Toxins
·
2019
·Vol. 11
·期 9
·497
·
IF 3.895
Zhi-Zhen Pan,Lian Xu,Yi-Shu Zheng,Li-Yang Niu,Bo Liu,Yan Shi,Qing-Xi Chen,Yu-Jing Zhu,Xiong Guan
Bacillus thuringiensisinsecticidal proteins (Bt toxins) have been widely used in crops for agricultural pest management and to reduce the use of chemical insecticides. Here, we have engineered Bt toxin Cry2Ab30 and bioconjugated it with 4”-O-succinyl avermectin (AVM) to synthesize Cry2Ab–AVM bioconjugate. It was found that Cry2Ab–AVM showed higher insecticidal activity againstPlutella xylostella, up to 154.4 times compared to Cry2Ab30. The binding results showed that Cry2Ab–AVM binds to the cadherin-like binding protein fragments, the 10th and 11th cadherin repeat domains in theP. xylostellacadherin (PxCR10–11), with a much higher affinity (dissociation equilibrium constantKD= 3.44 nM) than Cry2Ab30 (KD= 28.7 nM). Molecular docking suggested that the macrolide lactone group of Cry2Ab–AVM ligand docking into the PxCR10–11is a potential mechanism to enhance the binding affinity of Cry2Ab–AVM to PxCR10–11. These findings offer scope for the engineering of Bt toxins by bioconjugation for improved pest management.Keywords:Cry2Ab–AVM bioconjugate;binding affinity;molecular dockingKey Contribution:The study develops an engineered Cry2Ab by bioconjugation with 4”-O-succinyl avermectin to enhance insecticidal potency againstP. xylostella.This engineering also improves its affinity to the cadherin-like binding fragments. Homology modeling and docking study are also carried out to investigate the binding model.
研究领域:
农业生物学
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昆虫学
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蛋白质工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Polymers
·
2022
·Vol. 14
·期 21
·4515
·
IF 4.967
Jiankun Xu,Shanmeng Lin,Hao Hu,Qi Xing,Jin Geng
Bufalin (buf) has poor solubility in aqueous solution, poor tumor targeting, and many non-specific toxic and side effects. The advantages of high-molecular-weight polymer conjugates are that they can improve the water solubility of buf, prolong plasma half-life, and reduce non-specific toxicity. A novel water-soluble polymer–drug conjugate with buf and fluorescein pendants was prepared by the combination of reversible addition-fragmentation transfer (RAFT) polymerization and click chemistry. Its anticancer performance and cellular uptake behavior against liver cancer were investigated in vitro. The polymer–buf conjugates exhibit controlled release and tumor-targeting capabilities, showing promise for clinical applications.Keywords:polymer–drug conjugate;liver cancer;esterase responsive;bufalin
研究领域:
药学
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2025
·
IF 5.2
Dongze Xu,Sha Guo,Zhiyun Qi,Pengfei He,Xiang Guo,Hanhan Li,Zhenhao Zhou,Xueyan Hu,Cui Wang,Chuanfei Yu,Hao Wu
Antibody-drug conjugate (ADC) plays a crucial role in the treatment of various diseases and intravenous injection is the primary administration route for ADCs due to its high bioavailability. However, this method requires drug preparation and dilution, which can compromise the stability of the solution and increase the risk of aggregation as excipient concentrations are reduced during dilution. Antibody drug dosing is often based on patient body weight and typically diluted in either 0.9% (w/v) sodium chloride or 5% (w/v) dextrose injections. Variations in patient body weight lead to differences in the final concentrations of both the drug and excipients, affecting stability. In this study, we examined the stability of intravenous dilutions for patients with varying body weights using trastuzumab and ado-trastuzumab emtansine ADCs. Analytical techniques including size-exclusion chromatography (SEC), fluid imaging microscopy (FIM), bicinchoninic acid (BCA) assay, and turbidity testing were employed to assess monomer, oligomer, and aggregate levels before and after dilution. Machine learning was applied to distinguish the morphology of sub-visible particles. Our findings reveal that weight-based dosing leads to significant stability differences in intravenous preparations. This study offers important insights into the formulation stability of biopharmaceuticals and their clinical use.
研究领域:
药学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
Theranostics
·
2020
·
IF 8.579
Liu Xu,Yutong Wang,Chenqi Zhu,Shujing Ren,Yurou Shao,Li Wu,Weidong Li,Xiaobin Jia,Rongfeng Hu,Rui Chen,Zhipeng Chen
Rationale: Both spatial accuracy and temporal persistence are crucial in drug delivery, especially for anti-tumor intravenous nanomedicines, which have limited persistence due to their small particle sizes and easy removal from tumors. The present study takes advantage of morphological transformation strategy to regulate intravenous nanomedicines to display different sizes in different areas, achieving high efficient enrichment and long retention in lesions. Methods: We designed and synthesized functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) consisting of self-assembled doxorubicin-peptide conjugates (DPCs) and an acidic-responsive shielding layer named the functional polylysine graft (FPG), which can regulate the assembly morphology of the DPCs from spherical DPC nanoparticles (DPC-NPs) to DPC-nanofibers (DPC-NFs) by preventing the assembly force from π-π stacking and hydrogen bond between the DPC-NPs. The morphology transformation and particle changes of FDPC-NPs in different environments were determined with DLS, TEM and SEM. We used FRET to explore the enhanced retention effect of FDPC-NPs in tumor site in vivo . HPLC-MS/MS analytical method was established to analyze the biodistribution of FDPC-NPs in H22 hepatoma xenograft mouse model. Finally, the antitumor effect and safety of FDPC-NPs was evaluated. Results: The FDPC-NPs were stable in blood circulation and responsively self-assembled into DPC-NFs when the FDPC-NPs underwent the acid-sensitive separation of the shielding layer in a mildly acidic microenvironment. The FDPC-NPs maintained a uniform spherical size of 80 nm and exhibited good morphological stability in neutral aqueous solution (pH 7.4) but aggregated into a long necklace-like chain structure or a crosslinked fiber structure over time in a weakly acidic solution (pH 6.5). These acidity-triggered transformable FDPC-NPs prolonged the accumulation in tumor tissue for more than 5 days after a single injection and improved the relative uptake rate of doxorubicin in tumors 31-fold. As a result, FDPC-NPs exhibited a preferable anti-tumor efficacy and a reduced side effect in vivo compared with free DOX solution and DOX liposomes. Conclusions: Morphology-transformable FDPC-NPs represent a promising therapeutic approach for prolonging the residence time of drugs at the target site to reduce side effect and enhance therapeutic efficacy. Our studies provide a new and simple idea for the design of long-term delivery systems for intravenous chemotherapeutic drugs.
研究领域:
药理学
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肿瘤学
·
纳米医学
✓ 已验证
DOI
PubMed
高影响因子
GYNECOLOGIC ONCOLOGY
·
2025
·
IF 4.1
Hanfei Xie,Lu Sun,Shili Yao,Xuefei Tian,Liming Jin,Yujie Dai,Yuanzheng Li,Yuxuan Li,Jianmin Fang,Peng Guo,Yingli Zhang
Objective The incidence of mortality and morbidity from endometrial cancer (EC) is increasing annually, and there is a paucity of effective targeted therapies for the condition. Antibody-drug conjugates (ADCs) represent a promising approach to tumor-targeted therapy. In this study, we aim to identify a novel molecular target for the preclinical development of EC-targeted ADCs. Methods Through quantitative and unbiased bioinformatics analyses intercellular adhesion molecule-1 (ICAM1) was identified as a potential cell membrane target. Two ADCs, ICAM1-MMAE and ICAM1-DXd, were subsequently developed by conjugating ICAM1 monoclonal antibodies with microtubule inhibitors and DNA topoisomerase inhibitors, respectively. The preclinical efficacy and biosafety of these ICAM1 ADCs were validated in both in vitro and in vivo models. Furthermore, transcriptomic analysis was conducted to elucidate the therapeutic effects of the ICAM1 ADCs. Results Quantitative flow screening and bioinformatics analyses revealed significant overexpression of ICAM1 in EC. ICAM1-MMAE and ICAM1-DXd were developed using clinically effective linkers and payloads. In preclinical models, ICAM1 ADCs showed superior antitumor efficacy compared to standard chemotherapy, achieving sustained tumor regression with an excellent safety profile in both subcutaneous and orthotopic xenograft models. Transcriptomic analysis further revealed that ICAM1-DXd potently activated tumor immunity. Conclusions ICAM1 was identified as a promising cell membrane protein target for ADC development in EC. As-synthesized ICAM1 ADCs demonstrated potent antitumor activity, favorable biosafety profiles in vitro and in vivo , and the ability to activate tumor immunity. These findings support the potential of ICAM1 ADCs as a therapeutic strategy and warrant further investigation in clinical studies.
研究领域:
肿瘤学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2025
·
IF 3.1
Minlu Cheng,Xianjing Li,Ya Li,Yiya Wang,Wenjia Li,Shuai Wang,Chang Shu,Qinxin Song,Li Ding
Recently, the approval of Trop-2 targeted antibody drug conjugate (ADC) has changed the dilemma of patients with advanced triple-negative breast cancer who rely on chemotherapeutics to improve their survival. FDA018, an ADC consisting of an anti-Trop-2 antibody conjugated with a topoisomerase inhibitor SN-38 via an acid-cleavable linker, is currently being investigated in clinical trials. Based on the urgent demand to evaluate the clinical pharmacokinetics of FDA018, ligand binding assays (LBAs) for the determination of SN-38-conjugated antibody and total antibody and LC-MS/MS methods for the determination of the free SN-38, its metabolite SN-38G and total SN-38 were developed. The comparability and DAR sensitivity evaluation of the ELISA strategies for SN-38-conjugated antibody and total antibody were emphasized. The sensitivity of the LC-MS/MS method for the simultaneous determination of SN-38 and SN-38G reached 0.500 ng/mL and 0.250 ng/mL, respectively. An effective solution has been proposed for the optical instability of the cleavable linker of FDA018 during the pretreatment process of biological samples. The established bioanalytical methods were comprehensively validated and the results satisfied the acceptable criteria of ICH M10. The validated bioanalytical methods have been applied to the single-dose pharmacokinetic study of FDA018 in patients with Trop-2-positive malignant tumors successfully, and the pharmacokinetic profiles of FDA018 and its constituent components were investigated.
研究领域:
肿瘤学
·
药物分析
·
临床药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
POLYMER
·
2010
·
IF 3.573
Honglei Fan,Jin Huang,Yaping Li,Jiahui Yu,Jinghua Chen
This research is aimed to develop a reduction-degradable micelle delivery system based on polymer-camptothecin (CPT) conjugate in order to enhance the solubility and stability of CPT in aqueous media. Firstly, disulfide-linked poly(amido amine) (SS-PAA) containing alkyne groups was synthesized by Michael addition polymerization between propargyl amine and N , N ′-bis(acryloyl) cystamine (BAC). And then, azide-functionalized CPT derivatives were conjugated with SS-PAA by click cycloaddition. Further grafting of residual alkyne groups in SS-PAA with azide-terminated poly(ethylene glycol) methyl ether (mPEG) gave mPEG- g -SS-PAA-CPT conjugate. At last, micelles with size of ca. 88 nm were fabricated from mPEG- g -SS-PAA-CPT conjugate, suggesting their passive targeting potential to tumor tissue. It was worthy of note that the drug-loaded system of mPEG- g -SS-PAA-CPT micelles improved the solubility and stability of CPT in aqueous media. Owing to the reduction degradability of disulfide linker in main chain of mPEG- g -SS-PAA-CPT, the CPT sustainably release from micelles together with the gradual cleavage of polymer in the presence of dithiothreitol (DTT) at the concentration of simulating the intracellular condition while almost no change occurred at the level of DTT corresponding to extracellular condition. Furthermore, the cell viability results showed the essential decrease of cytotoxicity to L929 cell line. These results present a strategy in designing anti-tumor CPT-polymer conjugates for highly selective delivery to tumor cells.
研究领域:
药学
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生物材料学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS
·
2024
·
IF 1.3
Yingying Hou,Jie Miao,Yajun Sun,Lili Shi,Lu Ouyang,Xiaoqiang Chen,Ziyi Li,Tingting Liu,Gang Qin,Qiuping Qin,Likun Gong
Background: Antibody-drug conjugates (ADCs) are an emerging class of targeted therapeutics and are receiving growing attention in the pharmaceutical field. Here we aimed to validate two ligand binding assays for the quantitation of GQ1001, an ADC made of Trastuzumab site-specifically conjugated with DM1, in cynomolgus monkey serum, and then apply the validated assays to a nonclinical study. Methods: The quantitative methods for conjugated GQ1001 and total GQ1001 were validated against regulatory guidance documents on bioanalytical method validation under a Good Laboratory Practice (GLP)-compliant environment. The validated assays were then applied to a single-dose pharmacokinetic (PK) study of GQ1001 conducted in cynomolgus monkeys. Results: Both intra- and inter-assay precision and accuracy met the priori-defined acceptance criteria. Neither matrix effect nor hemolysis effect were observed, and the impact of specific interferents on the assays was evaluated. Dilution linearity was good with the expected dilution factors and no hook effect till up to 20.2 mg/mL of GQ1001 was noted. Besides, the stability of the ADC in monkey serum was found to be sufficient to cover the time required for sample storage and analysis. Furthermore, the assays demonstrated good parallelism determined with a study sample and good reproducibility acquired by incurred sample reanalysis (ISR). Using the validated assays, we obtained serum concentrations for the conjugated GQ1001 and the total GQ1001 in the single-dose PK study, and thereafter, evaluated their exposures over the dosing period. Conclusions: All tested performance parameters of the assays met the validation acceptance criteria, which supported the application of the two assays in the nonclinical PK study and allowed the evaluation of the related PK parameters for GQ1001.
研究领域:
生物分析
·
药物研发
·
临床前研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2025
·
IF 5.7
Buwei Hu,Chenlin Ji,Zhuohang Zhou,Xuehan Xu,Luyi Wang,Tingting Cao,Jianjun Cheng,Rui Sun
Photodynamic therapy (PDT), utilizing a photosensitizer (PS) to induce tumor cell death, is an effective modality for cancer treatment. PS–peptide conjugates have recently demonstrated remarkable antitumor potential in preclinical trials. However, the limited cell membrane binding affinity and rapid systemic clearance have hindered their transition to clinical applications. To address these challenges, we investigated whether in vivo covalent chemistry could enhance tumor accumulation and potentiate antitumor efficacy. Specifically, we synthesized a PS–peptide conjugate termed P-DBCO-Ce6, with chlorin e6 (Ce6) and dibenzocyclooctyne (DBCO) conjugated to a negatively charged short peptide. By employing metabolic glycoengineering and bioorthogonal reactions, P-DBCO-Ce6 achieves covalent bonding to the cell membrane, enabling prolonged retention of the PS on the cell surface and the in situ generation of reactive oxygen species (ROS) on cell membranes to kill tumor cells. In vivo studies demonstrated a 3.3-fold increase in tumor accumulation of the PS through bioorthogonal reactions compared to the control group, confirming that click chemistry can effectively enhance PS tumor accumulation. This approach allows for the effective elimination of tumors with a single treatment. The improved efficiency of this strategy provides new insights into the design of PDT systems for potential clinical applications.
研究领域:
药理学
·
肿瘤学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
American Journal of Cancer Research
·
2024
·Vol. 14
·期 12
·5752
·
IF 3.6
Xiaobo Cai,Min Cao,Qingliang Yang,Xiazhen Yu,Xin-Hua Feng,Robert Yongxin Zhao
Gastric cancer is a common malignant tumor with high incidence and mortality. The overexpression of Human epidermal growth factor receptor 2 (HER2) is associated with increased metastatic potential and poor clinical outcome in gastric cancer. Despite the proven clinical response rates of approved HER2-targeted therapies, including Trastuzumab combined with chemotherapy, their limited long-term clinical benefits and inevitable disease progression still pose significant challenges to the clinical treatment of gastric cancer. Hence, exploring novel strategies to enhance therapeutic outcomes for HER2-positive patients is extremely crucial and urgent. Here, we reported that DX126-262, a novel HER2-targeted antibody-drug conjugate, generated by conjugating a potent Tubulysin B analogue (Tub-114) to humanized anti-HER2 monoclonal antibody, exhibited a significant synergistic inhibitory effect with both Cisplatin and 5-FU in HER2-positive gastric cancer NCI-N87 cells. Moreover, the triple-drug combination strategy of DX126-262 combined with Cisplatin and 5-FU showed much better in vitro and in vivo therapeutic efficacy than monotherapy or double-drug combination (Cisplatin plus 5-FU) or first-line standard-of-care (SOC, Herceptin plus Cisplatin and 5-FU), and comparable or even superior in vivo efficacy than third-line SOC (DS-8201a) in NCI-N87 cells and xenograft models. Meanwhile, the triple-drug combination therapy did not exhibit superimposed toxicity. Taken together, our findings provide compelling evidence that DX126-262 in combination with Cisplatin and 5-FU exerts synergistic antitumor activity and is a promising strategy to improve the clinical efficacy of HER2-positive advanced or metastatic gastric cancer.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2014
·
IF 7.261
Shixian Lv,Zhaohui Tang,Dawei Zhang,Wantong Song,Mingqiang Li,Jian Lin,Huaiyu Liu,Xuesi Chen
The synthesis of polymer–drug conjugate (PDC) capable of convenient preparation and controlled release of therapeutic agents is still an urgent requirement in drug delivery field. Herein, we develop a novel anti-cancer PDC engineered with side groups of disulfide and ester bonds for on-demand delivery of paclitaxel (PTX) with redox and pH dual sensitive behaviors. A simple polymer, 3,3′-dithiodipropionic acid functionalized poly(ethylene glycol)- b -poly( l -lysine) (mPEG- b -P(LL-DTPA)), was synthesized and PTX was directly conjugated to the carboxyl groups of mPEG- b -P(LL-DTPA) to obtain the disulfide-containing polymer–PTX conjugate (P(L-SS-PTX)). Another structural similar polymer–PTX conjugate without disulfide bonds (P(L-PTX)) was also prepared to verify the function of disulfide linkages. The P(L-SS-PTX) micelles showed rapid drug release under tumor-relevant reductive conditions as designed. Interestingly, the PTX release from P(L-SS-PTX) micelles could also be promoted by the increased acidity (pH ≈ 5). In vitro cytotoxicity study showed that the P(L-SS-PTX) micelles exhibited significantly enhanced cytotoxicity against a variety of tumor cells compared to the non-sensitive P(L-PTX) micelles. The in vivo studies on B16F1 melanoma bearing C57BL/6 mice demonstrated the superior antitumor activity of P(L-SS-PTX) over both free PTX and P(L-PTX). This dual-sensitive prodrug provides a useful strategy for anti-tumor drug delivery.
研究领域:
药学
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生物医学工程
·
肿瘤学
✓ 已验证
DOI
高影响因子
POLYMER
·
2013
·
IF 3.379
Yashuo Xu,Xiangyang Wu,Xingyi Xie,Yinping Zhong,Robert Guidoin,Ze Zhang,Qiang Fu
Traditional poly(ethylene glycol) (PEG)-modified polyurethanes usually exhibit high biocompatibility, but still lack reactivity with biological molecules to induce appropriate cell and tissue responses. In this study, PEG diglycidyl ether ( M n = 526 Da) and PEG bis(amine) ( M n = 1000 Da) were respectively grafted onto carboxyl-group-containing poly(carbonate urethane) backbones that chain-extended with lysine, to generate reactivity while maintaining biocompatibility. The PEG chains disordered and plasticized the hard segments where they attached, reducing H-bonded urea groups and lowering glass transition temperatures . The M n ranged from 33,000 to 70,000 Da for the precursor polyurethanes, which largely decreased by 24–75% following PEG grafting. Hemocompatibility was enhanced due to the flexibility and hydrophilicity of the PEG chains. Solutions of the PEG-grafted polyurethanes were transformed into hydrocolloids when dropped into water. Reactivity was proved by immobilization of albumin onto the colloidal particles. These new functional PEG-grafted polyurethanes can potentially form multifunctional bioconjugates for applications as biomaterials and in pharmaceutics.
研究领域:
材料科学
·
生物医学工程
·
药学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）