafaji A, Chidi A, Loughran P, Mowen K . Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress. Cancer Res. 2016; 76(6):1367-80. PMC: 4794393. DOI: 10.1158/0008-5472.CAN-15-1591. View

11.

Clough K, Kaufman G, Nos C, Buccimazza I, Sarfati I . Improving breast cancer surgery: a classification and quadrant per quadrant atlas for oncoplastic surgery. Ann Surg Oncol. 2010; 17(5):1375-91. DOI: 10.1245/s10434-009-0792-y. View

12.

Leng Q, Li Y, Zhou P, Xiong K, Lu Y, Cui Y . Injectable hydrogel loaded with paclitaxel and epirubicin to prevent postoperative recurrence and metastasis of breast cancer. Mater Sci Eng C Mater Biol Appl. 2021; 129:112390. DOI: 10.1016/j.msec.2021.112390. View

13.

Liu Y, Yu F, Dai S, Meng T, Zhu Y, Qiu G . All-Trans Retinoic Acid and Doxorubicin Delivery by Folic Acid Modified Polymeric Micelles for the Modulation of Pin1-Mediated DOX-Induced Breast Cancer Stemness and Metastasis. Mol Pharm. 2021; 18(11):3966-3978. DOI: 10.1021/acs.molpharmaceut.1c00220. View

14.

Murphy D, Cheng H, Yang T, Yan X, Adjei I . Reversing Hypoxia with PLGA-Encapsulated Manganese Dioxide Nanoparticles Improves Natural Killer Cell Response to Tumor Spheroids. Mol Pharm. 2021; 18(8):2935-2946. DOI: 10.1021/acs.molpharmaceut.1c00085. View

15.

Huang X, Zhong Y, Li Y, Zhou X, Yang L, Zhao B . Black Phosphorus-Synergic Nitric Oxide Nanogasholder Spatiotemporally Regulates Tumor Microenvironments for Self-Amplifying Immunotherapy. ACS Appl Mater Interfaces. 2022; 14(33):37466-37477. DOI: 10.1021/acsami.2c10098. View

16.

Chao Y, Wei T, Li Q, Liu B, Hao Y, Chen M . Metformin-containing hydrogel scaffold to augment CAR-T therapy against post-surgical solid tumors. Biomaterials. 2023; 295:122052. DOI: 10.1016/j.biomaterials.2023.122052. View

17.

Cassetta L, Pollard J . Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discov. 2018; 17(12):887-904. DOI: 10.1038/nrd.2018.169. View

18.

Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso M . Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014; 2014:149185. PMC: 4036716. DOI: 10.1155/2014/149185. View

19.

Sun R, Liu Y, Li S, Shen S, Du X, Xu C . Co-delivery of all-trans-retinoic acid and doxorubicin for cancer therapy with synergistic inhibition of cancer stem cells. Biomaterials. 2014; 37:405-14. DOI: 10.1016/j.biomaterials.2014.10.018. View

20.

Liu J, Zhao Z, Qiu N, Zhou Q, Wang G, Jiang H . Co-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy. Nat Commun. 2021; 12(1):2425. PMC: 8065121. DOI: 10.1038/s41467-021-22407-6. View