Date of Award

2011

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Professor Mauro Adamo

Second Supervisor

Professor Paola Grieco

Third Supervisor

Dr Marc Devocelle

Funder/Sponsor

This work was funded by thye HRB of Ireland.

Keywords

Thrombosis, Vascular Diseases, Platelet Aggregation Inhibitors

Abstract

The aim of the project is the development of novel MRI imaging agents for the early diagnosis of platelet-rich thrombi. These novel agents were designed to allow use of multiple reporting techniques such as MRI, UV-fluorescence, near IR fluorescence and to target the platelet specific integrin GPIIbIIIIa. Progress in the understanding of the central importance of platelets in cardiovascular disease, combined with the development of new classes of antiplatelet agents, has dramatically altered the landscape in terms of the clinical management of vascular diseases. There are, however, significant drawbacks with existing therapies, including issues related to limited efficacy and safety.

Tirofiban and Abciximab for example are known GPIIb/IIIIa receptor antagonists both of which have considerable side effects such as, increased risk of bleeding and thrombocytopenia. In order for such compounds to be effective antagonists, it is necessary for them to be available at concentrations that cause more than 80% occupancy of the platelet integrin. This has proven to be impractical and unsuitable in therapeutics. However, this observation can work to our advantage in the development of a diagnostic reagent, since it is established that a compound that binds to 20% or less of the GPIIb/IIIIa molecules on the platelet surface has little or no side effects.

The tri-amino acid sequence KGD- (Lysine, Glycine, Aspartic acid) has been shown to be a specific and potent platelet antagonist. With this data in hand, we conducted a proof-ofconcept study to prepare a family of KGD-peptidomimetics, which can subsequently conjugated to a class of novel MRI contrast agents. We then aim to demonstrate incorporation of this novel compound into human thrombus so that it can then be imaged by magnetic resonance scanning. If successful, we plan on pursuing clinical application of this technique to enhance intravascular thrombus detection and diagnosis.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

File Size

8,387 KB

Comments

A thesis submitted to the Royal College of Surgeons in Ireland for the degree of Doctor of Philosophy from the National University of Ireland in 2011.

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