國家衛生研究院 NHRI:Item 3990099045/9666
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    题名: Zinc-dipicolylamine directed pharmaceutical delivery system (ZAPS) as an innovative cancer drug delivery platform
    作者: Tsou, LK;Liu, YW;Chen, YY;Lo, CF;Yeh, TK;Wu, CH;Shia, KS;Shih, JC;Gary, BD;Pek, KY;Chen, CT
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: Drug delivered by conjugate with antibody is expected to increase drug concentrations at the tumor sites for improved antitumor effects. Showing some successes, the antibody-drug conjugate system has certain limitations such as difficulties in protein characterization, high cost and individual variations in expression of the epitope, which might abrogate the antibody recognition and cause premature drug release arising from antibody-drug linker instability and thus ineffectiveness. Phosphatidylserine (PS) exists in bulk amount in the tumor microenvironment. Studies showed that a small sized Zinc (II)-dipicolylamine (Zn-DPA) molecule was superior in locating PS surrounding the apoptotic sites in vivo. Although Zn-DPA has been constructed incorporating fluorescent dyes as optical tools for imaging the PS-exposed cell membranes to identify tumor sites from healthy cells in animals, drug conjugates with Zn-DPA has never been described. We aimed to design, synthesize and evaluate a Zinc-dipicolylAmine directed Pharmaceutical delivery System (ZAPS), a platform for spatial- and temporal-release of drug specifically at the targeted tumor site. Zn-DPA was conjugated through standard coupling conditions with various linkers to SN-38 and the Zn-DPA-linker-SN-38 conjugates were obtained and investigated for structure-activity relationships on the chemical stability in plasma and cytotoxicity against cancer cells. Promising ZAPS-SN-38 conjugates were evaluated for activities against tumor growths in nude mice. CPT-11 and SN-38 were included for comparisons. ZAPS-SN-38 conjugates were examined for tolerable doses in mice. Among the ZAPS-SN-38 conjugates synthesized, ZAPS001 was found chemically stable in mouse plasma and in vitro active against several cancer cells. ZAPS001 dose-dependently inhibited the growth of Colo205 tumors in nude mice. Zn-DPA-linker001 (ZAPS001 without SN-38) showed no inhibition effect on the tumor growth. Intriguingly, employing only 40% of the SN-38 delivered by CPT-11 (40 mg/kg), ZAPS001 resulted in 8-fold increase in antitumor activity compared to that of CPT-11 given at the same dose regimen. Furthermore, ZAPS001 is also active against pancreatic Mia-Paca2 and BxPC-3 tumors in mice. An increased SN-38 level delivered by ZAPS001 to the tumors in mice was also observed. ZAPS is thus capable of selectively associating with PS-exposing tumor cells/tissues to achieve site-specific delivery of anticancer agents. Our findings strongly support that ZAPS conferred an “in situ dose amplification” effect, i.e., the cytotoxics-induced PS exposure could specifically recruit more ZAPS-drug conjugates to the tumor site and further enhance its therapeutic effect. ZAPS provides spatial and temporal controls to increase drug concentration at targeted disease sites, reduce drug dosage, lessen the toxic side effects, and thus increase therapeutic index of the anticancer drugs.
    日期: 2015-08
    關聯: Cancer Research. 2015 Aug;75(Suppl. 15):Abstract number 4413.
    Link to: http://dx.doi.org/10.1158/1538-7445.am2015-4413
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0008-5472&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000371597104044
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