BIOMATERIALS
·
2020
·
IF 10.317
Lu Wang,Ye He,Tingting He,Genhua Liu,Chuanchua Lin,Ke Li,Lu Lu,Kaiyong Cai
Toll-like receptor (TLR) agonists are the potent stimulants of innate immune system and hold promises as an adjuvant for anticancer immunotherapy. Unfortunately, most of them are limited by a prompt dissemination, and thus caused “wasted inflammation”. Hence, how to restrict their action radius into lymphoid tissues is of great relevance to enhance their efficacy and concomitantly alleviates the side effects. Here, imiquimod (R837), a TLR 7 agonist, was loaded into mesoporous polydopamine (MPDA) nanocarriers with high efficiency. Moreover, its surface was modified by polyvinyl pyrrolidone (PVP) to enhance their lymphatic drainage ability. These nano-adjuvants have obvious advantages in promoting dendritic cell (DC) maturation in comparison to free R837. Moreover, their transportation and retention ability in proximal lymph nodes (LNs) were also confirmed, by which lymphatic drug exposure can be maximized to a great extent. Consequently, effective DC activation and CD8 + T cell responses were observed as expected by R837 released in draining LNs. This effect was further enhanced by the presence of endogenous tumor antigens from apoptosis debris induced by MPDA-based photothermal effect, and thus led to the growth inhibition of subcutaneous B16 melanomas. The results demonstrated the great potency against melanoma of the designed [email protected] nano-adjuvants by combining photothermal conversion property of MPDA with lymphatic-focused immune-activation.
研究领域:
癌症免疫治疗
·
纳米技术
·
药学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Advances
·
2022
·Vol. 3
·期 5
·2505-2514
·
IF 0
Wenzhu Yin,Dechun Xuan,Bihua Deng,Mingxu Zhou,Fang Ma,Jinqiu Zhang,Yu Lu
Adjuvants have proven to be integral components in most vaccines for promoting appropriate immune responses at both innate and adaptive levels. Imiquimod (IMQ, R837), an agonist for Toll-like receptors 7 (TLR7), is a potent molecular activator of the innate immune system and has been developed as an adjuvant for immunotherapy. However, due to its pharmacokinetic profile, IMQ may induce strong local and systemic inflammatory reactions and is poorly tolerated. To overcome these hurdles, herein, we conjugate IMQ and lauryl alcohol (LA) to the backbone of biodegradable poly (γ-glutamic acid) (γ-PGA) to prepare an amphiphilic polymer (shortened to γ-PGA-IMQ-LA) with improved stability and biodistribution of IMQ. In order to investigate the distribution of the amphiphilic polymer in vitro and in vivo, fluorescein was grafted to the lateral chain to synthesize fluorescent-labeled γ-PGA-IMQ-LA-FL (shortened to FIP). The novel amphiphilic FIP polymer was characterized via1H NMR, FI-IR, UV-vis, fluorescence spectra and zeta potential. Using ovalbumin (OVA) as a model antigen and FIP as an adjuvant for immunization, the formulations of FIP + OVA in different dosages could significantly promote the production of OVA-specific IgG in mice and prolong immune responses with acceptable safety.
研究领域:
免疫学
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药剂学
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聚合物化学
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生物医学工程
✓ 已验证
产品关联
DOI
JOURNAL OF INVESTIGATIVE DERMATOLOGY
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2023
·
IF 6.5
Qinqin Meng,Mei Bai,Meiliang Guo,Zhengxiao Li,Wanwen Liu,Xiaojing Fan,Rui Sun,Xinrong Yang,Dingfen Yuan,Yuling Shi,Hui Deng
Although the anti-inflammatory effect of serum- and glucocorticoid-regulated protein kinase 1 (SGK1) has been established in other diseases, the possible regulatory role of SGK1 in psoriasis and the underlying molecular mechanisms remain largely unknown. In this study, we found that SGK1 expression was decreased in macrophages from patients with psoriasis. Moreover, a specific pharmacological SGK1 inhibitor, EMD638683, significantly enhanced imiquimod-mediated toll-like receptor 7/8 activity and proinflammatory cytokine production in RAW264.7 cells, and this result was confirmed by Sgk1 small interfering RNA . Further mechanistic data showed that SGK1 inhibition increased the phosphorylation of Bruton’s agammaglobulinemia tyrosine kinase ; moreover, Bruton’s agammaglobulinemia tyrosine kinase inhibition abrogated the proinflammatory effects of the SGK1 inhibitor on toll-like receptor 7/8 activation, thereby validating that SGK1 inhibition enhances the toll-like receptor 7/8 pathway by increasing Bruton’s agammaglobulinemia tyrosine kinase phosphorylation. In addition, our in vivo results showed that SGK1 inhibition significantly increased the secretion of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, and the infiltration of T helper 17 cells in an imiquimod-induced psoriasis mouse model. Altogether, these results show that SGK1 plays a critical role in the pathogenesis of psoriasis by modulating inflammatory responses in skin lesions , indicating that SGK1‒Bruton’s agammaglobulinemia tyrosine kinase signaling could be a novel therapeutic target for the control of psoriasis.
研究领域:
免疫学
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皮肤病学
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药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Zhen Wang,Zhangyi Miao,Zhiting Cao,Jianye Ren,Xiaohong Zhu,Yu Sheng,Hao Cheng,Huaqing Zhang,Jianping Zhou,Yang Ding
Epicutaneous immunotherapy (EPIT) is effective and safe to induce sustained protection against anaphylaxis with small doses of allergens. To penetrate the barrier of the stratum corneum, a coaxial nanofiber patch is designed that incorporates natural phase-change materials (PCM) for mild hyperthermia-assisted skin permeability, while minimizing the risk of systemic events during immunotherapy. For adaptive immune activation, Toll-like receptor 7/8 ligand of resiquimod (R848) is combined with ovalbumin (OVA) allergen, thereby stimulating the Th1 pathway and strengthening therapeutic efficacy. For sequential administration, coaxial electrospinning technology is utilized for multiple drug encapsulation and sequential release, where the shell layer consists of poly(vinyl alcohol) (PVA) with OVA dispersion, and the core region is a mixture of PCM and R848. Under mild hyperthermia irritation, the nanofiber patches perform an efficient immunomodulation by manipulating the skin immune system via allergen/adjuvant combinations, which inhibits the secretion of OVA-specific IgE, and improves lung functions sufficiently in a mouse model of allergic asthma. Mechanistically, the treatment favors IgG2a expression from a Th1-biased immune response and induces protective regulatory immunity against allergen exposure. Overall, the simplicity and potency of mild hyperthermia mediated EPIT qualifies as a translational strategy for IgE-mediated allergies with long-lasting curative effects.
研究领域:
生物医学工程
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免疫治疗
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纳米技术
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药学
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过敏与免疫学
✓ 已验证
产品关联
DOI
高影响因子
ACS Nano
·
2022
·
IF 18.027
Xilin Li,Jingmei Pan,Yan Li,Funeng Xu,Jianwen Hou,Guang Yang,Shaobing Zhou
How to precisely reprogram tumor-associated macrophages (TAMs) and combine them with immunogenic cell death (ICD) is still a great challenge in enhancing the antitumor immunotherapeutic effect. Here, we developed a localized drug delivery system with a step-by-step cell internalization ability based on a hierarchical-structured fiber device. The chemotherapeutic agent-loaded nanomicelles are encapsulated in the internal chambers of the fiber, which could first be internalized by actively targeting tumor cells to induce ICD. Next, the rod-like microparticles can be gradually formed from long to short shape through hydrolysis of the fiber matrix in the tumor microenvironment and selectively phagocytosed by TAMs but not to tumor cells when the length becomes less than 3 μm. The toll-like receptors 7 (TLR7) agonist imiquimod could be released from these microparticles in the cytoplasm to reprogram M2-like TAMs. The in vivo results exhibit that this localized system can synergistically induce an antitumor immune response and achieve an excellent antitumor efficiency. Therefore, this system will provide a promising treatment platform for cancer immunotherapy.
研究领域:
癌症研究
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药学
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免疫治疗
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药物递送系统
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Jiamin Chen,Xingxing Liu,Shujing Zhao,Hongyican Chen,Tao Lu,Jinfeng Wang,Jiahui Han,Wangran Wu,Xian Shen,Chao Li
Due to the intrinsic weak immunogenicity of tumor cells and the quantitatively and functionally different populations of immune cells, immunosuppression has become the major obstacle for cancer immunotherapy. In this study, the biocompatible alginate was chemically modified with the carboxyethyl linker to facilitate the esterification reaction of the resultant carboxymethylated alginate (CMA) and resiquimod (R848), the agonist of Toll-like receptor 7/8 (TLR7/8a). In aqueous solution, the hydrophilic CMA and the hydrophobic R848 formed stable nanomicelles (CMA-R848) by self-assembling. After combined administration of CMA-R848 and cisplatin (Cis) in a gastric cancer (GC) model, the long-circulating CMA-R848 micelle reached the mild acidic tumor microenvironment (TME); the ester bonds were quickly cleaved by the ubiquitous esterase and released the single molecule of R848. In vitro and in vivo results demonstrated that the released R848 efficiently promoted co-stimulatory molecules’ expression of dendritic cells (DCs), enhanced the antigen uptake and cross-presentation, and primed the cytotoxic T lymphocytes’ (CTLs) infiltration and killing effects, thereby reprogramming the “cold tumor” into the “hot tumor”. In addition, the ex vivo tumor sections revealed that the released R848 effectively repolarized the M2-like tumor-associated macrophages (TAMs) into M1-like macrophages, exerted synergistic antitumor activity, reduced the tumor burden, and prolonged the overall survival duration of the GC animal model. Our study provided a targeting therapeutic strategy overcoming the limitations of R848 in vivo, and enhanced the efficacy of GC chemotherapy and immunotherapy by TME modulation.
研究领域:
肿瘤学
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药学
·
免疫学
·
生物技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2021
·Vol. 12
·期 1
·1-16
·
IF 14.919
Wang Yongchao,Gong Ningqiang,Ma Chi,Zhang Yuxuan,Tan Hong,Qing Guangchao,Zhang Jimei,Wang Yufei,Wang Jinjin,Chen Shizhu,Li Xianlei,Ni Qiankun,Yuan Yuan,Gan Yaling,Chen Junge,Li Fangzhou,Zhang Jinchao,Ou Caiwen,Zhao Yongxiang,Liu Xiaoxuan,Liang Xing-Jie
Immunological adjuvants are essential for successful cancer vaccination. However, traditional adjuvants have some limitations, such as lack of controllability and induction of systemic toxicity, which restrict their broad application. Here, we present a light-activable immunological adjuvant (LIA), which is composed of a hypoxia-responsive amphiphilic dendrimer nanoparticle loaded with chlorin e6. Under irradiation with near-infrared light, the LIA not only induces tumour cell lysis and tumour antigen release, but also promotes the structural transformation of 2-nitroimidazole containing dendrimer to 2-aminoimidazole containing dendrimer which can activate dendritic cells via the Toll-like receptor 7-mediated signaling pathway. The LIA efficiently inhibits both primary and abscopal tumour growth and induces strong antigen-specific immune memory effect to prevent tumour metastasis and recurrence in vivo. Furthermore, LIA localizes the immunological adjuvant effect at the tumour site. We demonstrate this light-activable immunological adjuvant offers a safe and potent platform for in situ cancer vaccination.
研究领域:
癌症研究
·
免疫学
·
纳米技术
·
药学
✓ 已验证
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2021
·Vol. 10
·期 21
·2101222
·
IF 9.933
Peng Yan,Yang Luo,Xinyang Li,Yingmin Li,Yi Wang,Jian Wu,Shaobing Zhou
In situ vaccination can trigger an antitumor immune response. However, the therapeutic effect is still limited since the high expression of adenosine binding to G protein-coupled receptor A2AR induces an immunosuppressive effect. In this work, a new formulation is presented with the combination of a nanovaccine based on redox-responsive polymer micelles and A2AR antagonist SCH58261. The micelles simultaneously encapsulate immunogenic cell death (ICD) inducer doxorubicin (DOX) and adjuvant toll-like receptor 7 and 8 (TLR7/8) agonist R848, acting as the potent in situ vaccines. A high concentration of glutathione in tumor cells leads to the disintegration of these micelles, releasing DOX and R848 to mediate ICD, inducing the activation of dendritic cells and initiating an immune response. Meanwhile, A2AR antagonist SCH58261, a generation immune checkpoint blocker, inhibits the immunosuppressive adenosinergic pathway in the tumor microenvironment, activating natural killer (NK) cells and CD8 + T cells, and inhibiting the proliferation of regulatory T cells. Therefore, this formulation can trigger a robust systemic antitumor immune response.
研究领域:
癌症研究
·
免疫学
·
纳米医学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small Methods
·
2023
·Vol. 7
·期 5
·2201327
·
IF 12.4
Xinyang Li,Yang Luo,Zhengjie Huang,Yi Wang,Jian Wu,Shaobing Zhou
In the treatment of solid tumors, the complex barriers composed of cancer-associated fibroblasts (CAFs) prevent drug delivery and T cells infiltration into tumor tissues. Although nanocarriers hold great prospects in drug delivery, fibrosis causes the biological barrier and immunosuppressive tumor microenvironment (ITM) that impairs the anti-tumor efficacy of nanocarriers. Here, a small dendritic macromolecule loaded with doxorubicin (PAMAM-ss-DOX) (DP) is synthesized and encapsulated into pH-responsive nanoliposome, together with adjuvant toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) and losartan (LOS). The pH-responsive liposome facilitates the simultaneous and effective delivery of DP, R848, and LOS, which can decompose and release these drugs under the acidic tumor microenvironment. The small sized DP (≈25 nm) with the ability to penetrate into tumor tissue and immunogenic cell death (ICD) can reverse the ITM and elicit immune response, which is equivalent to the effect of an in situ vaccine. Moreover, LOS reduces the activity of CAFs effectively, which can contribute to the infiltration of T cells. Therefore, this nano-platform provides a new therapeutic strategy for enhanced chemo-immunotherapy.
研究领域:
肿瘤学
·
药学
·
免疫学
·
纳米技术
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2022
·Vol. 11
·期 12
·2102739
·
IF 11.092
Yanyun Hao,Hui Li,Huajun Zhao,Yutong Liu,Xiaoyan Ge,Xia Li,Hongfei Chen,Ailu Yang,Jing Zou,Xue Li,Xuechun Sun,Xinke Zhang,Xiao Wang,Zepeng Li,Qilu Zhang,Hao Wu,Guan Wang,Jian Zhang,Bruno G. De Geest,Zhiyue Zhang
Cancer immunotherapy is revolutionary in oncology and hematology. However, a low response rate restricts the clinical benefits of this therapy owing to inadequate T lymphocyte infiltration and low delivery efficiency of immunotherapeutic drugs. Herein, an intelligent nanovehicle (folic acid (FA)/1-(4-(aminomethyl) benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (IMDQ)-oxaliplatin (F/IMO)@CuS) armed with multifunctional navigation is designed for the accurate delivery of cargoes to tumor cells and dendritic cells (DCs), respectively. The nanovehicle is based on a near infrared-responsive inorganic CuS nanoparticles, acting as a photosensitizer and carrier of the chemotherapeutic agent oxaliplatin, and enters tumor cells owing to the presence of folic acid on the surface of CuS upon intratumoral injection. Furthermore, a toll-like receptor (TLR) 7/8 agonist-conjugated polymer, anchored on the surface of CuS, is modified with mannose to bind with DCs in the tumor microenvironment. Upon exposure to laser irradiation, nanovehicles disassemble, releasing oxaliplatin, to ablate tumor cells and amplify immunogenic cell death in combination with photothermal therapy. Mannose-modified polymer-TLR7/8 agonist conjugates are subsequently exposed, leading to the activation of DCs and proliferation of T cells. Collectively, these intelligent nanovehicles reduce tumor burden, exert a robust antitumor immune response, and generate long-term immune protection to prevent tumor recurrence.
研究领域:
肿瘤学
·
免疫学
·
纳米技术
·
药学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）