Blood-brain barrier (BBB)

The blood-brain barrier (BBB) prevents more than 98% of drugs from penetrating from the brain vasculature into tumors, rendering current treatment strategies for brain metastases largely ineffective.

Published: (Updated: )

Improved drug delivery to BM
T1 weighted (T1w) MRI and parametric images (AUC, Ktrans) of coronal MRI brain sections (top left). The Ktrans analysis demonstrates leakage of contrast agent from blood to tissue 10 and 30 min after injection of the K16ApoE peptide, compared with control animals (top right). Representative T1w and T2w MR images from each treatment group at week 6 (bottom left). The mean, total tumor volumes in the mouse brains decreases 6 weeks after start of combined treatment (bottom, middle). Combined treatment with dabrafenib and K6ApoE improves animal survival (bottom right). Photo: Frits Thorsen, Department of Biomedicine, UiB

We investigated a synthetic peptide (external link) designed to transiently permeabilize the BBB and enhance delivery of targeted therapies. Dynamic contrast-enhanced MRI (DCE-MRI) was performed on nod/scid mice to assess the therapeutic window of peptide-mediated BBB modulation. In vivo and in vitro assays were used to evaluate peptide toxicity and explore its mechanism of action. The peptide was combined with dabrafenib, a MAPK pathway inhibitor that targets BRAF-mutated melanoma cells but normally does not cross the intact BBB.

DCE-MRI showed that the peptide effectively opened the BBB for up to one hour. Mechanistic studies indicated a dose-dependent effect driven by endocytosis. Combined treatment with the peptide and dabrafenib significantly reduced brain metastatic burden and prolonged survival in mice. PET/CT imaging confirmed that the peptide facilitated the delivery of molecules up to 150 kDa into the brain.

In summary, we demonstrate that this peptide induces transient BBB permeabilization, enabling improved delivery and efficacy of drugs that would otherwise be excluded by an intact BBB.