ACS Applied Materials & Interfaces
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2024
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IF 8.3
Yaqing Kang,Jiao Yan,Xiaoqing Han,Xingbo Wang,Yanjing Wang,Panpan Song,Xiaochen Su,Abdur Rauf,Xuefei Jin,Fang Pu,Haiyuan Zhang
Cancer immunotherapy is developing as the mainstream strategy for treatment of cancer. However, the interaction between the programmed cell death protein-1 (PD-1) and the programmed death ligand 1 (PD-L1) restricts T cell proliferation, resulting in the immune escape of tumor cells. Recently, immune checkpoint inhibitor therapy has achieved clinical success in tumor treatment through blocking the PD-1/PD-L1 checkpoint pathway. However, the presence of M2 tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) will inhibit antitumor immune responses and facilitate tumor growth, which can weaken the effectiveness of immune checkpoint inhibitor therapy. The repolarization of M2 TAMs into M1 TAMs can induce the immune response to secrete proinflammatory factors and active T cells to attack tumor cells. Herein, hollow iron oxide (Fe3O4) nanoparticles (NPs) were prepared for reprogramming M2 TAMs into M1 TAMs. BMS-202, a small-molecule PD-1/PD-L1 inhibitor that has a lower price, higher stability, lower immunogenicity, and higher tumor penetration ability compared with antibodies, was loaded together with pH-sensitive NaHCO3 inside hollow Fe3O4 NPs, followed by wrapping with macrophage membranes. The formed biomimetic FBN@M could produce gaseous carbon dioxide (CO2) from NaHCO3 in response to the acidic TME, breaking up the macrophage membranes to release BMS-202. A series of in vitro and in vivo assessments revealed that FBN@M could reprogram M2 TAMs into M1 TAMs and block the PD-1/PD-L1 pathway, which eventually induced T cell activation and the secretion of TNF-α and IFN-γ to kill the tumor cells. FBN@M has shown a significant immunotherapeutic efficacy for tumor treatment.
研究领域:
生物医学工程
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肿瘤免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
Science Advances
·
2024
·Vol. 10
·期 40
·
IF 11.7
Feng Zhang,Qiuyu Jiang,Jialiang Cai,Fansheng Meng,Wenqing Tang,Zhiyong Liu,Xiahui Lin,Wenfeng Liu,Yi Zhou,Xizhong Shen,Ruyi Xue,Ling Dong,Si Zhang
The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway in hepatocellular carcinoma (HCC) is limited. NOD-like receptors (NLRs) comprise a highly evolutionarily conserved family of cytosolic bacterial sensors, yet their impact on antitumor immunity against HCC remains unclear. In this study, we uncovered that NOD1, a well-studied member of NLR family, exhibits predominant expression in tumor-associated macrophages (TAMs) and correlates positively with improved prognosis and responses to anti–PD-1 treatments in patients with HCC. Activation of NOD1 in vivo augments antitumor immunity and enhances the effectiveness of anti–PD-1 therapy. Mechanistically, NOD1 activation resulted in diminished expression of perilipin 5, thereby hindering fatty acid oxidation and inducing free fatty acid accumulation in TAMs. This metabolic alteration promoted membrane localization of the costimulatory molecule OX40L in a lipid modification–dependent manner, thereby activating CD8+ T cells. These findings unveil a previously unrecognized role for NOD1 in fortifying antitumor T cell immunity in HCC, potentially advancing cancer immunotherapy.
研究领域:
肿瘤学
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免疫学
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癌症生物学
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2023
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IF 10.8
Xiangwu Chen,Zeyu Jiang,Yang Lin,Cancan Yu,Xinxin Nie,Guixiang Xu,Wei Xu,Yue Jiang,Yuxia Luan
T cell-based immunotherapy (TCBI) is an emerging approach to combat tumors. However, the outcome of TCBI is still far from satisfaction clinically, owing to stumbling blocks from insufficient immunogenicity , T cell exhaustion and immune evasion from programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway. Herein, an injectable tumor lysates-constructed hydrogel is reported to address these issues. Chemically modified tumor lysates are, for the first time, designed as the gelator to intratumorally construct hydrogel, achieving a robust antigen reservoir to induce strong immunogenicity. Meanwhile, hydrogel-encapsulated nicotinamide riboside and SB415286 enable strong mitophagy in T cells to prevent their exhaustion as well as powerfully genetical suppression of PD-1 expression to regulate immune evasion. Thus, our injectable hydrogel creates a robust immune niche within tumor, enabling to significantly potentiate TCBI. Our strategy pharmacologically regulates body's own T cells in situ, demonstrating potent immunotherapeutic effects and offering a conceptually new approach for TCBI.
研究领域:
肿瘤学
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免疫学
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药学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
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IF 8.2
Qiuyang Huang,Xiaoling Zang,Zhiwei Zhang,Hang Yu,Baoyan Ding,Zhuangzhuang Li,Simin Cheng,Xin Zhang,Mustafa R.K. Ali,Xue Qiu,Zhihua Lv
The discovery of new anti-cancer drugs targeting the PD-1/PD-L1 pathway has been a research hotspot in recent years. In this study, biological affinity ultrafiltration (BAU), UPLC-HRMS, molecular dynamic (MD) simulations and molecular docking methods were applied to search for endogenous active compounds that can inhibit the binding of PD-L1 to PD-1. We screened dozens of potential cancer related endogenous compounds. Surprisingly, cyclic adenosine monophosphate (cAMP) was found to have a direct inhibitory effect on the PD-1/PD-L1 binding with an in vitro IC 50 value of about 36.4 ± 9.3 μM determined by homogeneous time-resolved fluorescence (HTRF) assay. cAMP could recover the proliferation of Jurkat T cells co-cultured with DU-145 cells and may suppress PD-L1 expression of DU-145 cells. cAMP was demonstrated to bind and induce PD-L1 dimerization by FRET assay, and also predicted by MD simulations and molecular docking. The finding of cAMP as a potential inhibitor directly targeting the PD-1/PD-L1 interaction could advance our understanding of the activity of endogenous compounds regulating PD-L1.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2021
·Vol. 9
·期 42
·8809-8822
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IF 6.331
Rui Zhang,Ge Cheng,Shengnan Liu,Hongying Lv,Juan Li
Designing a multi-target nanomedicine without a carrier is pivotal for successful cancer nanotherapy. This study details a novel four-in-one RRX/BMS/CA4/PTX nanomedicine by simple nanoprecipitation. In this multi-target pure nanomedicine, paclitaxel (PTX) causes the immunogenic cell death of 4T1 tumour cells and the differentiation of marrow-derived suppressor cells (MDSCs) into dendritic cells (DCs) at low dose; repertaxin (RRX) selectively depletes cancer stem cells (CSCs) that are not killed by paclitaxel to inhibit lung metastasis from the breast; BMS-1 blocks the PD-1/PD-L1 pathway for proliferating effector T cells; and combretastatin A4 (CA4) targets tumour microvessels to cut off the blood supply in the tumour microenvironment. The synergy of multi-target therapies results in excellent antitumour effects. The tumour inhibition rate of 4T1 tumours is 92.5%, and the lung metastasis suppression rate exceeds 90%; no relapse is observed at 46 days after the treatment endpoint, and the survival of 50% of mice is prolonged by 95 days. Due to the low dose of PTX administration, the systemic toxicity of the RRX/BMS/CA4/PTX nanomedicine is not found. Our results suggest a strategy for designing multi-target pure nanomedicines with simple construction and efficacious therapeutic responses that present potential for clinical transformation.
研究领域:
纳米技术
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肿瘤学
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药学
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免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2022
·
IF 5.364
Nan Zhang,Jing Li,Wenxia Gao,Wangwei Zhu,Jianqin Yan,Ziyun He,Li Li,Fang Wu,Yuji Pu,Bin He
The combined delivery of chemotherapeutics with checkpoint inhibitors of the PD-1/PD-L1 pathway provides a new approach for cancer treatment. Small-molecule peptide inhibitors possess short production cycle, low immunogenicity, and fewer side effects; however, their potential in cancer therapy is hampered by the rapid biodegradation and a nanocarrier is needed for efficient drug delivery. Herein, anticancer drug doxorubicin (DOX) and PD-L1 inhibitor peptide P-12 are co-loaded by a lipid polymer nanocomplex based on poly(lactic-co-glycolic acid) (PLGA) and DSPE-PEG. Octaarginine (R8)-conjugated DSPE-PEG renders the LPN efficient internalization by cancer cells. The optimal nanomedicine LPN-30-R82K@DP shows a diameter of 125 nm and a DOX and P-12 loading content of 5.0 and 6.2%, respectively. LPN-30-R82K@DP exhibits good physiological stability and enhanced cellular uptake by cancer cells. It successfully induces immunogenic cell death and PD-L1 blockade in CT26 cancer cells. The in vivo antitumor study further suggests that co-loaded nanomedicine efficiently suppresses CT26 tumor growth and elicits antitumor immune response. This study manifests that lipid polymer nanocomplexes are promising drug carriers for the efficient chemo-immunotherapy of cancer.
研究领域:
药学
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生物医学工程
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肿瘤学
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药物递送系统
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免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2023
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IF 10
Chun Wang,Yuanhao Jing,Wenting Yu,Jie Gu,Zijian Wei,Anni Chen,Ying-Tzu Yen,Xiaowen He,Lanqi Cen,Aoxing Chen,Xueru Song,Yirong Wu,Lixia Yu,Gaojian Tao,Baorui Liu,Shoufeng Wang,Bin Xue,Rutian Li
Doxorubicin (DOX) is the classic soft tissue sarcomas (STS) first-line treatment drug, while dose-dependent myelosuppression and cardiotoxicity limit its application in clinic. This research intends to apply DOX, which is also an inducer of immunogenic cell death as a part for “in situ vaccination” and conjointly uses PD-1 inhibitors to enhance antitumor efficacy. In order to achieve the sustained vaccination effect and real-time monitoring of distribution in vivo, the in situ forming and injectable hydrogel platform with the function of visualization is established for local delivery. The hydrogel platform is synthesized by hyaluronic acid-dopamine coordinated with gadolinium ions (Gd 2+ ). Gd 2+ provides the ability of magnetic resonance imaging, meanwhile further cross-linking the hydrogel network. Experiments show excellent ability of sustained release and imaging tracking for the hydrogel platform. In mouse STS models, the “in situ vaccination” hydrogels show the best effect of inhibiting tumor growth. Further analysis of tumor tissues show that “in situ vaccination” group can increase T cell infiltration, promote M1-type macrophage polarization and block elevated PD-1/PD-L1 pathway caused by DOX. These results are expected to prove the potential for synthesized hydrogels to achieve a universal platform for “in situ vaccination” strategies on STS treatments.
研究领域:
癌症研究
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药学
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生物医学工程
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免疫治疗
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医学成像
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2024
·
IF 9.4
Jianying Ye,Jiang Yu,Mingming Zhao,Yingxi Zhang,Zhaomeng Wang,Shuo Li,Baoyue Zhang,Haolin Zhang,Tengfei Zhou,Yuhang Wang,Xin Li,Zhonggui He,Hongzhuo Liu,Yongjun Wang
Cancer immunotherapy has emerged as a potent treatment strategy by harnessing the host immune system to target cancer cells. However, challenges including low tumor vaccine immunogenicity and tumor heterogeneity hinder its clinical efficacy. To address these issues, we propose a novel nanoplatform integrating photothermal material gold nanorods (GNRs) with polyphenols for enhanced immunotherapy efficacy via photothermal therapy. Polyphenols, natural compounds with phenolic hydroxyl groups, are known for their ability to bind tightly to various molecules, making them ideal for antigen capture. We synthesized GNRs modified with polyphenols (GNR-PA and GNR-GA) and demonstrated their ability to induce immunogenic cell death upon laser irradiation, releasing tumor-associated antigens (TAAs). The surface polyphenols on GNRs effectively captured released TAAs to shield them from clearance. In vivo studies confirmed increased accumulation of GNR-GA in lymph nodes and enhanced dendritic cell maturation, leading to promoted effector T cell infiltration into tumors. Furthermore, treatment combined with PD-1/PD-L1 pathway blockade demonstrated potent tumor regression and systemic immunotherapy efficacy. Our findings highlight the potential of this photothermal nanoplatform as a promising strategy to overcome the limitations of current cancer immunotherapy approaches and improve therapeutic outcomes.
研究领域:
癌症免疫疗法
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纳米技术
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光热疗法
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-18
·
IF 14.7
Tang Xudong,Shang Yangyang,Yang Hong,Song Yalan,Li Shan,Qin Yusi,Song Jingyi,Chen Kang,Liu Yang,Zhang Dinglin,Chen Lei
The PD-1/PD-L1 pathway in mucosal immunity is currently actively explored and considered as a target for inflammatory bowel disease (IBD) treatment. However, systemic PD-L1 administration may cause unpredictable adverse effects due to immunosuppression. Here we show that reactive oxygen species (ROS)-responsive nanoparticles enhance the efficacy and safety of PD-L1 in a mouse colitis model. The nanoparticles control the accumulation and release of PD-L1 fused to Fc (PD-L1-Fc) at inflammatory sites in the colon. The nanotherapeutics shows superiority in alleviating inflammatory symptoms over systemic PD-L1-Fc administration and mitigates the adverse effects of PD-L1-Fc administration. The nanoparticles-formulated PD-L1-Fc affects production of proinflammatory and anti-inflammatory cytokines, attenuates the infiltration of macrophages, neutrophils, and dendritic cells, increases the frequencies of Treg, Th1 and Tfh cells, reshapes the gut microbiota composition; and increases short-chain fatty acid production. In summary, PD-L1-Fc-decorated nanoparticles may provide an effective and safe strategy for the targeted treatment of IBD.
研究领域:
药理学
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免疫学
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纳米技术
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胃肠病学
✓ 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）