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Please use this identifier to cite or link to this item:
http://ir.nhri.org.tw/handle/3990099045/12018
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| Title: | Linker optimization and therapeutic evaluation of phosphatidylserine-targeting zinc dipicolylamine-based drug conjugates |
| Authors: | Liu, YW;Chen, YY;Hsu, CY;Chiu, TY;Liu, KL;Lo, CF;Fang, MY;Huang, YC;Yeh, TK;Pak, KY;Gray, BD;Hsu, TA;Huang, KH;Shih, C;Shia, KS;Chen, CT;Tsou, LK |
| Contributors: | Institute of Biotechnology and Pharmaceutical Research |
| Abstract: | We report that compound 13, a novel phosphatidylserine-targeting zinc(II) dipicolylamine drug conjugate, readily triggers a positive feedback therapeutic loop through the in situ generation of phosphatidylserine in the tumor microenvironment. Linker modifications, pharmacokinetics profiling, in vivo antitumor studies, and micro-Western array of treated-tumor tissues were employed to show that this class of conjugates induced regeneration of apoptotic signals, which facilitated subsequent recruitment of the circulating conjugates through the zinc(II) dipicolylamine-phosphatidylserine association and resulted in compounding antitumor efficacy. Compared to the marketed compound 17, compound 13 not only induced regressions in colorectal and pancreatic tumor models, it also exhibited at least 5-fold enhancement in antitumor efficacy with only 40% of the drug employed during treatment, culminating in a >12.5-fold increase in therapeutic potential. Our study discloses a chemically distinct apoptosis-targeting theranostic, with built-in complementary functional moieties between the targeting module and the drug mechanism to expand the arsenal of antitumor therapy. |
| Date: | 2019-07-11 |
| Relation: | Journal of Medicinal Chemistry. 2019 Jul 11;62(13):6047-6062. |
| Link to: | http://dx.doi.org/10.1021/acs.jmedchem.9b00173 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-2623&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000475543300007 |
| Cited Times(Scopus): | https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85068148444 |
| Appears in Collections: | [鄒倫] 期刊論文
[陳炯東] 期刊論文
[夏克山] 期刊論文
[石全(2014-2017)] 期刊論文
[徐祖安] 期刊論文
[葉燈光] 期刊論文
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| PUB31181158.pdf | | 5377Kb | Adobe PDF | 333 | View/Open |
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