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

被引:18
作者
Aasen, Synnove Nymark [1 ,2 ]
Espedal, Heidi [2 ,3 ]
Holte, Christopher Florian [2 ]
Keunen, Olivier [4 ]
Karlsen, Tine Veronika [5 ]
Tenstad, Olav [5 ]
Maherally, Zaynah [6 ]
Miletic, Hrvoje [2 ,7 ]
Tuyen Hoang [2 ]
Eikeland, Anne Vaag [8 ]
Baghirov, Habib [9 ]
Olberg, Dag Erlend [10 ,11 ]
Pilkington, Geoffrey John [6 ]
Sarkar, Gobinda [12 ]
Jenkins, Robert B. [12 ]
Sundstrom, Terje [2 ,13 ,14 ]
Bjerkvig, Rolf [2 ,4 ]
Thorsen, Frits [2 ,3 ]
机构
[1] Haukeland Hosp, Dept Oncol & Med Phys, Bergen, Norway
[2] Univ Bergen, Kristian Gerhard Jebsen Brain Tumour Res Ctr, Dept Biomed, Bergen, Norway
[3] Univ Bergen, Mol Imaging Ctr, Dept Biomed, Bergen, Norway
[4] Luxembourg Inst Hlth, Dept Oncol, Luxembourg, Luxembourg
[5] Univ Bergen, Dept Biomed, Bergen, Norway
[6] Univ Portsmouth, Brain Tumour Res Ctr, Inst Biomed & Biomol Sci, Portsmouth, Hants, England
[7] Haukeland Hosp, Dept Pathol, Bergen, Norway
[8] Haukeland Hosp, Dept Radiol, Bergen, Norway
[9] Norwegian Univ Sci & Technol, Dept Phys, Trondheim, Norway
[10] Univ Oslo, Dept Pharmaceut Chem, Oslo, Norway
[11] Oslo Univ Hosp, Norwegian Cyclotron Ctr, Oslo, Norway
[12] Mayo Clin, Div Expt Pathol, Rochester, MN USA
[13] Haukeland Hosp, Dept Neurosurg, Bergen, Norway
[14] Univ Bergen, Dept Clin Med, Bergen, Norway
关键词
EFFICACY; DABRAFENIB; ULTRASOUND; BIOLOGY; CANCER;
D O I
10.1158/1535-7163.MCT-19-0160
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 themitogen-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.
引用
收藏
页码:2171 / 2181
页数:11
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