关键词： 5-ALA, 5-aminolevulinic acid 5-FU, 5-fluorouracil ALKP, alkaline phosphatase ALT, alanine aminotransferase APCs, antigen-presenting cells AST, aminotransferase ATP, adenosine triphosphate AUC, area under curves Bioresponsive CLSM, confocal laser scanning microscope CPT-11, irinotecan CRE, creatinine CRT, calreticulin Ce6, chlorin e6 Chemotherapy DAMPs, damage-associated molecular patterns DCs, dendritic cells DDSs, drug delivery systems DLN, draining lymph nodes DM NGs, doxorubicin-based mannose nanogel DOC, docetaxel DOX, doxorubicin DTT, d,l-dithiothreitol Doxorubicin FCM, flow cytometry FDA, Fluorescein diacetate GEM, gemcitabine GSH, glutathione H&E, hematoxylin-eosin HCPT, 10-hydroxy camptothecin HCT, hematocrit HGB, hemoglobin concentration HMGB1, high migrating group box 1 ICB, immune checkpoint blockade ICD, immunogenic cell death ICG, indocyanine Green IHC, immunohistochemistry ITM, immunosuppressive tumor microenvironment Immunogenic cell death Immunotherapy LDH, lactate dehydrogenase LYM, lymphocyte ratio MAN, mannose MCHC, mean corpuscular hemoglobin concentration MCSs, multicellular spheroids MFI, mean fluorescence intensity MPV, mean platelet volume Mannose NGs, nanogels Nanogel OXA, oxaliplatin P18, purpurin 18 PDI, polydispersity index PLT, platelets PTX, paclitaxel Prodrug RBC, red blood cell count RDW, variation coefficient of red blood cell distribution width TAAs, tumor-associated antigens TAM, tumor-associated macrophages TGF-β, transforming growth factor-β TMA, tissue microarrays TME, tumor microenvironment Urea, urea nitrogen WBC, white blood cell count irAEs, immune-related adverse events 5-ALA, 5-aminolevulinic acid 5-FU, 5-fluorouracil ALKP, alkaline phosphatase ALT, alanine aminotransferase APCs, antigen-presenting cells AST, aminotransferase ATP, adenosine triphosphate AUC, area under curves Bioresponsive CLSM, confocal laser scanning microscope CPT-11, irinotecan CRE, creatinine CRT, calreticulin Ce6, chlorin e6 Chemotherapy DAMPs, damage-associated molecular patterns DCs, dendritic cells DDSs, drug delivery systems DLN, draining lymph nodes DM NGs, doxorubicin-based mannose nanogel DOC, docetaxel DOX, doxorubicin DTT, d,l-dithiothreitol Doxorubicin FCM, flow cytometry FDA, Fluorescein diacetate GEM, gemcitabine GSH, glutathione H&E, hematoxylin-eosin HCPT, 10-hydroxy camptothecin HCT, hematocrit HGB, hemoglobin concentration HMGB1, high migrating group box 1 ICB, immune checkpoint blockade ICD, immunogenic cell death ICG, indocyanine Green IHC, immunohistochemistry ITM, immunosuppressive tumor microenvironment Immunogenic cell death Immunotherapy LDH, lactate dehydrogenase LYM, lymphocyte ratio MAN, mannose MCHC, mean corpuscular hemoglobin concentration MCSs, multicellular spheroids MFI, mean fluorescence intensity MPV, mean platelet volume Mannose NGs, nanogels Nanogel OXA, oxaliplatin P18, purpurin 18 PDI, polydispersity index PLT, platelets PTX, paclitaxel Prodrug RBC, red blood cell count RDW, variation coefficient of red blood cell distribution width TAAs, tumor-associated antigens TAM, tumor-associated macrophages TGF-β, transforming growth factor-β TMA, tissue microarrays TME, tumor microenvironment Urea, urea nitrogen WBC, white blood cell count irAEs, immune-related adverse events

来  源：   DOI：10.1016/j.apsb.2021.05.016   PDF(Sci-hub)   PDF(Pubmed)

Abstract：
The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death (ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment (ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin (DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels (DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful anti-tumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.
摘要：
化疗和免疫疗法的结合通过引发免疫原性细胞死亡（ICD）来激发强大的免疫系统，在抑制肿瘤生长和改善免疫抑制肿瘤微环境（ITM）方面显示出巨大的潜力。然而,低劣的药物生物利用度限制了治疗效果。在这里，我们报道了一种通用的生物响应性阿霉素（DOX）基纳米凝胶，可实现肿瘤特异性药物共递送。设计并选择基于DOX的甘露糖纳米凝胶（DMNG）作为示例，以阐明联合化学免疫疗法的机制。不出所料,DMNG表现出显著的胶束稳定性，选择性药物释放和延长生存时间，受益于增强肿瘤通透性和延长血液循环。我们发现由DMNG递送的DOX可以通过促进ICD来诱导强大的抗肿瘤免疫应答。同时,从DMNGs释放的甘露糖被证明在体外和体内对乳腺癌具有强大的协同治疗作用，通过破坏糖酵解和三羧酸循环中的葡萄糖代谢。总的来说,基于DOX的纳米凝胶对肿瘤微环境的调节有望成为一种有效的候选策略，以克服基于ICD的免疫治疗的当前局限性。为免疫调节纳米药物的开发提供了范例。
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