PhD defence by Grace de Malona Eriksen

On Friday 7 June, Grace de Malona Eriksen will defend her PhD thesis "Exploring the Endothelial Protein C Receptor (EPCR) as a Therapeutic Target: Mapping Distribution and Correlation with Nanoparticle Targeting".

Time: 13:00

Place: Building 421, Auditorium 71 & zoom: https://dtudk.zoom.us/meeting/register/u5AsduCqrTssGNCAnKrNJs1O_tjRggbiGd6P

Please be aware that the PhD defense may be recorded - This will also be informed at the beginning of the PhD defense.

Supervisor: Associate Professor Andrew James Urquhart

Co-supervisor: Professor Thomas L. Andresen, DTU Health Tech

Assessment committee:
Associate Professor Johan Ulrik Lind, DTU Health Tech
Professor Luisa Iruela-Arispe, Northwestern University, USA
Associate Professor Yvonne Adams, University of Copenhagen

Chairperson:
Associate Professor Jonas Nyvold Pedersen, DTU Health Tech

Abstract:
Cardiovascular diseases (CVD) claim over 20.5 million lives annually. CVDs encompass conditions such as atherosclerosis, strokes, diabetes, chronic liver and kidney disease, which are strongly related to endothelial dysfunction. The endothelial protein C receptor (EPCR) is a multiligand and multifunctional protein, mainly involved in coagulation. This protein is widely expressed throughout the body and associated with endothelial function. Therefore, we speculate whether EPCR can be exploited as a novel nanomedicine active target. This PhD thesis provides a comprehensive examination of the intricate role of EPCR in vascular biology and its potential in mediating the uptake and distribution of nanoparticles (NPs) within the vascular system.

To map the distribution of EPCR, its expression in tissue-specific endothelial cells were explored in vitro and in vivo. For optimized active targeting of EPCR, antibody-antigen interactions were analyzed for their binding affinities. To explore the biodistribution of NPs, formulations were synthesized and intravenously injected into mice, where two anti-EPCR antibody surface functionalized NP delivery systems were employed: i) liposomes (LIP) loaded with platinum (Pt) and ii) lipid NPs (LNPs) encapsulated with Luciferase mRNA.

The expression of EPCR explored in vitro revealed uniform expression patterns. This contrasted both with in vivo findings of significantly higher expression levels of EPCR in the liver and kidney compared to other organs, and previous studies claiming that EPCR is primarily expressed in large blood vessels. EPCR is routinely measured in plasma but has not previously been shown in the blood as demonstrated by our findings. The biodistribution of the NP delivery systems showed significant accumulation in the liver and spleen, with differential distribution patterns in other organs. The results indicate that the nanomedicine models actively target these organs compared to an IgG control and demonstrate that antibody binding affinity to EPCR correlates with liver targeting. The significantly high expression of EPCR in the liver supports that NPs target EPCR and NP accumulation is not exclusively ascribed to metabolic clearance.

These novel insights into EPCR as a potential therapeutic molecule contribute to a more nuanced understanding of its part in vascular health and pathology. Furthermore, the study highlights the role of blood flow dynamics and shear stress in NP behavior, emphasizing the complexity of achieving targeted delivery in diverse physiological environments.