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
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生物医学工程
✓ 已验证
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
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药物分析
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临床药理学
✓ 已验证
产品关联
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
POLYMER
·
2010
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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
Polymers
·
2021
·Vol. 13
·期 9
·1515
·
IF 4.329
Xiukun Xue,Yanjuan Wu,Xiao Xu,Ben Xu,Zhaowei Chen,Tianduo Li
Polymeric prodrugs, synthesized by conjugating chemotherapeutic agents to functional polymers, have been extensively investigated and employed for safer and more efficacious cancer therapy. By rational design, a pH and reduction dual-sensitive dextran-di-drugs conjugate (oDex-g-Pt+DOX) was synthesized by the covalent conjugation of Pt (IV) prodrug and doxorubicin (DOX) to an oxidized dextran (oDex). Pt (IV) prodrug and DOX were linked by the versatile efficient esterification reactions and Schiff base reaction, respectively. oDex-g-Pt+DOX could self-assemble into nanoparticles with an average diameter at around 180 nm. The acidic and reductive (GSH) environment induced degradation and drug release behavior of the resulting nanoparticles (oDex-g-Pt+DOX NPs) were systematically investigated by optical experiment, DLS analysis, TEM measurement, and in vitro drugs release experiment. Effective cellular uptake of the oDex-g-Pt+DOX NPs was identified by the human cervical carcinoma HeLa cells via confocal laser scanning microscopy. Furthermore, oDex-g-Pt+DOX NPs displayed a comparable antiproliferative activity than the simple combination of free cisplatin and DOX (Cis+DOX) as the extension of time. More importantly, oDex-g-Pt+DOX NPs exhibited remarkable reversal ability of tumor resistance compared to the cisplatin in cisplatin-resistant lung carcinoma A549 cells. Take advantage of the acidic and reductive microenvironment of tumors, this smart polymer-dual-drugs conjugate could serve as a promising and effective nanomedicine for combination chemotherapy.Keywords:polymeric prodrug;dual-sensitive;combination chemotherapy;drug conjugation;dextran
研究领域:
肿瘤学
·
药剂学
✓ 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 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
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
·
生物医学工程
·
肿瘤学
✓ 已验证
DOI
高影响因子
Science Translational Medicine
·
2021
·Vol. 13
·期 579
·
IF 17.992
Fan-En Kong,Guang-Meng Li,Yun-Qiang Tang,Shao-Yan Xi,Jane Ho Chun Loong,Mei-Mei Li,Hao-Long Li,Wei Cheng,Wen-Jie Zhu,Jia-Qiang Mo,Yuan-Feng Gong,Hui Tang,Yue Zhao,Yan Zhang,Stephanie Ma,Xin-Yuan Guan,Ning-Fang Ma,Mao-Bin Xie,Ming Liu
Tumor lineage plasticity is emerging as a critical mechanism of therapeutic resistance and tumor relapse. Highly plastic tumor cells can undergo phenotypic switching to a drug-tolerant state to avoid drug toxicity. Here, we investigate the transmembrane tight junction protein Claudin6 (CLDN6) as a therapeutic target related to lineage plasticity for hepatocellular carcinoma (HCC). CLDN6 was highly expressed in embryonic stem cells but markedly decreased in normal tissues. Reactivation of CLDN6 was frequently observed in HCC tumor tissues as well as in premalignant lesions. Functional assays indicated that CLDN6 is not only a tumor-associated antigen but also conferred strong oncogenic effects in HCC. Overexpression of CLDN6 induced phenotypic shift of HCC cells from hepatic lineage to biliary lineage, which was more refractory to sorafenib treatment. The enhanced tumor lineage plasticity and cellular identity change were potentially induced by the CLDN6/TJP2 (tight junction protein 2)/YAP1 (Yes-associated protein 1) interacting axis and further activation of the Hippo signaling pathway. A de novo anti-CLDN6 monoclonal antibody conjugated with cytotoxic agent (Mertansine) DM1 (CLDN6-DM1) was developed. Preclinical data on both HCC cell lines and primary tumors showed the potent antitumor efficiency of CLDN6-DM1 as a single agent or in combination with sorafenib in HCC treatment.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
DOI
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2024
·Vol. 86
·期 1
·e70043
·
IF 3.5
Qingqing Li,Yufeng Liu,Yilin Cheng,Huaibao Cao,Kunda Du,Tianyu Zhu,Defeng Xu,Hang Hu
Poor selectivity to tumor cells is a major drawback in the clinical application of the antitumor drug docetaxel (DTX). Peptide–drug conjugates (PDCs) constructed by modifying antitumor drugs with peptide ligands that have high affinity to certain overexpressed receptors in tumor cells are increasingly assessed for their possibility of tumor-selective drug delivery. In the present research, DTX is condensed with 3-(pyridin-2-yldisulfanyl) propanoic acid via ester bond to obtain the intermediate Py-SS-DTX. Two conjugates GSS-DTX and RGDC-SS-DTX were obtained by conjugation of Py-SS-DTX with glutathione (GSH) and RGDC peptide through a thiol-disulfide exchange reaction. Afterwards, these two peptide–DTX conjugates were characterized by proton nuclear magnetic resonance, Fourier transform infrared spectroscopy, and high-resolution mass spectrometry. The GSS-DTX and RGDC-SS-DTX were further evaluated in terms of drug release, cell cycle inhibition, cell apoptosis, and cytotoxicity. The results show that both the GSS-DTX and RGDC-SS-DTX exhibit reduction-responsive drug release and RGDC-SS-DTX exhibit higher reduction-responsiveness. The in vitro antitumor activity study shows that RGDC-SS-DTX exhibits enhanced G2/M phase arrest, cell apoptosis rate, and cytotoxicity as compared to GSS-DTX and free DTX. Besides, RGDC-SS-DTX shows reduced cytotoxicity on normal cells as compared to free DTX. The RGDC-SS-DTX synthesized in this study represents a novel DTX conjugate to effectively and selectively inhibit tumor cells.
研究领域:
药学
·
肿瘤学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYTICA CHIMICA ACTA
·
2016
·
IF 4.712
Hua Sang,Gaoyuan Lu,Yazhong Liu,Qiyue Hu,Weifeng Xing,Dongbing Cui,Fang Zhou,Jingwei Zhang,Haiping Hao,Guangji Wang,Hui Ye
Trastuzumab-MCC-DM1 (T-DM1) is an antibody-drug conjugate (ADC) that consists of a monoclonal antibody (mAb) trastuzumab non-cleavably linked to a cytotoxic drug DM1. During production, the DM1 agents were conjugated to the lysine residues of the mAb in a non-specific manner, yielding a heterogeneous mixture of ADC molecules that differ with respect to both the number and the conjugation sites of DM1 per mAb molecule. Since drug conjugation sites of ADC can significantly impact properties such as stability and pharmacokinetic behaviors, a rapid and reliable approach for conjugation site analysis of ADCs is highly demanded. Herein, we have employed a signature ion fingerprinting approach to specifically determine lysine residues with DM1 conjugation, and developed a normalized peak area quantitation method to characterize the percentage of DM1-conjugated lysine for each putative site using a T-DM1 biosimilar as a model drug. With this integrative approach, 38 lysine residues were identified with DM1 conjugation among 90 possible sites. More interestingly, we found that the T-DM1 biosimilar exhibited a specific preference of DM1-conjugation for several lysine residues, and such preference was consistent among three production batches. A molecular modeling approach was subsequently utilized to analyze all the conjugation sites, and revealed an intriguing correlation of the conjugated residue's microenvironment with the conjugation level. In summary, our study introduced an approach that is widely applicable to ADCs of interest for conjugation site analysis. Moreover, it suggests the necessity of performing conjugation site analysis for product and process characterization and also for routine use in lot release and stability testing of manufactured ADCs.
研究领域:
生物化学
·
药物分析
·
蛋白质组学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）