Skip to Main Content
Frequently Asked Questions
Submit an ETD
Global Search Box
Need Help?
Keyword Search
Participating Institutions
Advanced Search
School Logo
Files
File List
ucin1078283884.pdf (9.4 MB)
ETD Abstract Container
Abstract Header
Fibrinogen-Coated Droplets of Olive Oil for the Targeted Delivery of Docetaxel to Fibrin(ogen)-Rich Tumors: Evaluation of Efficacy and Mechanism
Author Info
Accurso, Charity Einhaus
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1078283884
Abstract Details
Year and Degree
2004, PhD, University of Cincinnati, Medicine : Pathobiology and Molecular Medicine.
Abstract
Fibrinogen, a protein associated with all malignant tumors, binds rapidly and near irreversibly to hydrophobic surfaces, including droplets of olive oil. When administered to a mouse, fibrinogen-coated oil droplets will accumulate at fibrin(ogen)-rich sites, i.e., inflammatory regions and tumors. For my thesis research I show that fibrinogen-coated oil droplets can be used effectively to target lipophilic drugs to fibrin(ogen)-rich tumors. I use the lipophilic anticancer taxane docetaxel for my experiments. I demonstrated, first, that packaging docetaxel into fibrinogen-coated oil droplets does not limit the drug’s cytotoxicity. Preliminary survival studies demonstrate that the formulation prolongs the survival of B16F10 melanoma-bearing mice by 330% when compared to survival conferred by the clinical formulation, Taxotere®. Using the TA3/St ascites tumor model, I then show that the formulation increases the lifespan of tumor-bearing mice 211% as compared to 53% for Taxotere®. I demonstrate next that thrombin activity has a role in the retention of droplets, and that inhibition of thrombin activity reduces the efficacy of the formulation to that of Taxotere®. Although mice treated with fibrinogen-coated oil droplets develop significant levels of anti-fibrinogen antibodies, those antibodies do not elicit an overt coagulopathy, they do not prolong the activated partial thromboplastin time, and they do not appear to have an effect on the therapeutic efficacy of the oil droplets. Taken together, my results and observations indicate that 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. I performed additional studies to achieve mechanistic understanding of fibrinogen binding to hydrophobic surfaces, and to identify a naturally-occurring system for the potential delivery/targeting of lipophilic drugs. Using proteolytic and radiologic methods, I demonstrate that fibrinogen binds to hydrophobic surfaces via its d2Dγ region. The protein and its binding orientation of fibrinogen is concentration dependent. I also demonstrate that fibrinogen binds to, and remains functional on, chylomicrons in the gastrointestinal lymph, a phenomenon that I believe may be exploited for drug delivery.
Committee
Dr. Gregory Retzinger (Advisor)
Pages
144 p.
Subject Headings
Health Sciences, Pathology
Keywords
fibrinogen
;
drug delivery
;
emulsion
;
ascites
;
docetaxel
;
olive oil
Recommended Citations
Refworks
EndNote
RIS
Mendeley
Citations
Accurso, C. E. (2004).
Fibrinogen-Coated Droplets of Olive Oil for the Targeted Delivery of Docetaxel to Fibrin(ogen)-Rich Tumors: Evaluation of Efficacy and Mechanism
[Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1078283884
APA Style (7th edition)
Accurso, Charity.
Fibrinogen-Coated Droplets of Olive Oil for the Targeted Delivery of Docetaxel to Fibrin(ogen)-Rich Tumors: Evaluation of Efficacy and Mechanism.
2004. University of Cincinnati, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1078283884.
MLA Style (8th edition)
Accurso, Charity. "Fibrinogen-Coated Droplets of Olive Oil for the Targeted Delivery of Docetaxel to Fibrin(ogen)-Rich Tumors: Evaluation of Efficacy and Mechanism." Doctoral dissertation, University of Cincinnati, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1078283884
Chicago Manual of Style (17th edition)
Abstract Footer
Document number:
ucin1078283884
Download Count:
861
Copyright Info
© 2004, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.