Journal of Advanced Research
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2023
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IF 10.7
Wenjuan Tang,Yu Hu,Kaihui Tu,Zhengyan Gong,Man Zhu,Tianfeng Yang,Ammar Sarwar,Bingling Dai,Dongdong Zhang,Yingzhuan Zhan,Yanmin Zhang
Introduction Tumor-associated calcium signal transducer 2 (Trop2) has been used as a transport gate for cytotoxic agents into cells in antibody–drug conjugate designs because of its expression in a wide range of solid tumors. However, the specific role of Trop2 itself in breast cancer progression remains unclear and small molecules targeting Trop2 have not yet been reported. Objectives To screen small molecules targeting Trop2, and to reveal its pharmacological effects and the molecular mechanisms of action. Methods Small molecule targeting Trop2 was identified by cell membrane chromatography, and validated by cellular thermal shift assay and point mutation analyses. We investigated the pharmacological effects of Trop2 inhibitor using RNA-seq, human foreskin fibroblast (HFF)-derived extracellular matrix (ECM), Matrigel drop invasion assays, colony-forming assay, xenograft tumor model, 4T1 orthotopic metastasis model and 4T1 experimental metastasis model. The molecular mechanism was determined using immunoprecipitation, mass spectrometry, immunofluorescence, immunohistochemistry and Western blotting. Results Here we identified Bruceine D (BD) as the inhibitor of Trop2, and demonstrated anti-metastasis effects of BD in breast cancer. Notably, Lys307 and Glu310 residues of Trop2 acted as critical sites for BD binding. Mechanistically, BD suppressed Trop2-induced cancer metastasis by blocking the formation of Trop2/β-catenin positive loop, in which the Trop2/β-catenin complex prevented β-catenin from being degraded via the ubiquitin-proteosome pathway. Destabilized β-catenin caused by BD reduced nucleus translocation, leading to the reduction of transcription of Trop2, the reversal of epithelial-mesenchymal transition (EMT) process, and the inhibition of ECM remodeling, further inhibiting cancer metastasis. Additionally, the inhibitory effects of BD on lung metastatic colonization and the beneficial effects of BD on prolongation of survival were validated in 4T1 experimental metastasis model. Conclusions These results support the tumor-promoting role of Trop2 in breast cancer by stabilizing β-catenin in Trop2/β-catenin positive loop, and suggest Bruceine D as a promising candidate for Trop2 inhibition.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF RADIOANALYTICAL AND NUCLEAR CHEMISTRY
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2026
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IF 1.7
Yu Jiayan,Wang Tao,Li Jiajia,He Zhiyou,Wang Jing,Zhao Peng,Chen Yue,Yang Xia
Antibody-targeted radioimmunotherapy holds significant potential for solid tumor treatment. However, intact antibodies (IgG) and fragments (F(ab’) 2 ) may exhibit distinct pharmacokinetic and radiation delivery properties due to differences in molecular size and Fc functionality. TROP2 is highly overexpressed in most malignant tumors but minimally expressed in normal tissues. Therefore, the anti-TROP2 antibody was selected as the targeting agent in this study. We prepared the F(ab’) 2 antibody fragments of anti-TROP2 antibody and systematically compared the in vitro and in vivo behaviors of [ 177 Lu]Lu-DOTA-anti-TROP2 antibody and [ 177 Lu]Lu-DOTA-anti-TROP2-F(ab’) 2 antibody fragments to optimize radioligand therapy strategies. Cell binding assays were conducted to evaluate their TROP2 antigen binding affinity. In vivo distributions in tumors and normal organs were investigated through Micro-SPECT/CT imaging and biodistribution studies using tumor-bearing mice. The results demonstrated that, compared to the anti-TROP2 antibody, the anti-TROP2-F(ab’) 2 antibody fragments exhibited superior blood clearance kinetics as well as lower accumulation in liver and spleen. This could reduce the radiation side effects of [ 177 Lu]Lu-DOTA-anti-TROP2-F(ab’) 2 antibody fragments on bone marrow or other full-antibody target normal organs. However, cutting Fc from the full anti-TROP2 antibody increased renal accumulation and exhibited shedding phenomena following tumor targeting.
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DOI
高影响因子
BIOMATERIALS
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2025
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IF 12.9
Zhiwei Yang,Bianfei Shao,Danni Wang,Hongwei Chen,Xiaohui Zhao,Minghui Zeng,Yimin Liu,Qingjian Li,Zhuofei Bi
Radioresistance in triple-negative breast cancer (TNBC) frequently results in local recurrence and distant metastasis, seriously affecting the prognosis of patients. The increased generation of cellular glutathione (GSH) and the upregulation of pro-malignant molecules are two major causes of radioresistance in TNBC, which need to be comprehensively considered in treatment. Herein, a TNBC-targeted reduction-responsive RNA interference (RNAi) nano-radiosensitizer (TREARA) was developed to reverse radioresistance by synergizing GSH depletion with combined inhibition of two promising pro-malignant molecules, Trophoblast cell surface antigen 2 (Trop2) and lncRNA Motor neuron and pancreas homeobox 1–antisense RNA1 (lncMNX1-AS1). Once arriving at the tumor sites with the prolonged circulation maintained by PEGylation, TREARA was rapidly internalized by tumor cells and blocked the Trop2-dominant pro-metastatic signaling through the anti-Trop2 antibody (αTrop2) modified on its surface. Subsequently, in response to the highly concentrated GSH in the cytoplasm, the shell of TREARA containing poly(disulfide amide) polymer (PDSA) was broken, unlashing the loaded lncMNX1-AS1 siRNA (siMNX1-AS1), which would suppress tumor progression by inactivating JAK3/STAT3 signaling. Benefiting from the integration of GSH-scavenging and dual-targeted inhibition of Trop2 and lncMNX1-AS1, TREARA significantly reversed radioresistance and restrained metastasis in murine models. Taken together, TREARA provides a promising comprehensive perspective for refractory radioresistant TNBC treatment.
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DOI
PubMed
高影响因子
ACS Nano
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2024
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IF 15.8
Taiyuan Liu,Xinghui Si,Liping Liu,Sheng Ma,Zichao Huang,Yu Zhang,Wantong Song,Yingchao Zhang,Xuesi Chen
Breast cancer is the most commonly diagnosed cancer, and surgical resection is the first choice for its treatment. With the development of operation techniques, surgical treatment for breast cancer is evolving toward minimally invasive and breast-conserving approaches. However, breast-conserving surgery is prone to an increased risk of cancer recurrence and is becoming a key challenge that needs to be solved. In this study, we introduce a one-shot injectable nano-in-gel vaccine (NIGel-Vax) for postoperative breast cancer therapy. The NIGel-Vax was constructed by mixing protein antigens with PEI-4BImi-Man adjuvant and then encapsulated in a hydrogel made with oxidized dextran (ODEX) and 4-arm PEG-ONH2. Using 4T1 tumor-extracted proteins as antigen, the NIGel-Vax achieved a 92% tumor suppression rate and a 33% cure rate as a postoperative therapy in the 4T1 tumor model. Using the tumor-associated antigen trophoblast cell-surface antigen 2 (TROP2) protein as the antigen, NIGel-Vax achieved a 96% tumor suppression rate and a 50% cure rate in triple-negative breast cancer (TNBC) models. This design provides an encouraging approach for breast cancer postoperative management.
研究领域:
肿瘤学
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药理学
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生物医学工程
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免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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