Research

Delivering molecules to specific regions of the body is a major scientific and medical challenge. The projects below describe delivery technologies that researchers in the Kastrup Lab are developing to overcome these challenges in the treatment of coagulation and cardiovascular disorders.

Developing new hemostatic materials to halt severe bleeding.
Propellant_NoPropellant_withTEXT Trauma, postpartum haemorrhaging, and coagulation disorders can contribute to major and life-threatening external bleeding. During episodes of severe bleeding, it is often necessary to initiate blood coagulation deep within wounds near the site of damaged vasculature. Current hemostatic agents are often not effective in these situations. To address this challenge, the Kastrup Lab is developing micro and nanoparticles that are water-reactive and can propel upstream through blood [1], with the goal of externally delivering pro-coagulants that can effectively halt severe haemorrhaging.

Uncovering new mechanisms of regulation for clot stabilization.
2016 Stage 2 CIHR foundations figure 1 schematic cascade 3Coagulation factor XIIIa (FXIIIa) is a transglutaminase that covalently crosslinks fibrin and several other coagulation factors to stabilize blood clots and reduce blood loss. Although the mechanism of synthesis and activation has been well characterized, the mechanism by which FXIIIa is inactivated has not been determined. We showed that plasmin can cleave FXIIIa, but not the zymogen FXIII [2]. These results indicate that the fibrinolytic system can regulate the coagulation system’s crosslinking agent, and this provides an additional point of regulation of clotting. The potential implications are that pathophysiological or therapeutic conditions that alter the fibrinolytic enzymes may inhibit the crosslinking of fibrin or cause aberrant crosslinking of other proteins.

Engineering platelets to produce RNA and proteins.
Fig2-01Nature has overcome the challenge of delivering molecules to areas of inflammation and thrombosis in part by using platelets as delivery vehicles for molecules. Platelets are anucleate cells found within the blood and are important mediators of hemostasis and inflammation. At sites of vascular injury platelets become activated, undergoing several biochemical and structural changes that allow them to adhere to the vascular cell wall and contribute to blood clotting. During activation, platelets release chemicals into the surrounding bloodstream, including small molecules, nucleic acids and proteins. Using nanomedicine-based techniques [3,4,5,6,7], the Kastrup Lab is developing an approach for the delivery of nucleic acids and therapeutics to isolated platelets, with the goal of using these modified platelets to deliver their cargo to targeted regions of disease.

Developing drug-eluting materials that can be implanted inside blood vessels.
Kastrup_KI_image_2_Inverted A major challenge in the treatment of cardiovascular diseases is the delivery of molecules to segments of diseased blood vessels, such as those containing atherosclerotic plaques. Local delivery of therapeutics is difficult because these diseased segments may only encompass small portions of the kilometers of vasculature within humans. The Kastrup Lab is developing materials that can be directly implanted inside blood vessels and used to deliver therapeutics to the surrounding vasculature. Current clinical techniques such as stenting rely on mechanical forces to implant materials in vessels. As an alternative method, the Kastrup Lab is developing adhesive gels to controllably glue materials and therapeutics to vessels. The lab was part of a team that synthesized adhesive gels which permanently coated atherosclerotic plaques and reduced inflammation in the plaques, using a mechanism which mimics the chemistry that marine mussels use to adhere to surfaces in the ocean [8]. Current projects focus on developing strategies to control the polymerization of drug-eluting materials inside blood vessels using components of blood coagulation, a crosslinking system that already exists in the vasculature [9]. Other uses for these intravascular implants are also being explored. To develop these materials, both microfluidic devices that mimic aspects of the vasculature and biological models of coagulation and atherosclerosis are being used.

 

Aspects of the above projects are currently funded by CIHR, NSERC, and Grand Challenges Canada.

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