Pharmaceutics
·
2023
·Vol. 15
·期 4
·1241
·
IF 5.4
Zun Yang,Haijiao Li,Wenrui Zhang,Mingzu Zhang,Jinlin He,Zepeng Yu,Xingwei Sun,Peihong Ni
Tumor-associated macrophages (TAMs)-based immunotherapy is a promising strategy. Since TAMs are mainly composed of M2-type macrophages, they have a promoting effect on tumor growth, invasion, and metastasis. M2-type macrophages contain a specific receptor CD163 on their surface, providing a prerequisite for active targeting to TAMs. In this study, we prepared CD163 monoclonal antibody modified doxorubicin-polymer prodrug nanoparticles (abbreviated as mAb-CD163-PDNPs) with pH responsiveness and targeted delivery. First, DOX was bonded with the aldehyde group of a copolymer by Schiff base reaction to form an amphiphilic polymer prodrug, which could self-assemble into nanoparticles in the aqueous solution. Then, mAb-CD163-PDNPs were generated through a “Click” reaction between the azide group on the surface of the prodrug nanoparticles and dibenzocyclocytyl-coupled CD163 monoclonal antibody (mAb-CD163-DBCO). The structure and assembly morphology of the prodrug and nanoparticles were characterized by1H NMR, MALDI-TOF MS, FT-IR UV-vis spectroscopy, and dynamic light scattering (DLS). In vitro drug release behavior, cytotoxicity, and cell uptake were also investigated. The results show that the prodrug nanoparticles have regular morphology and stable structure, especially mAb-CD163-PDNPs, which can actively target TAMs at tumor sites, respond to the acidic environment in tumor cells, and release drugs. While depleting TAMs, mAb-CD163-PDNPs can actively enrich drugs at the tumor site and have a strong inhibitory effect on TAMs and tumor cells. The result of the in vivo test also shows a good therapeutic effect, with a tumor inhibition rate of 81%. This strategy of delivering anticancer drugs in TAMs provides a new way to develop targeted drugs for immunotherapy of malignant tumors.Keywords:anti-tumor;TAMs;CD163 monoclonal antibody;targeted drug delivery;prodrug;click reaction;doxorubicin;immunotherapy
研究领域:
肿瘤学
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药学
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免疫治疗
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产品关联
DOI
PubMed
高影响因子
Regenerative Biomaterials
·
2024
·
IF 5.6
Zhang Ju,Shan Hui,Guo Jinglin,Wang Xiaoying,Wang Weiwei
Due to its highly insidious and rapid progression, deep tissue pressure injury (DTPI) is a clinical challenge. Our previous study found that DTPI may be a skeletal muscle injury dominated by macrophage immune dysfunction due to excessive iron accumulation. Decellularized skeletal muscle matrix (dECM) hydrogel promotes skeletal muscle injury repair. However, its role in polarizing macrophages and regulating iron metabolism in DTPI remains unclear. Here, porcine dECM hydrogel was prepared, and its therapeutic function and mechanism in repairing DTPI were investigated. The stimulus of dECM hydrogel towards RAW264.7 cells resulted in a significantly higher percentage of CD206+ macrophages and notably decreased intracellular divalent iron levels. In mice DTPI model, dECM hydrogel treatment promoted M1 to M2 macrophage conversion, improved iron metabolism, and reduced oxidative stress in the early stage of DTPI. In the remodeling phase, the dECM hydrogel remarkably enhanced revascularization and accelerated skeletal muscle repair. Furthermore, the immunomodulation of dECM hydrogels in vivo was mainly involved in the P13k/Akt signaling pathway, as revealed by GO and KEGG pathway analysis, which may ameliorate the iron deposition and promote the healing of DTPI. Our findings indicate that dECM hydrogel is promising in skeletal muscle repair, inflammation resolution, and tissue injury healing by effectively restoring macrophage immune homeostasis and normalizing iron metabolism.
研究领域:
组织工程
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免疫学
·
伤口愈合
·
肌肉骨骼疾病
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产品关联
DOI
PubMed
高影响因子
BMC Veterinary Research
·
2026
·
IF 3.1
Jing Yang,Xiaoli Zhang,Hao Wu,Wei Peng,Weiwei Su,Peibo Li
Background: Porcine reproductive and respiratory syndrome virus (PRRSV) poses a major threat to global swine production, with no clinically approved specific therapeutics. Archidendron clypearia (AC), a medicinal plant traditionally used for human upper respiratory infections, exhibits broad-spectrum antiviral activity. This study systematically evaluated the antiviral efficacy of AC against PRRSV, elucidated its pharmacodynamic material basis through comprehensive chemical profiling, and explored the targeted molecular mechanisms of its core active component, 7-GTDF. Results: Screening of 30 herbal ethanol extracts based on a PRRSV-EGFP fluorescence phenotype identified AC as possessing significant anti-PRRSV activity. In Marc-145 cells and porcine alveolar macrophages (PAMs), AC inhibited the replication of PRRSV-Li11 and PRRSV-CHR6 at both the mRNA and protein levels. Time-of-addition assays indicated that AC acts by inactivating the virus and interfering with early infection stages. Phytochemical analysis identified 40 constituents in AC, with 7-O-galloyltricetiflavan (7-GTDF) quantified via high-performance liquid chromatography (HPLC) as the predominant compound, accounting for 37.59% of the total peak area. Network pharmacology combined with experimental validation demonstrated that AC suppresses the PRRSV-induced overexpression of TNF-α, IL-1β, and IL-6 in PAMs by modulating the TLR4/NF-κB signaling pathway. Subsequent screening of the primary compounds in AC revealed that 7-GTDF exhibits significant anti-PRRSV activity. Molecular docking and molecular dynamics simulations indicated a stable interaction between 7-GTDF and the host CD163 receptor. Finally, cellular thermal shift assay (CETSA) confirmed this target engagement, demonstrating that 7-GTDF binds to the CD163 receptor and reduces its thermal stability. Conclusions: These data indicate that AC and its constituent 7-GTDF inhibit PRRSV infection through mechanisms involving CD163 targeting and inflammatory pathway modulation. These findings provide a pharmacological basis for evaluating AC as a potential antiviral candidate in swine health management.
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DOI
PubMed
高影响因子
MOLECULAR CARCINOGENESIS
·
2019
·Vol. 58
·期 8
·1481-1491
·
IF 3.411
Yuan-yuan Guo,Chen Xu,Yan Fang,Cai-e Wang,Na Gao,Qiang Wen,Hai-ling Qiao
Cytochrome P450 2E1 (CYP2E1) is an important drug-metabolizing enzyme that has been recognized as one of the risk factors for hepatofibrosis. Macrophages play key roles in regulating hepatofibrosis progression and resolution. However, whether CYP2E1 is involved in the regulation of macrophage polarization during hepatofibrosis is still unclear. Herein, we measured CYP2E1 activity and the expression of CD163 (an M2 marker) and CD68 (a pan-macrophage marker) in hepatofibrotic tissue from HCC patients (n = 26) with comparison to normal liver tissue (n = 26). The relationship of CYP2E1 activity in vivo and the CD163/CD68 ratio (an indicator of M2 polarization), as well as the extent of hepatofibrosis, were evaluated in diethylnitrosamine (DEN)-treated Sprague-Dawley rats. Strikingly, CYP2E1 activity and expression of CD68 increased and the CD163/CD68 ratio decreased, especially in hepatofibrotic tissue with higher CYP2E1 activity. Expression of α-SMA, Ki67, and PCNA were positively correlated with CYP2E1 activity and inversely correlated with the CD163/CD68 ratio. Furthermore, CYP2E1 activity showed an inverse correlation with the CD163/CD68 ratio. Overall, high CYP2E1 activity aggravates hepatofibrosis by restraining M2 macrophage polarization, providing a novel insight for understanding the profibrotic activity of CYP2E1 and a promising avenue for hepatofibrosis therapy.
研究领域:
肝病学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2024
·
IF 27.4
Zhiyan Li,Xianghui Li,Yanjun Lu,Xudong Zhu,Wenxuan Zheng,Kai Chen,Xingzhou Wang,Tao Wang,Wenxian Guan,Zhi Su,Song Liu,Jinhui Wu
Immunotherapy has emerged as a highly effective therapeutic strategy for cancer treatment. Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon gene (STING) pathway activation facilitates tumor-associated macrophage (TAM) polarization toward M1 phenotype, and Mn 2+ are effective agents for this pathway activation. However, the high in vivo degradation rate and toxicity of Mn 2+ hamper clinical application of immunotherapy. Here, this work has newly synthesized and screened manganese porphyrins for Mn 2+ transport, referred to as photo-STING agonists (PSAs), and further encapsulate them into core-shell nanoparticles named Rm@PP-GA with dual specificity for tumor tissue and TAMs. Not only do PSAs achieve higher Mn 2+ delivery efficiency compared to Mn 2+ , but they also generate reactive oxygen species under light exposure, promoting mitochondrial DNA release for cGAS-STING pathway activation. In Rm@PP-GA, globin and red blood cell membranes (Rm) are used for erythrocyte efferocytosis-mimicking delivery. Rm can effectively prolong the in vivo circulation period while globin enables PSAs to be taken up by TAMs via CD163 receptors. After Rm rupture mediated by perfluorohexane in nanoparticles under ultrasonication, drugs are specifically released for TAM repolarization. Further, dendritic cells mature, as well as T lymphocyte infiltrate, both of which favor tumor eradication. Therefore, cancer immunotherapy is optimized by novel PSAs delivered by erythrocyte efferocytosis-mimicking delivery pattern.
研究领域:
肿瘤学
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免疫疗法
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药学
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纳米技术
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细胞生物学
✓ 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）