Improved Drug Delivery to Brain Metastases by Peptide-Mediated Permeabilization of the Blood-Brain Barrier.

Abstract

Patients with melanoma have a high risk of developing brain metastasis, which is associated with a dismal prognosis. During early stages of metastasis development, the blood-brain barrier (BBB) is likely intact, which inhibits sufficient drug delivery into the metastatic lesions. We investigated the ability of the peptide, K16ApoE, to permeabilize the BBB for improved treatment with targeted therapies preclinically. Dynamic contrast enhanced MRI (DCE-MRI) was carried out on NOD/SCID mice to study the therapeutic window of peptide-mediated BBB permeabilization. Further, both in vivo and in vitro assays were used to determine K16ApoE toxicity and to obtain mechanistic insight into its action on the BBB. The therapeutic impact of K16ApoE on metastases was evaluated combined with the mitogen-activated protein kinase pathway inhibitor dabrafenib, targeting BRAF mutated melanoma cells, which is otherwise known not to cross the intact BBB. Our results from the DCE-MRI experiments showed effective K16ApoE-mediated BBB permeabilization lasting for up to 1 hour. Mechanistic studies showed a dose-dependent effect of K16ApoE caused by induction of endocytosis. At concentrations above IC50, the peptide additionally showed nonspecific disturbances on plasma membranes. Combined treatment with K16ApoE and dabrafenib reduced the brain metastatic burden in mice and increased animal survival, and PET/CT showed that the peptide also facilitated the delivery of compounds with molecular weights as large as 150 kDa into the brain. To conclude, we demonstrate a transient permeabilization of the BBB, caused by K16ApoE, that facilitates enhanced drug delivery into the brain. This improves the efficacy of drugs that otherwise do not cross the intact BBB.

• Authors: Synnøve Nymark Aasen, Heidi Espedal, Christopher Florian Holte, Olivier Keunen, Tine Veronika Karlsen, Olav Tenstad, Zaynah Maherally, Hrvoje Miletic, Tuyen Hoang, Anne Vaag Eikeland, Habib Baghirov, Dag Erlend Olberg, Geoffrey John Pilkington, Gobinda Sarkar, Robert B Jenkins, Terje Sundstrøm, Rolf Bjerkvig, Frits Thorsen
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 18 Issue 11 Pg. 2171-2181 (11 2019) ISSN: 1538-8514 [Electronic] United States
• PMID: 31467182 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Imidazoles
• Oximes
• Peptides
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• dabrafenib

Topics

• Animals
• Blood-Brain Barrier (chemistry)
• Brain Neoplasms (drug therapy, genetics, secondary)
• Cell Line, Tumor
• Dogs
• Dose-Response Relationship, Drug
• Endocytosis
• Humans
• Imidazoles (administration & dosage, pharmacokinetics)
• Madin Darby Canine Kidney Cells
• Melanoma (drug therapy, genetics)
• Mice
• Mutation
• Oximes (administration & dosage, pharmacokinetics)
• Peptides (administration & dosage, pharmacokinetics)
• Proto-Oncogene Proteins B-raf (genetics)
• Rats
• Xenograft Model Antitumor Assays