JOURNAL OF PROTEOME RESEARCH
·
2024
·
IF 3.8
Meiling Qi,Chenyue Zhu,Yi Chen,Chenxi Wang,Xinyuan Ye,Sen Li,Zhongzhe Cheng,Hongliang Jiang,Zhifeng Du
Antibody–drug conjugate (ADC) consists of engineered antibodies and cytotoxic drugs linked via a chemical linker, and the stability of ADC plays a crucial role in ensuring its safety and efficacy. The stability of ADC is closely related to the conjugation site; however, no method has been developed to assess the stability of different conjugation sites due to the low response of conjugated peptides. In this study, an integrated strategy was developed and validated to assess the stability of different conjugation sites on ADC in serum. Initial identification of the conjugated peptides of the model drug ado-trastuzumab emtansine (T-DM1) was achieved by the proteomic method. Subsequently, a semiquantitative method for conjugated peptides was established in liquid chromatography–hybrid linear ion trap triple quadrupole mass spectrometry (LC–QTRAP-MS/MS) based on the qualitative information. The pretreatment method of the serum sample was optimized to reduce matrix interference. The method was then validated and applied to evaluate the stability of the conjugation sites on T-DM1. The results highlighted differences in stability among the different conjugation sites on T-DM1. This is the first study to assess the stability of different conjugation sites on the ADC in serum, which will be helpful for the design and screening of ADCs in the early stages of development.
研究领域:
药学
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分析化学
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生物化学
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药物开发
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2017
·Vol. 6
·期 24
·1700829
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IF 5.11
Wenxiu He,Xu Hu,Wei Jiang,Ruiling Liu,Di Zhang,Jing Zhang,Zhonghao Li,Yuxia Luan
Herein, two careful selected anticancer drugs camptothecin (CPT) and cytarabine (Ara-C) with different biological action mechanisms and different water solubility are conjugated together through a glutathione (GSH) cleavable disulfide bond to construct a redox-sensitive drug–drug conjugate, which can self-assemble into nanoparticles, thus notably improving the water solubility of CPT and the cell membrane permeability of Ara-C. Compared with free drugs, the self-assembled CPT-ss-Ara nanoparticles can concentrate in tumor tissues through the enhanced permeability and retention (EPR) effect, then they can be rapidly internalized by tumor cells and degrade into free drugs for killing the tumor cells when exposed to the reductive environment (GSH) of tumor cells, thereby reducing the injury to normal cells. Meanwhile, the CPT-ss-Ara nanoparticles can effectively protect CPT and Ara-C molecules from biological inactivation before their arrival in tumor microenvironment since free CPT and Ara-C are easy to partly lose their therapy efficacy due to their structure degradation in blood circulation. The in vitro and in vivo anticancer experimental results indicate that simultaneous release of free CPT and Ara-C can realize synergistic chemotherapy effects, thus markedly improve their anticancer activity. Therefore, our designed carrier-free, redox-sensitive CPT-ss-Ara nanoparticles might have promising clinical application to combat cancers.
研究领域:
药学
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纳米技术
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肿瘤学
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药物递送系统
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生物医学工程
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2022
·
IF 3.322
Hui Feng,Yi Liu,Mengyao Zhang,Ruimin Liu,Jincheng Wang,Wenjuan Wang,Pengcheng He,Penghui Zhang,Fan Niu
Acute myeloid leukemia (AML) is the most common blood cancer in adults. Patients' 5-year overall survival is less than 30% thus having a poor prognosis. To date, the development of novel target therapies is still necessary to ameliorate patients’ survival. Antibody-drug conjugates (ADCs) represent a promising class of drugs for the treatment of AML. CD33 is highly expressed on AML cells, and the FDA-approved CD33-targeted ADC drug-gemtuzumab ozogamicin (GO) has proved the feasibility of CD33-targeted ADC drug design. In this study, we constructed a novel CD33-targeted ADC drug composed of a humanized anti-CD33 antibody and oridonin as a payload with a cleaved chemical linker. Oridonin is a natural product that has great cancer therapy potential while its poor bioavailability and targeting ability limited its clinical use. Herein, we demonstrated that antiCD33-oridonin specifically delivered oridonin in AML cells improved AML cells killing ability of oridonin. Meanwhile, it did not show any non-specific toxicity on CD33 negative cells. In summary, we developed a novel AML targeting ADC with clinical application potential, and therefore provided a new solution for the druggability improvement of oridonin.
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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产品关联
DOI
PubMed
高影响因子
RSC Advances
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2023
·Vol. 13
·期 16
·10840-10846
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IF 3.9
Qiu-Yan Zhang,Qing-Long Yu,Wei-Jing Luan,Tong-Fang Li,Ya-Ni Xiao,Li Zhang,Yi Li,Rong Rong,Chun-Guang Ren
Colorectal cancer (CRC) is one of the most prevalent cancers worldwide as well as a significant cause of mortality. The conventional treatment could cause serious side effects and induce drug resistance, recurrence and metastasis of cancers. Hence, specific targeting of cancer cells without affecting the normal tissues is currently an urgent necessity in cancer therapy. The emerging of peptide–drug conjugates (PDC) is regarded as a promising approach to address malignant tumors. LWJ-M30, a conjugate of DM1 and B6 peptide, targeted transferrin receptors (TfRs) on the surface of the CRC cells, showing a powerful anti-cancer effect. LWJ-M30 significantly inhibited the HCT116 cells proliferation and migration in vitro. LWJ-M30 also dramatically decreased the level of polymeric tubulin, while the disruption of microtubules caused the cell cycle to be arrested in the G2/M phase. LWJ-M30 induced the HCT116 cells apoptosis both in vivo and in vitro. The results in vivo demonstrated that LWJ-M30 could inhibit the HCT116 growth without affecting the mouse body weight. Taking these results together, our data indicated that LWJ-M30 could improve the therapeutic effects of DM1 while reducing the systemic toxicity in normal tissues.
研究领域:
肿瘤学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2020
·
IF 4.831
Jiaguo Li,Dian Xiao,Fei Xie,Wei Li,Lei Zhao,Wei Sun,Xiaohong Yang,Xinbo Zhou
Antibody-drug conjugates (ADCs) are being developed worldwide with the potential to revolutionize current cancer treatment strategies. However, off-target toxicity caused by the instability of linkers remains one of the main issues to be resolved. Developing a novel photocontrol-ADC with good stability and photocontrolled release seemed to be an attractive and practical solution. In this study, we designed, for the first time, a novel ultraviolet (UV) light-controlled ADC by carefully integrating the UV-cleavable o -nitro-benzyl structure into the linker. Our preliminary work indicated that the ADC exhibited good stability and photocontrollability while maintaining a targeting effect similar to that of the naked antibody. Upon irradiation with UV light, the ADC rapidly released free cytotoxins and exerted significant cytotoxicity toward drug-resistant tumor cells. Compared to those of the unirradiated cells, the EC 50 values of ADCs increased by up to 50-fold. Furthermore, our research confirmed that the degradation products of unirradiated ADC, Cys- 1a, were relatively less toxic, thus potentially reducing the off-target toxicity caused by nonspecific uptake of ADCs. The novel design strategy of UV light-controlled ADCs may provide new perspectives for future research on ADCs and promote the development of photocontrol systems.
研究领域:
癌症治疗
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药学
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分子生物学
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化学工程
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DOI
PubMed
高影响因子
Marine Drugs
·
2024
·
IF 4.9
Xin Sun,Jiangnan Hu,Maomao Ren,Hong Chang,Dongting Zhangsun,Baojian Zhang,Shuai Dong
α-Conotoxins, as selective nAChR antagonists, can be valuable tools for targeted drug delivery and fluorescent labeling, while conotoxin-drug or conotoxin-fluorescent conjugates through the disulfide bond are rarely reported. Herein, we demonstrate the [2,4] disulfide bond of α-conotoxin as a feasible new chemical modification site. In this study, analogs of the α-conotoxin LsIA cysteine[2,4] were synthesized by stapling with five linkers, and their inhibitory activities against human α7 and rat α3β2 nAChRs were maintained. To further apply this method in targeted delivery, the alkynylbenzyl bromide linker was synthesized and conjugated with Coumarin 120 (AMC) and Camptothecin (CPT) by copper-catalyzed click chemistry, and then stapled between cysteine[2,4] of the LsIA to construct a fluorescent probe and two peptide-drug conjugates. The maximum emission wavelength of the LsIA fluorescent probe was 402.2 nm, which was essentially unchanged compared with AMC. The cytotoxic activity of the LsIA peptide-drug conjugates on human A549 was maintained in vitro. The results demonstrate that the stapling of cysteine[2,4] with alkynylbenzyl bromide is a simple and feasible strategy for the exploitation and utilization of the α-conotoxin LsIA.
研究领域:
药物化学
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生物化学
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分子生物学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Zekun Zeng,Zhiwei Yang,Chenghao Li,Shujing Liu,Wei Wei,Ye Zhou,Simeng Wang,Mengjun Sui,Mengdan Li,Shumei Lin,Yangyang Cheng,Peng Hou
Despite the considerable achievements of antibodies targeting PD-1/PD-L1 in cancer immunotherapy, limitations in antitumor immune response and pharmacokinetics hinder their clinical adoption. Small molecules toward PD-L1 degradation signifies an innovative avenue to modulate PD-1/PD-L1 axis. Herein, we unveil a comprehensive engineering involving the development of new PD-L1 degraders based on the berberine (BBR) and palmatine (PMT) bioactive frameworks and explore their translational potential for cancer immunotherapy using a peptide-drug conjugate strategy. Chemical modifications at the O-9 position of PMT dramatically enhance the PD-L1 degradation capacity. Further conjugation of PMT degraders with an anti-PD-L1 peptide featuring disulfide linkers enables efficient GSH-specific prodrug activation, yielding synergistic immunotherapeutic benefits through both external PD-L1 blockade and internal PD-L1 degradation mechanisms. This work elucidates the compelling charm of the discovery and application of PD-L1 degraders, offering solutions to the challenges in advancing cancer immunotherapy in widespread clinics.
研究领域:
肿瘤学
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免疫学
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药学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2018
·
IF 4.556
Kaili Wang,Chunjing Guo,Xue Dong,Yueming Yu,Bingjie Wang,Wanhui Liu,Daquan Chen
Many cancers, such as human breast cancer and lung cancer, easily metastasize to bones, leading to the formation of secondary tumors in advanced stages. On the basis of the CD44-targeted effect of oHA and the bone-targeted effect of ALN, we prepared a reduction-responsive, CD44 receptor-targeting and bone-targeting nanomicelle, called CUR-loaded ALN-oHA-S-S-CUR micelles. In this study, we aimed to evaluate the antitumor activity and bone-targeting ability of CUR-loaded ALN-oHA-S-S-CUR micelles. The in vivo experiment results showed that a larger number of micelles was gathered in the bone metastatic tumor tissue and reduced the bone destruction. The CUR-loaded ALN-oHA-S-S-CUR micelles markedly inhibited the tumor growth. So the CUR-loaded ALN-oHA-S-S-CUR micelles constitute a promising drug delivery system for bone tumor therapy.
研究领域:
药学
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癌症研究
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纳米技术
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
ACS Omega
·
2023
·
IF 4.1
Hao Wu,Xuefeng Ding,Yun Chen,Yanfei Cai,Zhaoqi Yang,Jian Jin
Antibody–drug conjugates (ADC) are an inevitable trend in the development of modern “precision medicine”. The goal of this work is to produce enzyme-responsive antibody nanoparticle-loaded medication (FMSN-Dox-H2-AE01) based on the EGFR antibody (AE01) and human serum albumin (HSA) shelled mesoporous silica nanoparticles. HSA and antibodies on the surface of the particlescan not only enhance the biocompatibility of the particle and avoid early drug leakage but also allow selective biodegradation triggered by matrix metalloproteinase-2 (MMP-2), which are overexpressed enzymes in some tumor tissues. The cytotoxicity test confirmed favorable safety and efficacy of the ADC. The mortality rate of cancer cells is about 85–90%. Moreover, the antibody nanoparticle-loaded drug showed distinguishing controlled release efficiency toward cancer cells induced by different levels of MMP-2 and pH. This enzyme-responsive FMSN-Dox-H2-AE01 offers a promising option for cancer therapy.
研究领域:
药学
·
纳米技术
·
癌症研究
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Yijia Min,Yu Chen,Lei Wang,Yong Ke,Fan Rong,Qunye He,Pameila Paerhati,Huifang Zong,Jianwei Zhu,Yin Wang,Baohong Zhang
Antibody therapy of anti-HER2 monoclonal antibody (mAb) has been an important strategy in treating HER2-positive cancers. However, the efficacy is restricted by many factors, including the level of HER2 expressed by tumor cells and antibody resistance. To overcome these and boost the efficacy, a novel nanoparticle (NP) was constructed in this study for combined antibody therapy of antibody and photothermal therapy (PTT). This novel NP was assembled from 1-pyrenecarboxylic acid (PCA) functionalized anti-HER2 mAb and indocyanine green (ICG), a photothermal transduction agents (PTA), by non-covalent interactions, which was named as Anti-HER2 mAb-pyrene-indocyanine green (H-P-I). Notably, the constructed H-P-I NP not only maintained the affinity and cytotoxicity of anti-HER2 mAb, but also exhibited high photothermal conversion efficiency mediated by ICG. Both in vitro and in vivo assessments confirmed that compared with monotherapy of antibody or ICG, H-P-I demonstrated preferable efficacy in treating HER2-positive cancers. Further biochemistry analysis and pathological analysis ensured the biosafety of H-P-I administration. Taked together, this study proposes a feasible method for constructing tumor-targeted nano PTA based on anti-HER2 mAb through supramolecular self-assembly strategy, achieving synergistic antibody photothermal anticancer treatment, which has the potential to be a promising candidate for combination therapy of HER2-positive cancers.
研究领域:
癌症治疗
·
纳米技术
·
生物医学工程
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药学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2022
·Vol. 32
·期 16
·2109173
·
IF 19.924
Jie Deng,Deqing Lin,Xiangyu Ding,Yuan Wang,YuHan Hu,Hui Shi,Lin Chen,Bingyang Chu,Lei Lei,Chunmei Wen,Jiaqing Wang,Zhiyong Qian,Xingyi Li
Peptide-drug conjugates (PDCs) are an important class of therapeutic agents that combine one or more active molecules with a short peptide via a biodegradable spacer to generate prodrugs. Here an antioxidant (i.e., 3,5-dihydroxybenzoic acid), a non-steroidal anti-inflammatory drug (i.e., ibuprofen, IPF), and a self-assembled peptide motif (i.e., Gly-Phe-Phe-Tyr-Asp, GFFYD) are integrated to produce a peptide-drug amphiphile, which self-assembles to form hydrogel and further exerts the synergistic effects, and consequently emerges high therapeutic efficacy. In the in vitro study toward lipopolysaccharide-activated RAW264.7 macrophages, the resulting hydrogel significantly reduces the production of cytokines (e.g., IL-1β, IL-6 and tumor necrosis factor-α (i.e., TNF-α)) compared with that of native IPF via the inhibition of nuclear factor-κB (i.e., NF-κB), janus kinase-signal transducer and activator of transcription (i.e., JAK-STAT) signals and NLR family pyrin domain containing 3 (i.e., NLRP3) inflammasome activation. Moreover, a rabbit model of endotoxin induced uveitis evidences the superior therapeutic efficacy of the resulting hydrogel over that of clinically used 0.1 wt% diclofenac sodium eyedrop. Overall, this work offers new insights into the anti-inflammatory mechanism of PDCs hydrogel and presents the therapeutic values in the treatment of ocular disorders, and ultimately fulfils the potential clinical benefits of PDCs.
研究领域:
药学
·
材料科学
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免疫学
·
眼科学
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DOI
高影响因子
Biomaterials Research
·
2024
·
IF 8.1
Jingwei Bi,Limin Zhang,Pengfei Zhang,Shulei Xu,Yuhao Liu,Xiaolai Zhang,Xiaoyong Qiu,Yanwen Bi,Fangfang Yan,Hui Wei,Xin Cui,Xin Pan,Jun Huang,Yunpeng Zhao
Osteoarthritis (OA) is a common age-related degenerative disease characterized by changes in the local tissue environment as inflammation progresses. Inspired by the wind-dispersal mechanism of dandelion seeds, this study develops responsive biomimetic microsphere-drug conjugate for OA therapy and protection. The conjugate integrates dibenzaldehyde polyethylene glycol (DFPEG) with chitosan and polyethylene glycol diacrylate (PEGDA) through dynamic covalent bonds to form a dual-network hydrogel microsphere. Based on the progression of OA, the conjugate with the surface-anchored cyclic peptide cortistatin-14 (CST-14) achieves targeted drug therapy and a self-regulating hydrogel network. In cases of progressing inflammation (pH < 5), CST-14 dissociates from the microsphere surface (viz. the drug release rate increased) and inhibits TNF-α signaling to suppress OA. Concurrently, the monomer DFPEG responsively detaches from the hydrogel network and scavenges reactive oxygen species (ROS) to protect the cartilage tissue. The ROS scavenging of DFPEG is comparable to that of coenzyme Q10 and vitamin C. The degraded PEGDA microspheres provide tissue lubrication through reused conjugates. The rat OA model successfully achieved a synergistic therapeutic effect greater than the additive effect (1 + 1 > 2). This strategy offers an approach for anchoring amine-containing drugs and has marked potential for OA treatment and protection.
研究领域:
生物医学工程
·
药学
·
组织工程
·
骨科
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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）