BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
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IF 3.322
Sansong Chen,Xuetao Li,Hao Wang,Guangliang Chen,Youxin Zhou
Angiogenesis is a key physiological process that plays a key role in glioblastoma (GBM) progression and displays therapeutic resistance to antiangiogenic therapies. In this study, we aimed to identify whether vascular endothelial growth factor receptor 2(VEGFR2)monoclonal antibodies(mab)could inhibit tumorigenicity and the formation of vascular mimicry (VM) in GBM. The bioinformatic analysis from TCGA, CGGA, and TCPA databases and Immunohistochemistry (IHC) revealed that VEGFR2 is highly expressed in glioma tissues and results in a poor prognosis and is positively associated with VM markers (CD34 and PAS). The anti-VEGFR2 monoclonal antibodies(MSB0254)could inhibit the invasion, migration, and VM formation of U251 and primary glioma cells in vitro. In vivo, MSB0254 (m) could not only inhibit the growth of transplanted tumors of U251 and GL261 cells, but also significantly inhibit the expression of CD34 , VEGFR2, Ki67, MMP2 , MMP9 and reduce the expression of CD34/PAS and inhibit VM formation. The VEGFR2 monoclonal antibody could inhibit the angiogenesis and tumor growth of GBM by blocking the signaling pathway mediated by VEGFR2. It may become a new supplementary treatment for GBM.
研究领域:
肿瘤学
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分子生物学
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医学
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PubMed
高影响因子
Nature Communications
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2023
·Vol. 14
·期 1
·1-14
·
IF 16.6
Liu Di,Song Yanling,Chen Hui,You Yuchan,Zhu Luwen,Zhang Jucong,Xu Xinyi,Hu Jiahao,Huang Xiajie,Wu Xiaochuan,Xu Xiaoling,Jiang Saiping,Du Yongzhong
Poor renal distribution of antibody-based drugs is the key factor contributing to low treatment efficiency for renal diseases and side effects. Here, we prepare F(ab′) 2 fragmented vascular endothelial growth factor receptor 2 antibody (anti-VEGFR2 (F(ab′) 2 ) to block VEGFR2 overactivation in diabetic nephropathy (DN). We find that the anti-VEGFR2 F(ab′) 2 has a higher accumulation in DN male mice kidneys than the intact VEGFR2 antibody, and simultaneously preserves the binding ability to VEGFR2. Furthermore, we develop an antibody fragment drug conjugate, anti-VEGFR2 F(ab′) 2 -SS31, comprising the anti-VEGFR2 F(ab′) 2 fragment linked to the mitochondria-targeted antioxidant peptide SS31. We find that introduction of SS31 potentiates the efficacy of anti-VEGFR2 F(ab′) 2 . These findings provide proof of concept for the premise that antibody fragment drug conjugate improves renal distribution and merits drug validation in renal disease therapy.
研究领域:
药理学
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肾病学
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糖尿病
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高影响因子
INVESTIGATIONAL NEW DRUGS
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2023
·Vol. 41
·期 5
·664-676
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IF 3.4
Pan Mingzhu,Liu Yali,Sang Tian,Xie Jiajun,Lin Huishu,Wei Jianpeng,Shao Shuai,Zheng Yanying,Zhang Juan
Liposomal doxorubicin exhibits stronger drug accumulation at the tumor site due to the Enhanced Permeability and Retention (EPR) effect. However, the prognosis for the patient is poor due to this drug’s lack of targeting and tumor metastasis during treatment. Vascular epidermal growth factor receptor (VEGFR2) plays an important role in angiogenesis and cancer metastasis. To enhance antitumor efficacy of PEGylated liposomal doxorubicin, we constructed a VEGFR2-targeted and doxorubicin-loaded immunoliposome (Lipo-DOX-C00) by conjugating a VEGFR2-specific, single chain antibody fragment to DSPE-PEG2000-MAL, and then we inserted the antibody-conjugated polymer into liposomal doxorubicin (Lipo-DOX). The immunoliposome was formed uniformly with high affinity for VEGFR2. In vitro, Lipo-DOX-C00 enhanced doxorubicin internalization into LLC and 4T1 cells compared with non-conjugated, liposomal doxorubicin. In vivo, Lipo-DOX-C00 delivered DOX to tumor tissues effectively, which exhibited an improved antitumor and anti-metastasis efficacy in both LLC subcutaneous tumor models and 4T1 tumor models. In addition, the combined therapy of a VEGFR2–MICA bispecific antibody (JZC01) and Lipo-DOX-C00 achieved enhanced inhibition of cancer growth and metastasis due to activation of the immune system. Our study provides a promising approach to clinical application of liposomal doxorubicin.
研究领域:
肿瘤学
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药学
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免疫疗法
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药物递送系统
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癌症生物学
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Marine Drugs
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2025
·Vol. 23
·期 1
·22
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IF 5.4
Xia Zheng,Xiaofei Liu,Zhuo Wang,Rui Li,Qiaoli Zhao,Bingbing Song,Kit-Leong Cheong,Jianping Chen,Saiyi Zhong
Chondroitin sulfate (CS), a class of glycosaminoglycans covalently attached to proteins to form proteoglycans, is widely distributed in the extracellular matrix and cell surface of animal tissues. In our previous study, CS was used as a template for the synthesis of seleno-chondroitin sulfate (SeCS) through the redox reaction of ascorbic acid (Vc) and sodium selenite (Na2SeO3) and we found that SeCS could inhibit tumor cell proliferation and invasion. However, its effect on angiogenesis and its underlying mechanism are unknown. In this study, we analyzed the effect of SeCS on tube formation in vitro, based on the inhibition of tube formation and migration of human umbilical vein endothelial cells (HUVECs), and evaluated the in vivo angiogenic effect of SeCS using the chick embryo chorioallantoic membrane (CAM) assay. The results showed that SeCS significantly inhibited the angiogenesis of chicken embryo urothelium. Further mechanism analysis showed that SeCS had a strong inhibitory effect on VEGFR2 expression and its downstream PI3K/Akt signaling pathway, which contributed to its anti-angiogenic effects. In summary, SeCS showed good anti-angiogenic effects in an HUVEC cell model and a CAM model, suggesting that it may be a potential angiogenesis inhibitor.
研究领域:
肿瘤学
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分子生物学
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药理学
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JOURNAL OF ULTRASOUND IN MEDICINE
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2025
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IF 2.4
Likang Hou,Zhili Guo,Shun Liu,Xiaowen Liang,Meng Du,Zhiyi Chen
Objectives To assess the severity of intrauterine adhesion (IUA) after endometrial injury via ultrasound molecular imaging (USMI) of vascular endothelial growth factor receptor 2 (VEGFR2) expression on the uterine endothelium. Methods MB VEGFR2 was constructed via “biotin-avidin-biotin” bridging technology. A rat IUA animal model was constructed via chemical injury. Fourteen days after the model was constructed, MB Con and MB VEGFR2 contrast agents were injected into the standard group and the model group of rats, and simultaneous ultrasound molecular imaging was carried out and ultrasound molecular imaging was performed and the changes in ultrasound signals in vivo were normalized to differential targeted enhancement (dTE). In addition, immunohistochemistry was used to detect the expression levels of VEGFR2 and α-SMA in the uterine tissues of the rats in both groups. Results Targeted-VEGFR2 microbubble (MB VEGFR2 ) was successfully constructed, the average particle size of the targeted VEGFR2 microbubble contrast agent was 2309.6 ± 234.3 nm, with the average zeta potential -16.9 ± 0.15 mV and the dispersity coefficient less than 0.4. In addition, its essential performance and biosafety were examined, which revealed that the MB VEGFR2 contrast agent had an appropriate size, stable imaging performance, good target adhesion, and good biocompatibility. In vivo, ultrasound imaging results revealed that after the injection of the targeted MB VEGFR2 , the contrast ultrasound signal intensity of uterine tissues in the model group (62.5 ± 17.9 dB) was higher than in the normal group (33.5 ± 12.5 dB), and the difference was statistically significant ( P < .05). The immunohistochemistry results revealed that the expression of VEGFR2 and α-SMA in the uterine tissue of the model group was greater than that in the standard group ( P < .05), further indicating that the signal intensity of the MB VEGFR2 contrast agent can reflect the expression level of VEGFR2 molecules. Conclusions Ultrasound molecular imaging based on MB VEGFR2 can be used to evaluate the expression level of VEGFR2 in uterine vascular endothelial cells. This provides a potential approach for the early diagnosis and treatment monitoring of intrauterine adhesions after endometrial injury.
研究领域:
医学影像学
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生殖医学
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分子生物学
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PubMed
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Scientific Reports
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2026
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IF 4.9
Liu Siqi,Fang Fei,Jiang Yu
Chronic administration of glucocorticoids are being linked to an increased risk of osteoporosis. 5-Hydroxymethylfurfural (5-HMF) is a natural compound that possesses various biological activities, including osteogenic regulation. In this research, we sought to investigate the potential of 5-HMF to exert protective effects against glucocorticoid-induced osteoporosis. In cellular investigations, we deployed Western Blot (WB), Real-Time Quantitative real-time PCR (qRT-PCR), Alkaline phosphatase (ALP) and Alizarin S-red (ARS) staining to scrutinize the expression of osteogenic differentiation markers within MC3T3-E1 pre-osteoblasts and BMSCs. We used dexamethasone to establish a mouse model for glucocorticoid-Induced osteoporosis and administered 5-HMF to evaluate its influence on bone density and architecture through the use of micro-CT and histological analysis. In addition, we employed network pharmacology to elucidate the potential pathways and targets of 5-HMF. Finally, we explored the effect of AKT knockout on the treatment of 5-HMF. We found that 5-HMF significantly enhanced VEGFR2 phosphorylation, reestablishing angiogenesis and activating the PI3K/AKT pathway in vitro and in vivo. 5-HMF also inhibited Dexamethasone -induced apoptosis by regulating Bax and Bcl-2 expression. MK2206, an AKT inhibitor, abrogated 5-HMF’s protective properties against GCs. These results indicate that 5-HMF counteracts the negative effects of GCs on osteoblasts and has good bone-promoting differentiation effects.
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Frontiers in Oncology
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2021
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IF 6.244
Li Xiaoyu,Xia Shujun,Ji Ri,Zhan Weiwei,Zhou Wei
Objectives: A novel ultrasound contrast agent (UCA) VEGFR2-targeting iron-doped silica (SiO2) hollow nanoparticles (VEGFR2-PEG-HSNs-Fe NPs) was prepared and applied in microwave ablation for breast cancer to investigate its value in the evaluation of effectiveness after tumor ablation.Methods: VEGFR2-PEG-HSNs-Fe NPs were prepared by using nano-SiO2, which was regarded as a substrate and etched by ferrous acetate, and then modified with anti-VEGFR2 antibody. Laser confocal microscope and flow cytometry were used to observe its main physicochemical properties, and biological safety was also investigated. After the xenograft tumor was treated with microwave ablation, the extent of perfusion defect was evaluated by ultrasound by injecting VEGFR2-PEG-HSNs-Fe NPs.Results: The average particle size of VEGFR2-PEG-HSNs-Fe was 276.64 ± 30.31 nm, and the surface potential was −13.46 ± 2.83 mV. In vitro, the intensity of ultrasound signal increased with UCA concentration. Good biosafety was performed in in vivo and in vitro experiments. The enhanced ultrasound signal was detected in tumors after injection of VEGFR2-PEG-HSNs-Fe NPs, covering the whole tumor. The lesions, which were incompletely ablated, presented as contrast agent perfusion at the periphery of the tumor, and contrast enhanced ultrasound (CEUS) was performed again after complementary ablation. It was confirmed that all the lesions were completely ablated.Conclusion: Nano-targeted UCAs VEGFR2-PEG-HSNs-Fe NPs had good biosafety and ability of specific imaging, which might be used as a contrast agent in CEUS to evaluate the efficacy of tumor ablation.
研究领域:
医学影像学
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肿瘤学
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生物材料学
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PubMed
高影响因子
INTERNATIONAL DENTAL JOURNAL
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2026
·Vol. 76
·期 5
·109799
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IF 5.2
Xinda Li,Zhijia Liu,Xinzhu Liu,Jianing Wang,Jinlai Bao,Wuwei Li
Background To explore the osteogenic promotion of carboxymethyl chitosan (CMCS), clarify the signalling pathways involved and preliminarily evaluate the translational potential of CMCS in transcrestal sinus floor elevation. Methods Overlapping targets were identified by integrating potential CMCS targets and bone regeneration-related genes, and protein-protein interaction and GO/KEGG enrichment analyses were conducted. The GEO dataset GSE50743 was externally validated. Bone marrow-derived mesenchymal stem cells from mice were induced to osteogenic differentiation in vitro and treated with CMCS alone or in combination with the p38 inhibitor SB203580 or the VEGFR2 inhibitor SU5416. The osteogenic phenotypes and mechanism-related changes were determined by ALP, Alizarin Red S staining, RUNX2 immunofluorescence, qPCR and Western blotting. A retrospective comparative clinical study further evaluated radiographic, functional and patient-reported outcomes after transcrestal sinus floor elevation. Results We identified 187 common targets of CMCS-bone regeneration. Enrichment analyses revealed that these targets were primarily involved in cell adhesion, inflammatory and immune regulation, extracellular matrix remodelling, and osteogenesis-related pathways, including MAPK and VEGF signalling. Validation with GSE50743 confirmed significant positive enrichment of candidate gene set under osteogenic conditions. In vitro, CMCS increased ALP activity, mineralised nodule formation and the expression of RUNX2, ALP and OPN, whereas inhibition of p38 or VEGFR2 partially reduced these effects. Clinical findings showed that the two groups were generally similar in terms of safety, implant stability and patient-reported outcomes, whereas the CMCS group had better volume maintenance. Conclusions CMCS promotes osteogenesis and mineralisation, at least partly via p38 MAPK and VEGF–VEGFR2 signalling. Retrospective clinical findings also indicate its potential utility in transcrestal sinus floor elevation.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
·
IF 5.7
Tong Zhao,Luying Xu,Wenjie Huang,Cong Wang,Huanhuan Wang,Mengyue Du,Chang Yao,Yanlei Xu
Background Breast cancer progression depends on abnormal angiogenesis, driven by VEGF/VEGFR2/ERK and inhibited by Angiotensin-Converting Enzyme 2 (ACE2). Chrysophanol (CHR) shows anti-breast cancer efficacy, but its mechanism is unclear. Methods Anti-tumor effects were assessed by measuring tumor volume, H&E staining, Ki67 immunohistochemistry, MTT, scratch wound, and Transwell assays. Anti-angiogenic effects were evaluated via Platelet Endothelial Cell Adhesion Molecule-1 (CD31) immunohistochemistry, CAM assay and Western blot (WB) of VEGF-A, Hypoxia-Inducible Factor 1-α (HIF-1α), and VEGFA/VEGFR2/ERK pathway proteins. The mechanism was explored by WB analysis of ACE2 expression/ubiquitination, validated by siRNA knockdown and CETSA for binding site identification. Results Both in vivo and in vitro experiments demonstrated that chrysophanol reduces tumor cell viability, suppresses tumor cell growth, migration, and invasion, inhibiting the progression of breast cancer. Given the critical role of angiogenesis in tumor development, further studies revealed that chrysophanol downregulates the expression of proteins such as HIF-1α and Vascular Endothelial Growth Factor A (VEGFA), indicating that it inhibits tumor angiogenesis by suppressing the VEGFA/VEGFR2/ERK signaling pathway. Since prior evidence suggests that this pathway acts downstream of ACE2, we examined ACE2 protein levels and found that chrysophanol reduces ACE2 ubiquitination, and enhances its stability and expression. This upregulation of ACE2 further inhibits the downstream VEGFA/VEGFR2/ERK pathway. Moreover, molecular docking confirmed that chrysophanol binds specifically to the active pocket 888 of the ACE2 protein. All the observed inhibitory effects on breast cancer were dose-dependent. Conclusion All the data shows that chrysophanol can reduce tumor angiogenesis and alleviate breast cancer growth. It also confirms that chrysophanol can promote ACE2 expression to inhibit the VEGFa/VEGFR2/ERK signaling pathway, thereby suppressing breast cancer development.
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BIOORGANIC CHEMISTRY
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2026
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IF 5.1
Nannan Tian,Shuxian Zhao,Fan Xu,Ruiqi Liu,Wenhong Dong,Zhaorui Song,Yongkuan Suo,Zhen Cheng
Molecular imaging of tumor biomarkers represents a crucial direction for advancing precision cancer diagnosis and therapy. As a core regulator of tumor angiogenesis, VEGFR2 represents an ideal molecular imaging target. Herein, a novel VEGFR2-targeting peptide (HTMYYHHYQHHLSSSDICLPRWGCLWED, named as VTP) was designed and synthesized by conjugating a peptide K237 (HTMYYHHYQHHL), a flexible tripeptide linker (Ser-Ser-Ser, SSS), and an albumin-binding peptide (ABP, DICLPRWGCLWED). The surface plasmon resonance (SPR) analysis confirmed that VTP had high binding affinity for VEGFR2 ( K D = 15.4 nM). Although indocyanine green (ICG) has been widely used in clinical practice, its short half-life and lack of active targeting ability significantly restrict its potential for intraoperative navigation. In this study, the VEGFR2-targeting peptide VTP was conjugated with ICG to successfully construct a targeted fluorescent probe, ICG-VTP. Owing to ABP modification, this probe exhibits a longer blood half-life and shows accumulation characteristics that are highly positively correlated with VEGFR2 expression levels in multiple tumor models, including ovarian cancer, colorectal cancer, and non-small cell lung cancer. The probe yielded tumor-to-background ratios (TBR) of 2.95, 2.05, and 1.42 in high (SKOV3), moderate (HCT116), and low (A549) VEGFR2-expressing tumors at 10 h post-injection, respectively, confirming its specificity for VEGFR2 imaging. Further, the ICG-VTP probe enabled successful intraoperative fluorescence navigation and precise tumor resection. Safety assessments revealed no significant toxicity at cellular or tissue levels. In summary, the ICG-VTP probe demonstrates strong specificity and superior imaging contrast of VEGFR2-positive tumors, underscoring its high potential to advance biomedical research and clinical translation.
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Bioactive Materials
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2026
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IF 23.6
Xiaobin Luo,Toshitatsu Nagayasu,Yuhao Zhang,Zhi He,Jia Yang,Chengli Li,Guman Duan,Qunchuan Zong,Yun Liu,Kaiyuan Yang,Kaige Mao,Pengchao Ma,Zifan Li,Yating Zhao,KunKoo Kim,Jie Zhang,Zide Wang,Yuyang Luo,Jingsong Lu,Sengpav Tong,Jia-kuo Yu,Zhe Zhao,Zheng Cao,Shuhui Yang,Yongwei Pan,Xiumei Wang
Stump neuromas represent nonfunctional redundant tissue that frequently elicits neuropathic pain through disorganized axonal regeneration, pathological angiogenesis, scar hyperplasia, and chronic neuroinflammation. Current therapeutic strategies fail to adequately address the underlying pathophysiology, particularly the excessive production of reactive oxygen species resulting from dysregulated vascular proliferation and activation. To tackle this issue, we developed photo-crosslinked gelatin methacryloyl (GelMA) microspheres covalently functionalized with methacryloyl-modified anti-VEGFR2 peptides (MAVP) to modulate pathological angiogenesis. These functionalized microspheres were fabricated into linear arrays via 3D printing and integrated within a progressively spatial-constrictive conduit. This platform facilitated the self-resolution of the nerve end interface, including sustained suppression of VEGFR2 phosphorylation and coordinated mechanotransduction signaling, thereby inhibiting neuroinflammatory responses and angiogenesis. In a sciatic nerve ligation model, GelMA MAVP MPs system demonstrated markedly superior analgesic efficacy over the conventional VEGFR2 inhibitor vandetanib. In a stump neuroma model, GelMA MAVP MPs effectively normalized the peripheral end interface microenvironment by inhibiting neovascularization, M1 macrophage polarization, and fibrotic scar formation. Furthermore, GelMA MAVP MPs distributed in the peripheral nerve stumps indirectly downregulated pain-related proteins (TRPA1/CGRP) in dorsal root ganglia and suppressed spinal microglial activation. Overall, this study presents a comprehensive and safe vascular-targeted strategy promoting nerve end interface self-resolution and prevention of neuropathic pain.
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PHYTOMEDICINE
·
2025
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IF 8.3
Min Jiang,Chao Hong,Wenkui Zou,Zheng Ye,Kexu Gu,Yaning Ren,MingFang Li,Don Green,Tong Zhang,Yue Ding
Background Drug resistance severely hinders the clinical application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer (NSCLC). Notably, resistance caused by rare target mutations (with a mutation incidence rate below 5%) accounts for approximately 15% of total resistance cases in NSCLC. Due to the diversity and complexity of these mutations, targeted therapies against them are currently very limited. Purpose To address the challenge of multi-driver resistance in NSCLC, this study aimed to explore a novel therapeutic strategy that can simultaneously inhibit multiple resistance drivers and enhance drug resensitization to EGFR-TKIs, overcoming the limitations of conventional single-protein inhibitors. Methods Established gefitinib-resistant HCC827 cell models driven by rare co-activation of two EGFR-independent membrane proteins. Developed a strategy targeting lipid raft cholesterol to destabilize raft integrity, leveraging the cholesterol-modulating properties of ginsenosides. Evaluated the synergistic effect of co-administering ginsenoside Rg3 with gefitinib in both in vitro and in vivo models. Explored the mechanism of Rg3 action, including its binding to lipid raft cholesterol, disruption of membrane anchoring of resistance-associated receptor tyrosine kinases, and acceleration of their endocytic degradation. Results : Co-administration of ginsenoside Rg3 with gefitinib synergistically restored antitumor efficacy in both in vitro and in vivo models, outperforming conventional single-protein inhibitors. Mechanistically, Rg3 specifically binds to lipid raft cholesterol, disrupting the membrane anchoring of resistance-associated receptor tyrosine kinases (e.g., FGFR1 and VEGFR2) and accelerating their endocytic degradation. Structural-activity relationship analyses revealed that the cholesterol-binding capacity of ginsenosides—critical for resistance reversal—is modulated by the stereochemical configuration of sugar moieties at C3, C6, and C20 positions. Conclusions This study elucidates a novel membrane-centric paradigm for overcoming multi-driver resistance in NSCLC, where pharmacological perturbation of cholesterol-lipid raft interactions by natural compounds like Rg3 enables broad-spectrum suppression of coexisting resistance mechanisms. It not only provides novel insights into the mechanisms underlying resistance in NSCLC but also presents a promising clinical strategy that could significantly improve treatment outcomes for patients.
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