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Delivery and targeting of fibrinolytic agents to blood clots
Portugal (PorMSIC) - University of Lisbon, Lisbon
Institute of Molecular Medicine
English and Portuguese
Type of Research Project
- Basic science
What is the background of the project?
Cardiovascular diseases (CVDs) are the major cause of death worldwide, accounting for nearly 30% of all deaths. Along with other CVDs causative factors, blood fibrin clots are responsible for thrombotic events. The generation of a hemostatic clot requires thrombin-mediated conversion of fibrinogen to fibrin. There is increasing evidence for a consistent association between denser fibrin clot structure with CVD and (athero)thrombotic disorders. Physiologic thrombosis is counterbalanced by intrinsic antithrombotic properties and fibrinolysis. Fibrinolysis occurs when active plasmin dissolves fibrin fibers restoring blood flow. Plasmin is produced by tissue plasminogen activator (tPA)-mediated conversion of plasminogen into plasmin. Clinical therapeutics used to treat thrombosis include intravenous injection of free forms of fibrinolytic agents. However, those therapies have shorter circulating life-time and are highly associated with bleeding risks due to the incapacity to distinguish between circulating and fibrin-bound plasminogen. This leads to overproduction of plasmin and a systemic lytic state.
What is the aim of the project?
The aim of the project is to develop an encapsulated fibrinolytic therapeutic strategy to dissolve fibrin clots and restore blood flow. The development of this drug delivery system is expected to lead to a better treatment for resistant clots, dissolving them in a controlled manner, with lower bleeding risks. A stable and targeted lipid vesicle system will be developed for drug delivery. The group and I have extensive experience in developing different lipid systems which can lead to the formulation with a best performance. Targeting will be achieved by incorporating in the free end of polyethilenoglycol (PEG) functionalized lipids, a peptide that binds to fibrinogen. The designed peptide will bind the pocket b, located in the C-terminus of the fibrinogen ß-polypeptide chains, leading to lipid system incorporation during clot formation.
What techniques and methods are used?
Liposome preparation by extrusion methodology. Ultracentrifugation methodology. Dynamic Light Scattering, Zeta-Potential will be used for nanoparticle characterization to gain knowledge in nanoparticles size and surface charge, respectively. Atomic Force Microscopy will be used for nanoparticle characterization as well as for fibrin clot fibrinolysis evaluation by the nanoparticles
What is the role of the student?
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
The student will prepare by himself (under supervision) the liposomes to encapsulate the fibrinolytic agent, by extrusion method. The student will use the ultracentrifugation by himself (under supervision) method to separate the encapsulated material from the unencapsulated. The student will characterize by dynamic light scattering and zeta-potential the nanoparticles by himself (under supervision). The student will prepare the samples and will observe the measurements by atomic force microscopy under my supervision.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
The methodologies theory will be provided to the student by the tutor. The theoretical teaching of the project and the research files will be provided by the tutor and by literature reading.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a presentation - The student’s name will be mentioned in a future publication
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
It is recommended that the student knows the bacis of labwork, such as, pippeting.
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Pre-Medical students from the American-British system - Students in biomedical fields
- • P.M. Carvalho; M.R. Felício; N.C. Santos; S. Gonçalves; M.M. Domingues (2018) Front. Chem.; 6; 237. doi: 10.3389/fchem.2018.00237
- • M.M. Domingues; F.L. Macrae; C. Duval; H.R. McPherson; K.I. Bridge; R.A. Ajjan; V.C. Ridger; S.D. Connell; H. Philippou; R.A. Ariëns (2016) Blood; 127; 487-95.
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