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    Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/14332


    Title: Synthesis and evaluation of small molecule drug conjugates harnessing thioester-linked maytansinoids
    Authors: Lo, CF;Chiu, TY;Liu, YT;Huang, LR;Yeh, TK;Huang, KH;Liu, KL;Hsu, CY;Fang, MY;Huang, YC;Hsu, TA;Chen, CT;Tsou, LK
    Contributors: Institute of Biotechnology and Pharmaceutical Research;Institute of Molecular and Genomic Medicine
    Abstract: Ligand-targeting drug conjugates are a class of clinically validated biopharmaceutical drugs constructed by conjugating cytotoxic drugs with specific disease antigen targeting ligands through appropriate linkers. The integrated linker-drug motif embedded within such a system can prevent the premature release during systemic circulation, thereby allowing the targeting ligand to engage with the disease antigen and selective accumulation. We have designed and synthesized new thioester-linked maytansinoid conjugates. By performing in vitro cytotoxicity, targeting ligand binding assay, and in vivo pharmacokinetic studies, we investigated the utility of this new linker-drug moiety in the small molecule drug conjugate (SMDC) system. In particular, we conjugated the thioester-linked maytansinoids to the phosphatidylserine-targeting small molecule zinc dipicolylamine and showed that Zn8_DM1 induced tumor regression in the HCC1806 triple-negative breast cancer xenograft model. Moreover, in a spontaneous sorafenib-resistant liver cancer model, Zn8_DM1 exhibited potent antitumor growth efficacy. From quantitative mRNA analysis of Zn8_DM1 treated-tumor tissues, we observed the elevation of gene expressions associated with a “hot inflamed tumor” state. With the identification and validation of a plethora of cancer-associated antigens in the “omics” era, this work provided the insight that antibody- or small molecule-based targeting ligands can be conjugated similarly to generate new ligand-targeting drug conjugates.
    Date: 2022-06-21
    Relation: Pharmaceutics. 2022 Jun 21;14(7):Article number 1316.
    Link to: http://dx.doi.org/10.3390/pharmaceutics14071316
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1999-4923&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000833092600001
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85132968001
    Appears in Collections:[鄒倫] 期刊論文
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