PhD Defense: Nanocar: A nanobody-based carrier platform for targeting inside the blood vessel VHH-targeted approach for intravascular diagnostics and therapies of cardiovascular diseases

Cardiovascular diseases, such as myocardial infarction and stroke, are the leading cause of death worldwide, accounting for about one-third of all deaths. These diseases are characterized by the formation of blood clots that block blood vessels, leading to a lack of oxygen and nutrients. Current diagnostics are not effective in detecting narrowed blood vessels or small blood clots, whereas current therapeutics against blood clots have adverse effects. Nanobodies could improve both diagnosis and treatment.

Nanobodies are derived from antibodies found in llamas. In general, antibodies have the ability to bind to specific targets. Nanobodies, in particular, are 10 times smaller than human antibodies, which allows for even stronger target binding and improved tissue penetration without triggering an immune response. The first nanobody-based therapeutic agent was approved in 2018, and others are being investigated in clinical trials. Nanobodies have also proven to be valuable in imaging tumors and assisting with visualization during surgery.

This thesis underscores the versatility and potential of nanobody-targeting in diagnosing and treating cardiovascular diseases. Hereto, we developed a nanobody that interferes with the function of thrombomodulin, a molecule located inside diseased blood vessels. This nanobody could slow down blood clot formation. Another nanobody, targeting a clot component named Von Willebrand factor, was conjugated to a natural enzyme. This nanobody-enzyme combination was effective in breaking down blood clots in animal models of acute ischemic stroke. Lastly, we developed a nanobody targeting fibrin, another key component of blood clots, and coupled it to a fluorescent liposome. This nanobody-liposome combination was able to visualize local clot formation inside blood vessels.