Einhaus Charity M, Retzinger Andrew C, Perrotta Andre O, Dentler Michael D, Jakate Abhijeet S, Desai Pankaj B, Retzinger Gregory S
Department of Pathology and Laboratory Medicine, the University of Cincinnati, Cincinnati, Ohio 45267-0529, USA.
Clin Cancer Res. 2004 Oct 15;10(20):7001-10. doi: 10.1158/1078-0432.CCR-04-0118.
Micronized droplets of olive oil loaded with docetaxel and coated with functional fibrinogen were administered intraperitoneally to mice bearing the fibrin(ogen)-rich ascites form of the TA3/St mammary tumor. When compared with docetaxel administered intraperitoneally as its commercial formulation (i.e., Taxotere), docetaxel-loaded oil droplets coated with murine fibrinogen prolonged the median survival time of tumor-bearing mice from 14.5 to 29.5 days. Drug-free oil droplets provided no therapeutic benefit. Significantly more docetaxel was associated with tumor cells 24 and 48 hours after administration of the drug in fibrinogen-coated oil droplets than after its administration as Taxotere. Consistent with a role for thrombin in the retention of fibrinogen-coated oil droplets within the tumor microenvironment, hirudin significantly reduced the association of tumor cells with docetaxel delivered in fibrinogen-coated oil droplets and, at the same time, reduced the therapeutic efficacy of the droplets to that of Taxotere. Importantly, fibrinogen-coated oil droplets formed rosettes with tumor cells in vivo, a process prevented by hirudin. Although mice treated with oil droplets developed antifibrinogen antibodies, those antibodies seemed to be inconsequential. Taken together, our results and observations indicate fibrinogen-coated oil droplets markedly improve the therapeutic efficacy of docetaxel for the treatment of a mammary tumor grown in ascites form, a consequence of thrombin-mediated retention of the drug-loaded droplets within the tumor microenvironment.
将负载多西他赛并包被功能性纤维蛋白原的橄榄油微滴腹腔注射给患有富含纤维蛋白（原）的腹水型TA3/St乳腺肿瘤的小鼠。与以商业制剂（即泰索帝）腹腔注射多西他赛相比，包被小鼠纤维蛋白原的载多西他赛油滴将荷瘤小鼠的中位生存时间从14.5天延长至29.5天。不含药物的油滴没有治疗益处。在给予包被纤维蛋白原的油滴中的药物后24小时和48小时，与肿瘤细胞相关的多西他赛显著多于给予泰索帝后的情况。与凝血酶在将包被纤维蛋白原的油滴保留在肿瘤微环境中的作用一致，水蛭素显著降低了肿瘤细胞与包被纤维蛋白原的油滴中递送的多西他赛的结合，同时将油滴的治疗效果降低至泰索帝的水平。重要的是，包被纤维蛋白原的油滴在体内与肿瘤细胞形成玫瑰花结，水蛭素可阻止这一过程。尽管用油滴治疗的小鼠产生了抗纤维蛋白原抗体，但这些抗体似乎无关紧要。综上所述，我们的结果和观察表明，包被纤维蛋白原的油滴显著提高了多西他赛治疗腹水型生长的乳腺肿瘤的疗效，这是凝血酶介导的载药油滴在肿瘤微环境中保留的结果。
