ANALYTICA CHIMICA ACTA
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2023
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IF 6.2
Chendi Zhu,Hai Han,Zhiwei Chen,Yuan Shen,Qiaoxuan Zhang,Cai Bao,Jia-Huan Qu,Qiqin Wang,Zhengjin Jiang
Selective enrichment and analysis of therapeutic antibodies in biological fluids are crucial for the development of biopharmaceuticals. Recently, peptide-based affinity chromatography has exhibited fascinating prospects for antibody enrichment due to the high affinity and specificity of small peptides. However, the post-modification approach of peptide ligands on the material surface is complicated and time-consuming. In this study, a methacrylate modified tetrapeptide ( m -EDPW) was firstly demonstrated as the affinity ligand of trastuzumab ( K d = 1.91 ± 1.81 μM). Next, the m -EDPW based affinity monolith was prepared using a facile one-step polymerization method, which could overcome the drawbacks of traditional post-modification preparation strategies. Based on the monolith as described above, a simple enrichment approach was developed under the optimal washing and elution conditions. Based on the excellent properties, such as high porosity (53.09%), weak electrostatic interaction and suitable affinity (1.00 ± 2.14 μM for anti-HER2 ADC), this novel monolith exhibited good specificity and recovery for antibodies (91.6% for trastuzumab, 98.37% for anti-HER2 ADC), and low nonspecific adsorption for human serum albumin (DBC 10% = 0.5 mg/g polymer). Particularly, this material was successfully applied to enrich trastuzumab and its related antibody-drug conjugate (ADC) from different cell culture medias. The dynamic tracking analysis of ADC in the critical quality attributes (e.g., charge variants, drug to antibody ratio and subunit conjugation ratio) was also achieved by combining the enrichment approach, capillary electrophoresis or reversed phase liquid chromatography . In summary, the exploited peptide-based mimotope affinity materials showed a great potential for the application in biopharmaceutical analysis.
研究领域:
生物技术
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药学
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分析化学
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生物化学
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2016
·
IF 8.387
Leyong Zeng,Yuanwei Pan,Ruifen Zou,Jinchao Zhang,Ying Tian,Zhaogang Teng,Shouju Wang,Wenzhi Ren,Xueshan Xiao,Jichao Zhang,Lili Zhang,Aiguo Li,Guangming Lu,Aiguo Wu
To avoid the overheating effect of excitation light and improve the efficacy of photodynamic therapy (PDT) of upconversion nanoplatform, a novel nanoprobe based on 808 nm-excited upconversion nanocomposites ( [email protected] @mSiO 2 ) with low heating effect and deep penetration has been successfully constructed for targeted upconversion luminescence , magnetic resonance imaging (MRI) and high-efficacy PDT in HER2-overexpressed breast cancer. In this nanocomposite, photosensitizers (Ce6) were covalently conjugated inside of mesoporous silica to enhance the PDT efficacy by shortening the distance of fluorescence resonance energy transfer and to decrease the cytotoxicity by preventing the undesired leakage of Ce6 . Compared with [email protected] 2 @Ce6, [email protected] @mSiO 2 greatly promoted the singlet oxygen generation and amplified the PDT efficacy under the excitation of 808 nm laser . Importantly, the designed nanoprobe can greatly improve the uptake of HER2-positive cells and tumors by modifying the site-specific peptide, and the in vivo experiments showed excellent MRI and PDT via intravenous injection by modeling MDA-MB-435 tumor-bearing nude mice . Our strategy may provide an effective solution for overcoming the heating effect and improving the PDT efficacy of upconversion nanoprobes, and has potential application in visualized theranostics of HER2-overexpressed breast cancer.
研究领域:
纳米技术
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癌症研究
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治疗诊断学
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生物医学工程
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材料科学
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产品关联
DOI
PubMed
高影响因子
ONCOGENE
·
2021
·Vol. 40
·期 44
·6273-6283
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IF 9.867
Liu Zundong,Sang Xiaolin,Wang Min,Liu Yichao,Liu Jiao,Wang Xuefei,Liu Pixu,Cheng Hailing
Complete blockade of the HER2 protein itself and HER signaling network is critical to achieving effective HER2-targeted therapies. Despite the success of HER2-targeted therapies, the diseases will relapse in a significant fraction of patients with HER2 + breast cancers. How to improve the therapeutic efficacy of existing HER2-targeted agents remains an unmet clinical need. Here, we uncover a role of Melatonin in diminishing HER2-mediated signaling by destruction of HER2 protein. Mechanistically, Melatonin treatment attenuated the protective effect of the HSP90 chaperone complex on its client protein HER2, triggering ubiquitylation and subsequent endocytic lysosomal degradation of HER2. The inhibitory effect of Melatonin on HER2 signaling substantially enhanced the cytotoxic effects of the pan-HER inhibitor Neratinib in HER2 + breast cancer cells. Lastly, we demonstrate that dual inhibition of HER2 by combined use of Melatonin and Neratinib effectively blocked the growth of HER2 + breast tumor xenografts in vivo. Our findings shed light on the potential use of Melatonin in a novel dual HER2 blockade strategy for HER2 + breast cancer treatment.
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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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2022
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IF 8.039
Jiaqi Zhou,Xiaojian Bian,Zigui Kan,Zilong Cai,Yuxuan Jiang,Zike Wang,Yuanyuan Li,Wei Shi,Hai Qian
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptides P1GCGT1 and P1GCGCGT1 were designed using an in silico approach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain, P1GCGT1 and P1GCGCGT1 could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide–drug conjugates with camptothecin (CPT), among which I-1 and I-4 were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated that I-1 and I-4 induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed that I-1 and I-4 were effective at targeting HER2. Moreover, I-1 and I-4 showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.
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DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2024
·
IF 5.5
Qingrong Li,Xiaoyuan Yang,Xuelin Xia,Xiao-Xia Xia,Deyue Yan
Recombinant elastin-like polypeptides (ELPs) have emerged as an attractive nanoplatform for drug delivery due to their tunable genetically encoded sequence, biocompatibility, and stimuli-responsive self-assembly behaviors. Here, we designed and biosynthesized an HER2 (human epidermal growth factor receptor 2)-targeted affibody–ELP fusion protein (Z-ELP), which was subsequently conjugated with monomethyl auristatin E (MMAE) to build a protein–drug conjugate (Z-ELP-M). Due to its thermal response, Z-ELP-M can immediately self-assemble into a nanomicelle at physiological temperature. Benefiting from its active targeting and nanomorphology, Z-ELP-M exhibits enhanced cellular internalization and deep tumor penetration in vitro. Moreover, Z-ELP-M shows excellent tumor targeting and superior antitumor efficacy in HER2-positive ovarian cancer, demonstrating a relative tumor growth inhibition of 104.6%. These findings suggest that an affibody-functionalized elastin-like peptide–drug conjugate nanomicelle is an efficient strategy to improve antitumor efficacy and biosafety in cancer therapy.
研究领域:
生物医学工程
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肿瘤学
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药理学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2016
·Vol. 4
·期 8
·1219-1232
·
IF 3.614
Kongtong Yu,Yulin Zhou,Yuhuan Li,Xiangshi Sun,Fengying Sun,Xinmei Wang,Hongyan Mu,Jie Li,Xiaoyue Liu,Lesheng Teng,Youxin Li
Research on quantitatively controlling the ligand density on the surface of nanocarriers is in the frontier and becomes a technical difficulty for targeted delivery system designing. In this study, we developed an improved pre-conjugation (Imp) strategy, in which herceptin as a ligand was pre-conjugated with DSPE-PEG2000-Mal via chemical cross-linking, followed by conjugation onto the surface of pre-prepared paclitaxel-loaded PLGA/DODMA nanoparticles (PDNs) through hydrophobic interaction and electrostatic attraction for paclitaxel delivery. Compared with the post-conjugation (Pos) strategy, in which the ligand was conjugated onto the nanoparticle surface after the preparation of the nanoparticles, it realized a precise control targeting effect via adjustment of the herceptin density on the surface of the nanoparticles. Within the range of 0–20% of DSPE-PEG2000-herceptin in the blend, it showed a linear relation with the ligand density on the surface of the nanoparticles. The Imp strategy protected the bioactivity of the ligand during the preparation of nanoparticles. At the same time it avoided the waste of an excess amount of herceptin to drive the conjugation reaction in comparison with the post-conjugation (Pos) strategy. The nanoparticles from the Imp strategy showed much better cytotoxicity (p < 0.001), tumor targeting and cellular uptake efficiency (p < 0.001) than that of the other strategies in BT474 cells, in which BT474 cells were HER2 receptor over-expression breast cancer cell lines. A significant reduction in cellular uptake of the nanoparticles from the Imp strategy was observed in the presence of sucrose and cytochalasin D, indicating that clathrin-mediated and caveolae-dependent endocytosis was as a primary mechanism of cellular entry for these antibody-modified nanoparticles.
研究领域:
药剂学
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肿瘤学
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生物医学工程
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DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
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2025
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IF 7.7
Rong Qin,Mengqi Bai,Feiyi Zhang,Zengkai Wang,Fenglian Liu,Mingdong Dong,Lei Liu,Jian Xu
The detection of circulating tumor cells (CTCs) has emerged as a promising approach for the early diagnosis, therapeutic monitoring, and prognosis of malignant tumors. In this study, we present a novel magnetic nanoparticle (MP) functionalized with dual recognition peptides targeting the epithelial cell adhesion molecule (EpCAM) and human epidermal growth factor receptor 2 (HER2). Additionally, bovine serum albumin (BSA), an anti-fouling agent, is employed onto MP, effectively preventing the non-specific adhesion of platelets and proteins. This multifunctional peptide based magnetic biointerface (MPMB) platform effectively captures breast cancer cells in model systems and isolates CTCs from the blood of breast cancer patients. CTC enumeration of peripheral blood samples from 40 breast cancer patients, 30 benign breast tumor patients, and 30 healthy donors revealed a 70 % positivity rate in breast cancer patients (28/40), 6.7 % in benign breast tumor patients (2/30), and no positivity in healthy donors (0/30). CTC counts were significantly higher in breast cancer patients with advanced stages, particularly in those with distant metastasis, compared to early-stage patients ( p < 0.05). Moreover, among 10 breast cancer patients with positive CTC detection prior to surgery, 6 showed negative CTC results post-surgery. These findings indicate that the MPMB approach provides a simple, flexible, and efficient platform for monitoring therapeutic efficacy and evaluating prognosis in breast cancer patients undergoing treatment.
研究领域:
医学
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生物技术
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产品关联
DOI
高影响因子
Artificial Cells Nanomedicine and Biotechnology
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2018
·
IF 3.026
Ling-xin Meng,Qiang Ren,Qin Meng,Yu-xiu Zheng,Mao-lei He,Shu-yan Sun,Zhao-jun Ding,Bing-cheng Li,Hui-yun Wang
Untargeted delivery as well as low efficacy are two main obstacles for effective breast cancer therapy. Here in this study, we surface modified silica nanoparticles (SLN) with Trastuzumab (Tra) to construct a tumor-targeting carrier (Tra-SLN) for specific drug delivery to human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer cells. In addition, Tra-SLN could also loaded with broad-spectrum anticancer drug doxorubicin (DOX) to finally construct a drug delivery system (DDS) capable of co-delivering Tra and DOX (Tra-SLN/DOX). Our results demonstrated that the as-prepared Tra-SLN/DOX was nanoscale particles with spheroid appearance which showed preferable stability in physiological environments. In addition, the Tra-SLN/DOX could specifically target to HER2 overexpressed MCF-7 cells. Both in vitro and in vivo experiments revealed that the Tra-SLN/DOX exerted enhanced anticancer efficacy when compared with Tra or DOX alone. It was suggested that Tra-SLN/DOX might be a promising platform for enhanced therapy of breast cancer.
研究领域:
肿瘤学
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纳米医学
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药剂学
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DOI
PubMed
高影响因子
RSC Advances
·
2019
·Vol. 9
·期 4
·1982-1989
·
IF 3.049
Chao Zhang,HongLei Zhang,MengNan Han,XueLi Yang,ChaoHong Pei,ZhiDong Xu,Jie Du,Wei Li,Shengxi Chen
Cisplatin is the most widely used anticancer drug, but its side effects limit the maximum systemic dose. To circumvent the side effects, a DNA tetrahedron–affibody nanoparticle was prepared by combination of a DNA chain with cisplatin via interstrand crosslinks or adducts. Each nanocarrier can bind ∼68 molecules of cisplatin. This cisplatin nanoparticle exhibited high selectivity and inhibition for breast cancer HER2 overexpressing cells BT474 and lower toxicity in MCF-7 cells with low HER2 expression. The nano-drug inhibited the growth of BT474 cells by 94.57% at 512 nM (containing 33.3 μM cisplatin), which was higher than that of cisplatin (82.9%, 33.3 μM).
研究领域:
肿瘤学
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分子生物学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2021
·
IF 4.939
Xiaoyuan Yang,Xuelin Xia,Xiao-Xia Xia,Zhao Sun,Deyue Yan
Tumor necrosis factor-related apoptosis ligand (TRAIL) is a promising protein candidate for selective apoptosis of a variety of cancer cells. However, the short half-life and a lack of targeted delivery are major obstacles for its application in cancer therapy. Here, we propose a simple strategy to solve the targeting problem by genetically fusing an anti-HER2 affibody to the C-terminus of the TRAIL. The fusion protein TRAIL-affibody was produced as a soluble form with high yield in recombinant Escherichia coli. In vitro studies proved that the affibody domain promoted the cellular uptake of the fusion protein in the HER2 overexpressed SKOV-3 cells and improved its apoptosis-inducing ability. In addition, the fusion protein exhibited higher accumulation at the tumor site and greater antitumor effect than those of TRAIL in vivo, indicating that the affibody promoted the tumor homing of the TRAIL and then improved the therapeutic efficacy. Importantly, repeated injection of high-dose TRAIL-affibody showed no obvious toxicity in mice. These results demonstrated that the engineered TRAIL-affibody is promising to be a highly tumor-specific and targeted cancer therapeutic agent.
研究领域:
生物技术
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肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Dongyu Duan,Aiping Wang,Ling Ni,Liping Zhang,Xiuju Yan,Ying Jiang,Hongjie Mu,Zimei Wu,Kaoxiang Sun,Youxin Li
Introduction Nanoparticles (NPs) modified with bio-ligands represent a promising strategy for active targeted drug delivery to tumour. However, many targeted ligands, such as trastuzumab (TMAB), have high molecular weight, limiting their application for targeting. In this study, we prepared Fab’ (antigen-binding fragments cut from TMAB)-modified NPs (Fab′-NPs) with curcumin (Cur) as a model drug for more effective targeting of human epidermal growth factor receptor 2 (HER2/ErbB2/Neu), which is overexpressed on breast cancer cells.Material and methods The release kinetics was conducted by dialysis bags. The ability to kill HER2-overexpressing BT-474 cells of Fab′-Cur-NPs compared with TMAB-Cur-NPs was conducted by cytotoxicity experiments. Qualitative and quantitative cell uptake studies using coumarin-6 (fluorescent probe)-loaded NPs were performed by fluorescence microscopy and flow cytometry. Pharmacokinetics and biodistribution experiments in vivo were assessed by liquid chromatography–tandem mass spectrometry (LC-MS/MS).Results The release kinetics showed that both Fab′-Cur-NPs and TMAB-Cur-NPs provided continuous, slow release of curcumin for 72 h, with no significant difference. In vitro cytotoxicity experiments showed that Fab′-Cur-NPs manifested prominent ability to kill HER2-overexpressing BT-474 cells compared with TMAB-Cur-NPs. Qualitative and quantitative cell uptake studies indicated that the accumulation of Fab′-NPs was greater than that of TMAB-NPs in BT-474 (HER2+) cells; However, there was no significant difference in MDA-MB-231 (HER2−) cells. Pharmacokinetics and biodistribution experiments in vivo demonstrated that the half-life (t1/2) and area under the blood concentration-time curve (AUC0-t) of Fab′-Cur-NPs increased 5.30-fold and 1.76-fold relative to those of TMAB-Cur-NPs, respectively. Furthermore, the tumor accumulation of Fab′-Cur-NPs was higher than that of TMAB-Cur-NPs.Conclusion Fab′ fragment has greater capacity than the intact antibody to achieve tumor targeting through NP-based delivery.
研究领域:
药剂学
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肿瘤学
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生物医学工程
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DOI
PubMed
高影响因子
BIOINORGANIC CHEMISTRY AND APPLICATIONS
·
2021
·
IF 7.778
Meijuan Chen,Zhousheng Lin,Guangyu Yao,Xi Hong,Xiaolei Xue,Lujia Chen
TTRE, a photosensitizer molecule, has excellent biofluorescence imaging performance and effective antitumor properties for breast cancer. However, its application in breast cancer treatment is limited due to poor tumor selectivity and lack of targeting ability. In this study, TTRE and trastuzumab were combined to synthesize Tra-TTR-A, a novel near-infrared fluorescent nanoprobe for HER2 positive breast cancer. The targeting and antitumor abilities of Tra-TTR-A in breast cancer were also investigated. Like TTRE, Tra-TTR-A has a stable structure with remarkable optical properties and in vivo imaging capacity. However, Tra-TTR-A not only inhibits tumor growth by generating reactive oxygen species but also kills tumor cells by trastuzumab. In this study, Tra-TTR-A, a new type of near-infrared fluorescent nanoprobe that targets HER2-positive breast cancer, was successfully synthesized. Tra-TTR-A could be used in in vivo imaging, targeted photodynamic therapy, and diagnosis and treatment for breast cancer.
研究领域:
癌症研究
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生物医学工程
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分子生物学
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药学
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DOI
PubMed
高影响因子
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