Fibrinogen-Coated Droplets of Olive Oil for Delivery of Docetaxel to a Fibrin(ogen)-Rich Ascites Form of a Murine Mammary Tumor
Charity M¹. Einhaus¹, Andre O. Perrotta¹, Andrew C. Retzinger¹, Michael D. Dentler¹,
Abhijeet S. Jakate², Pankaj B. Desai², and Gregory S. Retzinger¹
¹Department of Pathology and Laboratory Medicine and the ²College of Pharmacy, the University of Cincinnati, Cincinnati, Ohio
Clinical Cancer Research Vol. 10, 7001–7010, October 15, 2004
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 fibrinogencoated 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.