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Ph.D. Defence by Kasper Bendix Johnsen

Kasper Bendix Johnsen will defend his Ph.D. thesis: "On the use of the transferrin receptor as a target for brain drug delivery"

Tidspunkt

09.03.2018 kl. 13.00 - 09.03.2018 kl. 13.00

Beskrivelse

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Abstract

Efficient drug delivery to the brain remains the largest obstacle for treatment of diseases related to the central nervous system. This obstacle is imposed by the presence of the blood-brain barrier (BBB), which constitutes the endothelial lining of the brain
capillaries. The brain capillary endothelial cells of the BBB are characterized by very tight interconnections and low passive permeability, and therefore, effectively excludes most molecules carried in the systemic circulation from entering the sensitive brain parenchyma. This also means that transport of medicines into the brain is severe impaired.
One strategy to overcome the issue of the BBB has been to target the medicines as drug constructs or nanomedicines to different nutrient receptor proteins expressed on the surface of the BBB. This would in theory drag the medicines into the brain parenchyma as a blind passenger in addition to the nutrient molecule. On popular receptor system utilized for brain drug delivery is the transferrin receptor, which normally is responsible for transporting iron atoms into the brain. However, despite vast amounts of preclinical progress in the past three decades on the use of transferrin receptors for brain drug delivery, there is still a lack of clinical translation.
In this dissertation, transferrin receptor-mediated brain drug delivery via nanomedicines was studied to obtain knowledge about specific design aspect that could improve the current standard of transport across the BBB. Specifically, we studied the impact
of ligand affinity, avidity, and valency on the subsequent uptake of gold nanoparticles and liposomes. Furthermore, we studied the fate of nanoparticles administrated directly into the brain compartment via intracerebroventricular injection. We find that between the different aspects studied, the impact imposed by decreasing the valency of the TfRtargeting ligand was superior with respect to increasing the brain parenchymal exposure of intravenously administrated nanoparticles. This amounted to a more than fivefold increase compared to current standards. We also find that a net negative surface charge is favorable for deep penetration of nanoparticles into the brain cortex after intracerebroventricular administration.
In conclusion, the results presented in this dissertation provide important information about how aspects known to impact antibody-based medicines for the brain also may impact the transport of nanomedicines into the brain..

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