K16ApoE increases drug-delivery across the blood brain barrier in an animal model of brain metastases

S. Aasen, H. Espedal, O. Keunen, C. Holte, H. Baghirov, R. Bjerkvig, T. Karlsen, O. Tenstad, D. Olberg, G. Sarkar, F. Thorsen

Research output: Contribution to journalMeeting Abstractpeer-review

Abstract

Individuals with metastatic disease within the brain usually await a poor prognosis. Regardless of the ongoing development of novel drugs, a significant challenge is the delivery of drugs across the blood brain barrier (BBB) and into the metastatic neoplasms. The BBB excludes almost all therapeutic compounds, as highly charged, hydrophilic or large compounds are unable to penetrate the BBB. Different strategies to temporarily open the BBB have been studied previously. Here, we describe a peptide transporter encompassing 16 lysine residues and 20 amino acid residues corresponding to the low density lipoprotein receptor (LDLR) binding domain of apolipoprotein E (ApoE). We show that this peptide, K16ApoE, is able to transiently open the BBB for drug-delivery into experimental brain metastases. The ability of the peptide to open the BBB was studied in vivo using dynamic contrast enhanced magnetic resonance imaging (DCE MRI) in nonobese diabetic/severe combined (nod/scid) mice. Further, cellular effects after treatment with the peptide was investigated in vitro using confocal microscopy, flow cytometry and impedance experiments. The biodistribution of the peptide was studied in blood plasma and several organs using isotope labeled K16ApoE. Finally, we treated animals with the peptide in combination with the B-RAF inhibitor Dabrafenib, only Dabrafenib or vehicle. After intravenously administering the K16ApoE peptide into the mice, a transient opening of the BBB for up to 4 hours was clearly demonstrated by DCE-MRI. Microscopy showed that the peptide disrupted brain endothelial cell monolayers by reducing the barrier properties of the cells. The impedance experiments displayed that the permeability through endothelial cell barriers was increased after treatment with K16ApoE, and dose-dependent cell death was seen. The peptide did not affect endothelial cell tight junctions. The biodistribution study showed that the peptide was eliminated from blood plasma in less than five minutes through the kidneys. In the treatment study it was observed that the group of animals receiving K16ApoE followed by Dabrafenib had smaller tumor volumes than the other two experimental groups. K16ApoE did in combination with Dabrafenib decrease the number of experimental brain metastases, as a therapeutic window up to 4 hours was seen when using the peptide. The described strategy could thus have the potential to improve the treatment of patients with brain metastatic disease.
Original languageEnglish
Article numberP13.04
Pages (from-to)iii101-iii101
JournalNeuro-Oncology
Volume19
Issue numberSuppl.3
DOIs
Publication statusPublished - May 2017
Event5th Quadrennial Meeting of the World Federation of Neuro-Oncology Societies (WFNOS) - Zurich, Switzerland
Duration: 4 May 20177 May 2017

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