Fibrinogen-coated droplets of olive oil for delivery of docetaxel to a fibrin(ogen)-rich ascites form of a murine mammary tumor.
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.
Einhaus
Charity M
CM
Department of Pathology and Laboratory Medicine, the University of Cincinnati, Cincinnati, Ohio 45267-0529, USA.
Retzinger
Andrew C
AC
Perrotta
Andre O
AO
Dentler
Michael D
MD
Jakate
Abhijeet S
AS
Desai
Pankaj B
PB
Retzinger
Gregory S
GS
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D001201:Ascites / Q000188:drug therapy* / Q000473:pathology; D000077143:Docetaxel; D016503:Drug Delivery Systems; D005260:Female; D005340:Fibrinogen / Q000737:chemistry; D007263:Infusions, Parenteral; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy*; D051379:Mice; D000069463:Olive Oil; D010938:Plant Oils; D043823:Taxoids / Q000008:administration & dosage* / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D000069463:Olive Oil; D010938:Plant Oils; D043823:Taxoids; D000077143:Docetaxel; D005340:Fibrinogen