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 bloodbrain 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 mela-noma 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 IC 50 , 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.

A Historical Review of Brain Drug Delivery

“…Given the highly cationic charge of the K16ApoE peptide, the likely mechanism of BBB transport is either AMT via a charge mechanism, or BBB disruption caused by the highly cationic peptide. Similar to other cationic import peptides, the K16ApoE peptide is rapidly removed from plasma in <5 min [543]. In an attempt to deliver the TPP1 enzyme to brain in TPP1 null mice, the enzyme was co-injected with the K16ApoE peptide at a dose of 40-120 nmol of the peptide.…”

Selective blood-brain barrier permeabilization of brain metastases by a type 1 receptor-selective tumor necrosis factor mutein

“…1 hour). 32 A similar idea based on receptor-mediated transcytosis using Fc fragments engineered to bind to the transferrin receptor (TfR) has also been described. 33 However, there is no evidence that endothelial cells associated with brain metastases express more TfR than endothelial cells in normal brain, which is critical to obtaining selective BBB opening.…”

Brain Metastasis Cell Lines Panel: A Public Resource of Organotropic Cell Lines

“…Sophisticated studies have also explored optimal partners and their respective timing/ sequencing for optimal combinations of systemic and local therapies (87), both mirroring and informing clinical research. Other studies have investigated methods of opening the BBB to improve delivery of drugs that would otherwise be too large to reach intracranial tumors (6,54,80,88,89).…”