Magnetic targeting of nanoparticles across the intact blood–brain barrier

• Published in: Journal of controlled release 2012-11, Vol.164 (1), p.49-57
• Main Authors: Kong, Seong Deok, Lee, Jisook, Ramachandran, Srinivasan, Eliceiri, Brian P., Shubayev, Veronica I., Lal, Ratnesh, Jin, Sungho
• Format: Article
• Language: English
• Subjects: animal models; Animals; atomic force microscopy; Biological and medical sciences; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Blood–brain barrier; Blotting, Western; brain; Brain - drug effects; Brain - metabolism; Drug Carriers - administration & dosage; Drug Carriers - adverse effects; Drug Carriers - pharmacokinetics; Drug delivery; drugs; Endocytosis - drug effects; endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; extracellular matrix; fluorescence; Fluorescent Antibody Technique; Fluorescent Dyes; General pharmacology; Humans; Ibuprofen - administration & dosage; Ibuprofen - pharmacokinetics; Image analysis; Injections, Intravenous; Luciferases, Firefly - genetics; Luminescent Measurements; Magnetic; magnetic fields; Magnetite Nanoparticles - administration & dosage; Magnetite Nanoparticles - adverse effects; Magnetite Nanoparticles - ultrastructure; Medical sciences; Mice; Mice, Transgenic; Microscopy, Confocal; Microscopy, Electron, Transmission; nanocapsules; Nanoparticles; parenchyma; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; radio waves; Solubility; Surface Properties; Tissue Distribution; toxicity; Transcranial Magnetic Stimulation
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2012.09.021

Delivery of therapeutic or diagnostic agents across an intact blood–brain barrier (BBB) remains a major challenge. Here we demonstrate in a mouse model that magnetic nanoparticles (MNPs) can cross the normal BBB when subjected to an external magnetic field. Following a systemic administration, an applied external magnetic field mediates the ability of MNPs to permeate the BBB and accumulate in a perivascular zone of the brain parenchyma. Direct tracking and localization inside endothelial cells and in the perivascular extracellular matrix in vivo was established using fluorescent MNPs. These MNPs were inert and associated with low toxicity, using a non-invasive reporter for astrogliosis, biochemical and histological studies. Atomic force microscopy demonstrated that MNPs were internalized by endothelial cells, suggesting that trans-cellular trafficking may be a mechanism for the MNP crossing of the BBB observed. The silica-coated magnetic nanocapsules (SiMNCs) allow on-demand drug release via remote radio frequency (RF) magnetic field. Together, these results establish an effective strategy for regulating the biodistribution of MNPs in the brain through the application of an external magnetic field. [Display omitted]