Acta Pharmaceutica Sinica B
·
2022
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IF 14.903
Jingwen Dong,Chenfei Zhu,Ying Huang,Quanhao Li,Jing Li,Zheng Wang,Yixin Wang,Zhanwei Zhou,Minjie Sun
Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors. Although degradation of fiber is a promising strategy, its application was still bottlenecked by the side effects of causing metastasis, resulting in the failure of immunotherapy. Here, we developed an antimetastatic polymer (HPA) for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator. Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis, and further promoted the sustained infiltration and activation of T cells for killing tumor cells. Moreover, metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs. The administration of stroma-alleviated immunotherapy increased the infiltration of CD8 + T cells to 52.5% in tumor tissues, inhibiting nearly 90% metastasis by HPA in distant organs. The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.
研究领域:
癌症生物学
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免疫治疗
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药学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
CHINESE JOURNAL OF CHEMISTRY
·
2023
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IF 5.4
Xu Huan,Yi Chen,Xiaozhen Wu,Hui Wang,Ying Yang,Pengkai Wu,Tianqing Liu,Kaikai Wang,Dan Ding
Comprehensive Summary Inflammation is associated with different stages of liver disease, including acute injury, fibrosis, cirrhosis, and hepatoma. During the progression of liver inflammation, activation of hepatic stellate cells (HSCs) and extracellular matrix (ECM) deposition are critical pathologies, and thus the combined therapy using HSCs and ECM as targets represents a promising strategy in the treatment of liver injury. Here, a novel CXCR4-inhibiting nanomedicine that can simultaneously deliver AMD3100 (CXCR4 antagonist) and siPAI-1 (siRNA of plasminogen activator inhibitor-1) was designed and developed to reverse liver fibrosis by inhibiting HSCs activation and degrading ECM deposition. With this goal in mind, a Zn (II) coordinated polymeric AMD3100 named PAMD/Zn polymer with siRNA delivery and CXCR4 antagonism capabilities was synthesized. Overall, our results suggest that PAMD/Zn recruits pro-inflammatory cells for fibrogenesis and inhibits the activation of HSCs for fibrolysis at various stages of liver injury. Its use in conjunction with PAI-1 silencing achieved satisfactory therapeutic efficacy in liver injury and fibrosis. The derivative CXCR4-inhibiting nanomedicine is a versatile platform that offers valuable benefits for the treatment of liver diseases. This article is protected by copyright. All rights reserved.
研究领域:
药理学
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纳米技术
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肝病学
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分子生物学
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产品关联
DOI
高影响因子
JOURNAL OF IMMUNOLOGY
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2024
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IF 3.6
Gao Along,Lin Yuhua,Chai Yiwen,Han Jugan,Wu Liting,Ye Jianmin
Chemokines play crucial roles in the regulation of immune cell migration and development. The CXCL12/CXCR4 axis has been extensively studied in mammals, but its regulatory mechanism in teleost fish remains unclear. In this study, we used Nile tilapia (Oreochromis niloticus) as a teleost model to investigate the mediation of the CXCL12/CXCR4 axis in IgM+ B cells. Our findings demonstrate that the CXCL12/CXCR4 axis exhibits chemotactic activity on IgM+ B cells and promotes the phagocytosis of IgM+ B cells. Blocking CXCR4 severely impairs the chemotaxis and phagocytosis of IgM+ B cells in vitro and reduces the percentages and numbers of IgM+ B cells that migrate to peripheral blood after pathogen infection in vivo. This reduction in migration leads to a decrease in the inflammatory response, an increase in tissue bacterial load, and a decrease in survival rate. We also discovered that the evolutionarily conserved PI3K-AKT signaling pathway and Girdin are involved in the immune response during Streptococcus agalactiae infection. Inhibitors of the PI3K-AKT signaling pathway prevent the chemotaxis and phagocytosis of IgM+ B cells, impair the expression and phosphorylation levels of related proteins in vitro, and prevent IgM+ B cells chemotaxis into the peripheral blood after pathogen infection in vivo. Furthermore, CXCR4 blocking significantly downregulates the expression of AKT and Girdin. Overall, our study reveals the regulatory mechanism of the CXCL12/CXCR4 axis on IgM+ B cells via the PI3K-AKT signaling pathway in tilapia, suggesting that the functions of the CXCL12/CXCR4 axis in B cells may be conserved between mammals and teleost fish.
研究领域:
免疫学
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分子生物学
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鱼类生理学
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病理生物学
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产品关联
DOI
PubMed
高影响因子
Bioactive Materials
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2022
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IF 16.874
Yuehua Wang,Zhenjie Wang,Fei Jia,Qing Xu,Zhilin Shu,Junlin Deng,Aimin Li,Meng Yu,Zhiqiang Yu
Clinical sorafenib treatment could activate C-X-C receptor type 4 (CXCR4)/stromal source factor-1α (SDF-1α) axis to aggravate intra-tumoral hypoxia of hepatocellular carcinoma (HCC), which further leads to progression, invasion, metastasis, and immunosuppression of tumors and in return causes resistance to sorafenib therapy. Therefore, a multi-functional oxygen delivery nanoplatform was rationally constructed based on an oxygen-saturated perfluorohexane (PFH)-cored liposome, with the CXCR4 antagonist LFC131 peptides modifying on the surface to simultaneously deliver sorafenib and the CSF1/CSF1R inhibitor PLX3397 (named [email protected] ) for sorafenib-resistant HCC treatment. The [email protected] was developed to overcome sorafenib resistance by synergistic effects of the following 3 roles: 1) the O 2 -saturated PFH core could alleviate the tumor hypoxia by O 2 supply; 2) the LFC131 peptide recognized the hypoxia-related overexpressed CXCR4 and then blocked SDF-1α/CXCR4 axis to re-sensitize the HCC cells to sorafenib; 3) PLX3397 activated the immune responses via inhibiting the CSF1/CSF1R pathway in TAMs, further enhanced CD8 + T cell infiltration to reverse immunosuppression in tumors. Antitumor performance on H22 tumor-bearing mice and HCC patient-derived tumor xenograft (PDX) model showed that [email protected] could overcome sorafenib resistance by synergistic effect of hypoxia attenuation, resistance-related gene regulation, and immune-microenvironment modification.
研究领域:
药理学
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肿瘤学
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纳米技术
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免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Today
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2022
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IF 18.962
Di Liu,Hongliang He,Fei Kong,Yixiang Cao,Fengchao Zang,Ming Ma,Ning Gu,Yu Zhang
Currently, multimodal synergistic nanoplatform emerges as an important cancer therapy paradigm, however, multimodal synergistic theranostic nanoplatform remains to be developed. Herein, using the mouse model of breast cancer, a versatile multimodal synergistic theranostic nanoplatform is rationally designed and synthesized for enhancing chemodynamic therapy (CDT), overcoming immunosuppression within tumor microenvironment , and inhibiting metastasis as well as tracking tumor. To fulfill our design, a composite Fe/Mn magnetic nanoparticle is first synthesized by loading with Fe 3 O 4 and BMS-202 (PD-L1 inhibitor) within a poly(lactide-co-glycolide)-based nanoparticle core, which are further modified with in situ synthesis of MnO 2 layer. Then, the composite metal-organic nanoparticle is coated with two targeting moieties hyaluronic acid (HA) and AMD3100 (CXCR4 antagonist), respectively, to achieve the multimodal synergistic theranostic nanoplatform ( [email protected] +AMD). With surface targeting modification, [email protected] +AMD exhibits enhanced tumor accumulation, where it effectively consumes endogenous glutathione to generate Mn 2+ allowing for the enhanced CDT effect, alleviates tumor hypoxia by O 2 generation and reverses the tumor immunosuppression. [email protected] +AMD blocks CXCR4 receptor on cancer cells, thus suppressing the CXCR4-mediated cancer metastasis and invasion. Additionally, [email protected] +AMD would synchronously be achieving tumor tracking by T 1 -T 2 dual-mode magnetic resonance imaging. Collectively, this strategy holds a novel multimodal synergistic theranostics for effective cancer management.
研究领域:
纳米技术
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癌症治疗
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医学成像
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免疫疗法
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药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2018
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IF 3.457
Lifeng Qin,Jinmei Qin,Xiumei Zhen,Qian Yang,Liyi Huang
The C-X-C motif chemokine 12/C-X-C chemokine receptor type 4 (CXCL12/ CXCR4) biological axis plays an important role in the pathogenesis of liver fibrosis . Curcumin is known to have an anti-fibrosis effect, but the specific mechanism needs to be elucidated. There is currently no evidence illustrating a connection between curcumin and the CXCL12/CXCR4 axis in liver fibrosis . Here, we investigated the contribution of curcumin on CXCL12/ CXCR4 biological axis in liver fibrosis. Our results showed that curcumin remarkably improved hepatic function and liver fibrosis, and the effects are similar as silymarin . The alleviation of liver fibrosis with curcumin treatment was associated with a reduction of CXCL12, CXCR4, α-SMA and RhoA. In addition, curcumin markedly inhibited the proliferation and migration of HSC-T6 cells. This study indicates that curcumin could protect against hepatic stellate cells activation and migration by inhibiting the CXCL12/CXCR4 biological axis in liver fibrosis.
研究领域:
药理学
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肝病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Theranostics
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2021
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IF 11.556
Li Luo,Guangchao Zang,Boyan Liu,Xian Qin,Yuchan Zhang,Yidan Chen,Haijun Zhang,Wei Wu,Guixue Wang
Rationale: As a potentially life-threatening disorder, cerebral ischemia-reperfusion (I/R) injury is associated with significantly high mortality, especially the irreversible brain tissue damage associated with increased reactive oxygen radical production and excessive inflammation. Currently, the insufficiency of targeted drug delivery and “on-demand” drug release remain the greatest challenges for cerebral I/R injury therapy. Bioengineered cell membrane-based nanotherapeutics mimic and enhance natural membrane functions and represent a potentially promising approach, relying on selective interactions between receptors and chemokines and increase nanomedicine delivery efficiency into the target tissues. Methods: We employed a systematic method to synthesize biomimetic smart nanoparticles. The CXCR4-overexpressing primary mouse thoracic aorta endothelial cell (PMTAEC) membranes and RAPA@HOP were extruded through a 200 nm polycarbonate porous membrane using a mini-extruder to harvest the RAPA@BMHOP. The bioengineered CXCR4-overexpressing cell membrane-functionalized ROS-responsive nanotherapeutics, loaded with rapamycin (RAPA), were fabricated to enhance the targeted delivery to lesions with pathological overexpression of SDF-1. Results: RAPA@BMHOP exhibited a three-fold higher rate of target delivery efficacy via the CXCR4/SDF-1 axis than its non-targeting counterpart in an in vivo model. Additionally, in response to the excessive pathological ROS, nanotherapeutics could be degraded to promote “on-demand” cargo release and balance the ROS level by p -hydroxy-benzyl alcohol degradation, thereby scavenging excessive ROS and suppressing the free radical-induced focal damage and local inflammation. Also, the stealth effect of cell membrane coating functionalization on the surface resulted in extended circulation time and high stability of nanoparticles. Conclusion: The biomimetic smart nanotherapeutics with active targeting, developed in this study, significantly improved the therapeutic efficacy and biosafety profiles. Thus, these nanoparticles could be a candidate for efficient therapy of cerebral I/R injury.
研究领域:
纳米医学
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药学
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神经科学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
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2023
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IF 3.3
Xiulian Zhang,Xueliang Li,Wei Ma,Fangying Liu,Pinxian Huang,Lei Wei,Li Li,Yechang Qian
Background Chronic obstructive pulmonary disease (COPD) has a high fatality rate and poses a great threat to human health. Astragaloside IV (AS-IV) is proven to attenuate cigarette smoke (CS)-induced pulmonary inflammation, based on which this research focuses on the mechanism of AS-IV in COPD.Methods To evaluate the effects of AS-IV, CD4+ T cells received different concentrations of AS-IV. CD4+ T cell viability, T helper 17 (Th17)/regulatory T (Treg) markers and CXCR4 expressions in CD4+ T cells or spleen/lung tissues were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay, quantitative real-time polymerase chain reaction and Western blot. The proportions of Treg and Th17 cells were assessed by flow cytometry. Enzyme-linked immune sorbent assay was employed to determine cytokine contents in serum and lung tissues.Results AS-IV with concentration exceeding 40 µM inhibited CD4+ T cell viability. In vitro, AS-IV suppressed the expressions of CXCR4, retinoid-related orphan receptor γt (RORγt), and interleukin (IL)-17A as well as Th17 cells but promoted the expressions of forkhead box p3 (Foxp3) and IL-10 as well as Treg cells, while CXCR4 overexpression reversed the effects of AS-IV. In vivo, AS-IV alleviated COPD, and CS-induced Th17/Treg imbalance in mice and reduced CS-induced down-regulation of IL-10 in serum and lung tissues and Foxp3 and up-regulation of IL-1β, tumor necrosis factor alpha (TNF-α), IL-6, and IL-17A in serum and lung tissues and RORγt. AS-IV mitigated CS-induced CXCR4 up-regulation. Above effects of AS-IV on mice were offset by CXCR4 overexpression.Conclusions AS-IV restores Th17/Treg balance via impeding CXCR4 to ameliorate COPD.
研究领域:
免疫学
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肺科学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2021
·
IF 9.776
Minglu Zhou,Chaohui Luo,Zhou Zhou,Lian Li,Yuan Huang
Triple negative breast cancer (TNBC) with highly metastatic features generally does not respond to anti–programmed cell death 1 ligand 1 (PD-L1) therapy due to multiple immunosuppressive mechanisms to exclude and disable T cells . Here, we develop a polymer-based combinatory approach consisting of both immunogenic cell death (ICD)-inducing and CXCR4-inhibiting function to prime tumor microenvironment and improve anti-PD-L1 therapy in TNBC. Our findings revealed that the combination therapy was able to spur the T cell response in primary tumors by increasing the tumor immunogenicity to recruit T cells, removing the physiological barriers of intratumoral fibrosis and collagen to increase T cell infiltration , and reducing the immunosuppressive cells to revive T cells. Meanwhile, such approach efficiently inhibited the formation of pre-metastatic niche in abscopal lung. Because of the significant promotion of anti-tumor and anti-metastasis immunity, the non-responding TNBC gained robust responsiveness to anti-PD-L1 therapy which resulted in complete eradication of orthotopic tumors, inhibition of pulmonary metastasis , and durable memory effects against tumor recurrence . Our work provided a generalizable approach of simultaneous ICD induction and CXCR4 blockade to apply anti-PD-L1 therapy in TNBC.
研究领域:
肿瘤学
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免疫疗法
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癌症生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2017
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IF 7.504
Dongdong Xiao,Hao Yan,Qiong Wang,Xiangguo Lv,Ming Zhang,Yang Zhao,Zhe Zhou,Jiping Xu,Qian Sun,Kang Sun,Wei Li,Mujun Lu
Bladder acellular matrix graft-alginate dialdehyde-gelatin hydrogel-silk mesh (BAMG-HS) encapsulated with adipose-derived stem cells (ASCs) was evaluated in a rat model of augmentation cystoplasty, including BAMG-HS-ASCs (n = 18, subgroup n = 6 for 2, 4, and 12 weeks), acellular BAMG-HS (n = 6 for 12 weeks) and cystotomy control (n = 6 for 12 weeks) groups. Equipped with good cytocompatibility and superior mechanical properties (elastic modulus: 5.33 ± 0.96 MPa, maximum load: 28.90 ± 0.69 N), BAMG-HS acted a trilayer “sandwich” scaffold with minimal interference in systemic homeostasis. ASCs in BAMG-HS promoted morphological and histological bladder restoration by accelerating scaffold degradation (p < 0.05), ameliorating fibrosis (p < 0.05) and inflammation (p < 0.01). Additionally, ASCs facilitated the recovery of bladder function by enhancing smooth muscle regeneration (p < 0.05), innervation (p < 0.01) and angiogenesis (p < 0.001). Except for a small number of endothelium-differentiated ASCs, the pro-angiogenic effects of ASCs were mainly related to ERK1/2 phosphorylation in the downstream of SDF-1α/CXCR4 pathway.
研究领域:
组织工程
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再生医学
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干细胞研究
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泌尿外科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CANCER GENE THERAPY
·
2026
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IF 6.4
Ling Fengyu,Zhang Meibiao,Kuang Jia,Wu Shuai,Yang Zhao
This study aimed to investigate how the CXCL12/CXCR4 axis facilitates immune evasion in gastric cancer (GC) by enhancing cellular communication between cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) using single-cell transcriptome sequencing. Single-cell RNA sequencing of tumor and normal gastric tissues in a murine GC model revealed an increased macrophage population in GC, characterized by predominantly M2-polarized TAMs. The study identified that the CXCL12/CXCR4 axis potentially triggers M2 macrophage polarization through mediating communication between CAFs and TAMs. In vitro experiments confirmed that CAFs induced M2 polarization through CXCL12/CXCR4 signaling. Inhibition of the PD-L1/PD-1 axis disrupted communication between M2 macrophages and T cells, which enhanced T cell activation. In vivo experiments showed that silencing CXCR4 reduced M2 macrophages and PD-L1 expression, leading to improved T cell proliferation, reduced immune evasion, and slower tumor growth. These findings highlight the role of the CXCL12/CXCR4 axis in driving immune evasion in GC by inducing M2 polarization and PD-L1-mediated T cell suppression, and indicate a promising therapeutic target for GC immunotherapy. Schematic Molecular Mechanism Illustrating CXCL12/CXCR4 Axis-Mediated Cellular Communication between CAFs and TAMs Promoting Gastric Cancer Immune Evasion.
✓ 已验证
DOI
高影响因子
Nanomaterials
·
2022
·Vol. 12
·期 10
·1692
·
IF 5.719
Yixiang Cao,Shiyin Zhang,Ming Ma,Yu Zhang
CXC chemokine receptor 4 (CXCR4) is a promising therapeutic target. Previous studies have shown that intracellular delivery of siRNA to knockdown CXCR4 expression in cancer cells is an effective therapeutic strategy. To prepare efficient magnetic nucleic acid carriers, it is now necessary to improve the endocytosis efficiency of PEGylated magnetic nanoparticles. In our work, Heptafluorobutyryl-polyethylene glycol-polyethyleneimine (FPP) was first prepared and then used to coat magnetic nanoparticles (MNPs) to obtain magnetic nanocarriers[email protected]The materials were characterized by19F-Nuclear Magnetic Resonance (NMR), transmission electron microscope (TEM), energy dispersive spectroscopy (EDS), and dynamic light scattering (DLS). The biosecurity of[email protected]was confirmed by cell viability and apoptosis experiments. Cellular uptake of[email protected]and siRNA transfection enhanced by external magnetic fields were detected by fluorescence microscopy, confocal laser microscopy, and flow cytometry. The results show that the cellular uptake efficiency of[email protected]was significantly improved, and transfection efficiency reached more than 90%. The knockdown of CXCR4 on the 4 T1 cell membrane was confirmed by real-time polymerase chain reaction (RT-PCR) and flow cytometry. In conclusion, the fluorinated cationic polymer-coated magnetic nanoparticles[email protected]can be loaded with siRNA to reduce CXCR4 expression as well as be expected to be efficient universal siRNA carriers.Keywords:magnetic nanoparticles;fluorination;polyethyleneimine;polyethylene glycol;RNA interference;CXC chemokine receptor 4
研究领域:
纳米技术
·
分子生物学
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药学
·
癌症研究
✓ 已验证
DOI
PubMed
高影响因子
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