BIOMATERIALS
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2020
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IF 10.317
Qilin Li,Jia Liu,Huiling Fan,Lin Shi,Yan Deng,Lei Zhao,Mengxi Xiang,Yunruo Xu,Xulin Jiang,Guobin Wang,Lin Wang,Zheng Wang
Immunogenic chemotherapy (IC) is a type of chemotherapy where certain chemodrugs induce immunogenic cancer cell death (ICD), which in turn arouses T cell antitumor immunity. However, IC concurrently upregulates a key immune suppressor, indoleamine-2,3-dioxygenase (IDO), in both cancer cells and immune cells . IDO-mediated immunosuppression significantly offsets IC's therapeutic benefits in cancer patients , suggesting a necessity of combination with IDO inhibitors. Here, we report an enzyme-, pH-, and redox-triple-sensitive nanosystem using mesoporous silica nanoparticles (MSNs) as a core encapsulating doxorubicin (DOX, an immunogenic chemodrug); the core is coated with a shell ( β -CD-PEI/Ge1MT) for co-delivering 1-methyl-D-tryptophan (1 MT, an IDO inhibitor). By using these responsivenesses sequentially triggering the release of 1 MT into tumor extracellular compartment and DOX into intracellular endo/lysosomal compartment, this nanosystem ( [email protected] ) precisely delivers the drugs to their target cells residing in different compartments. Released 1 MT uptake by IDO-expressing dendritic cells (DCs) and cancer cells suppresses IDO activity, reducing immunosuppressive Tregs' presence; DOX unloaded within cancer cells induces ICD, promoting effector T-cell infiltration . In two preclinical cancer models, [email protected] potentiate both tumor local and systemic antitumor immunity, suppressing primary tumor growth by 78% with an 83% reduction in metastatic foci, as well as extending animal survival, thus strongly demonstrating [email protected] GMTMSNs' clinical translational potential.
研究领域:
癌症研究
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纳米技术
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免疫疗法
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
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2020
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IF 7.242
Peipei Yang,Chao Lu,Wanbing Qin,Minglong Chen,Guilan Quan,Hu Liu,Lili Wang,Xuequn Bai,Xin Pan,Chuanbin Wu
Synergistic anti-tumor effect of anti-PD-1/L1 antibody (aPD-1/aPD-L1) and 1-methyl-D,L-tryptophan (1-MT) in melanoma has been well demonstrated, while efficient topical delivery systems are still largely unexplored. Here, a highly drug-concentrated hybrid core-shell microneedle (CSMN) system for co-delivery of checkpoint inhibitors was developed. Based on the specific drug-matrix interaction, the system concentrated aPD-L1 in the tips of microneedles through electrostatic interactions , and increased the amount of 1-MT loaded in CSMN by preventing its premature crystallization using PVA , the material used to prepare CSMN core. The prepared CSMN exhibited high transdermal delivery efficiency and long topical retention time of aPD-L1 for 2 days. Drug-loaded CSMN achieved better anti-tumor efficacy than the intra-tumor injection group at the same dose, which was likely because the former recruited more T lymphocytes to the tumor site. These findings suggested that this CSMN system was a promising local delivery system of both aPD-L1 and 1-MT for melanoma immunotherapy, and its unique core-shell structure could be readily adapted as a modular platform for various diseases, where combination therapy of both biomacromolecular drugs and other small-molecular agents were required. Statement of Significance In the present study, a core-shell microneedle (CSMN) system was constructed to achieve targeted co-delivery of checkpoint inhibitors to melanoma, while preventing significant systemic exposure. To overcome the drawback of insufficient drug loading of microneedles and effectively encapsulate two drugs simultaneously, microneedles were divided into two independent functional areas, a charged shell and a hydrophilic core and encapsulated drugs based on respective drug-matrix interaction. The charged shell prepared by chitosan could concentrate aPD-L1 in the tips of microneedles through electrostatic interactions. The core prepared by PVA successfully increased the amount of 1-MT loaded in microneedles by preventing its premature crystallization. The prepared CSMN exhibited high transdermal delivery efficiency and better anti-tumor efficacy than intra-tumor injection at the same dose.
研究领域:
药学科学
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免疫学
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癌症研究
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanoscale
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2020
·Vol. 12
·期 5
·3317-3329
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IF 6.895
Wei Du,Chen Chen,Peng Sun,Shengchang Zhang,Jing Zhang,Xiaoyu Zhang,Ying Liu,Rui Zhang,Chongzheng Yan,Changchun Fan,Jibiao Wu,Xinyi Jiang
Immune checkpoint blockade (ICB) has emerged as one of the breakthrough approaches for tumor immunotherapy. However, known as an immune “cold” tumor, breast cancer harbors an immunosuppressive tumor niche that compromises ICB-based therapy. Chemoimmunotherapy combines a chemotherapeutic with an immune-modulating agent, representing a promising tactic to combat cancers, while the lack of effectively targeted co-delivery strategy is one of the main obstacles to achieve the synergistic utilization. Herein, self-assembled PEGylated pure drug-based nanohybrids (DNH) were created, which could evoke immunogenic cell death (ICD), aiding ICB-based immunotherapy by controlling the spatiotemporal release of oxaliplatin (OXA) and small molecular inhibitor 1-methyl-D-tryptophan (1-MT). Furthermore, biomimetic functionalization was exploited by nature killer cell membrane camouflaging to target cancerous cells as well as by elicit immune response through inducing M1 macrophage polarization. The drug release profiles of the nanosystem were investigated in the presence of low pH and intracellular reductants. Systemic in vivo bio-behaviors were evaluated via pharmacokinetics and biodistribution. As an “all-in-one” pure drug-based codelivery system, our biomimetic nanoplatform possessed multiple immunomodulation functions, which markedly aided in increasing the frequency of immune responders and generate an immune “hot” breast tumor niche, and eventually allowed to boost breast cancer therapy.
研究领域:
肿瘤学
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药学
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纳米技术
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免疫学
✓ 已验证
DOI
PubMed
高影响因子
Nano Today
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2022
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IF 18.962
Xiyou Du,Xiaoye Yang,Yu Zhang,Shan Gao,Shangui Liu,Jianbo Ji,Guangxi Zhai
Enhancing skin penetration and facilitating tumor infiltration in melanoma treatment through transdermal administration remains an intractable challenge. In the present study, docetaxel- and 1-methyl- D -tryptophan-loaded heparin-modified graphene oxide (D-1/GH) nanosheets were developed to overcome these barriers. Through heparin (Hep)-mediated stratum corneum (SC) hydration, D-1/GH permeates the skin through the intercellular route and the appendage pathway. Based on the relatively leaky structure of the tumor and the high affinity of Hep for tumors, D-1/GH can infiltrate tumors. Subsequently, D-1/GH is transported to deeper tumors through blood and lymphatic vessels. Theoretically, D-1/GH is wrapped in lymphatic vessels through the lymphatic vessel endothelial receptor-1 (LYVE-1)-mediated lymphatic transmigratory cup structure and enters blood vessels through the enhanced permeation and retention (EPR) effect, which is reported here for the first time. D-1/GH-mediated combinational therapy augments the therapeutic effect of chemotherapy and photothermal therapy (PTT) while inducing immunogenic cell death (ICD), thereby recruiting immune cells , and eliciting an immune response. D-1/GH reverses the immunosuppressive tumor microenvironment to potentiate the immune response, thus suppressing abscopal tumors and lung metastases. Collectively, this study identified a novel permeation mode, providing a new perspective to improve antitumor efficacy, boost immune response, and avert systemic distribution.
研究领域:
药学
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纳米技术
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肿瘤学
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免疫学
✓ 已验证
产品关联
DOI
高影响因子
CHINESE JOURNAL OF CHEMISTRY
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2024
·
IF 5.5
Junfeng Ding,Tianran Wang,Yan Rong,Chaoliang He,Xuesi Chen
Comprehensive Summary Due to the immunosuppressive tumor microenvironment (TME), T cells are usually inactivated and tend to differentiate into regulatory T cells (Tregs) in the tumor tissues, which seriously hinders the anti-tumor efficiency of immunotherapy. In this study, an immune-stimulating polypeptide hydrogel conjugated with an indoleamine-2,3-dioxygenase (IDO) inhibitor, 1-methyl- D -tryptophan (D1MT), through a glutathione (GSH)-responsive spacer was developed as an immunotherapy platform capable of regulating the TME. A combined immunotherapy system was further constructed through encapsulating doxorubicin (Dox) and immune checkpoint blocking antibody targeting programmed cell death protein 1 (aPD-1) in the hydrogel. Dox released from the hydrogel could cause the immunogenic cell death (ICD) of tumor cells and induce the maturation of antigen presenting cells (APCs). After intratumoral injection, the multiple agent-loaded hydrogel elicited effective anti-tumor immunity in mice bearing B16F10 melanoma. Moreover, compared with the control hydrogel without D1MT, the immune-stimulating hydrogel showed better efficiency in improving the immunosuppressive TME with increased number of activated T cells and reduced number of Tregs. Therefore, the immune-stimulating hydrogel has great potential as a stimuli-responsive platform for regulating suppressive TME and enhanced anti-tumor chemo-immunotherapy.
研究领域:
癌症免疫疗法
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药学
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生物医学工程
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免疫学
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肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2024
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IF 9.4
Guanghui An,Heming Zheng,Lianshan Guo,Jingmei Huang,Congling Yang,Zhihao Bai,Nannan Wang,Wenhui Yang,Yanqiu Zhu
Tumors produce a hypoxic environment that greatly influences cancer treatment, and conventional chemotherapeutic drugs cannot selectively accumulate in the tumor region because of the lack of a tumor targeting mechanism, causing increased systemic toxicities and side effects. Hence, designing and developing new nanoplatforms that combine multimodal therapeutic regimens is essential to improve tumor therapeutic efficacy. Herein, we report the synthesis of ultrafine Cu nanoparticles loaded with a drug combination of cisplatin (Pt) and 1-methyl- d -tryptophan (1-MT) and externally coated with 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) photosensitizer, polydopamine (PDA) and CaO 2 of MIL-101(Fe) as a new nanoplatform (Cu@MIL-101@PMTPC). The nanoplatform synergistically combined chemodynamic therapy (CDT), photodynamic therapy (PDT), and immunochemotherapy. The Fe 3+ in MIL-101(Fe) and the surface Cu nanoparticles exhibited strong ability to consume intracellular glutathione (GSH), thereby generating a Fenton-like response in the tumor microenvironment (TME) with substantial peroxidase (POD)-like and superoxide dismutase (SOD)-like activities. In this design, we used the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-MT to overcome chemotherapy-induced immune escape phenomena including enhanced CD8 + and CD4 + T cell expression, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) production, and accelerated immunogenic cell death. The targeted release of cisplatin loaded into Cu@MIL-101@PMTPC also reduced toxic side effects of chemotherapy. TCPP generated a large amount of singlet oxygen ( 1 O 2 ) upon specific laser irradiation to effectively kill tumor cells. CaO 2 on the outer layer generated oxygen (O 2 ) and hydrogen peroxide (H 2 O 2 ) to ameliorate hypoxia in the tumor microenvironment, enhance the PDT effect, and provide a continuous supply of H 2 O 2 for the Fenton-like reaction. Thus, this nanocarrier platform exhibited a powerful chemodynamic, photodynamic, and immunochemotherapeutic cascade, providing a new strategy for cancer treatment.
研究领域:
纳米技术
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癌症治疗
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材料科学
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药学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）