title: Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound.
abstract: The blood-brain barrier (BBB) presents a significant obstacle for the treatment of many central nervous system (CNS) disorders, including invasive brain tumors, Alzheimer's, Parkinson's and stroke. Therapeutics must be capable of bypassing the BBB and also penetrate the brain parenchyma to achieve a desired effect within the brain. In this study, we test the unique combination of a non-invasive approach to BBB permeabilization with a therapeutically relevant polymeric nanoparticle platform capable of rapidly penetrating within the brain microenvironment. MR-guided focused ultrasound (FUS) with intravascular microbubbles (MBs) is able to locally and reversibly disrupt the BBB with submillimeter spatial accuracy. Densely poly(ethylene-co-glycol) (PEG) coated, brain-penetrating nanoparticles (BPNs) are long-circulating and diffuse 10-fold slower in normal rat brain tissue compared to diffusion in water. Following intravenous administration of model and biodegradable BPNs in normal healthy rats, we demonstrate safe, pressure-dependent delivery of 60nm BPNs to the brain parenchyma in regions where the BBB is disrupted by FUS and MBs. Delivery of BPNs with MR-guided FUS has the potential to improve efficacy of treatments for many CNS diseases, while reducing systemic side effects by providing sustained, well-dispersed drug delivery into select regions of the brain.
authors: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231 (USA).|Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218 (USA).
authors: Elizabeth
authors: E
authors: Nance
authors: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908 (USA).
authors: Kelsie
authors: K
authors: Timbie
authors: Department of Radiology, University of Virginia, Charlottesville, VA 22908 (USA).
authors: G Wilson
authors: GW
authors: Miller
authors: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908 (USA).
authors: Ji
authors: J
authors: Song
authors: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908 (USA).
authors: Cameron
authors: C
authors: Louttit
authors: Department of Internal Medicine, Cardiovascular Division, University of Virginia, Charlottesville, VA 22908 (USA).
authors: Alexander L
authors: AL
authors: Klibanov
authors: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218 (USA).
authors: Ting-Yu
authors: TY
authors: Shih
authors: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218 (USA).
authors: Ganesh
authors: G
authors: Swaminathan
authors: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231 (USA).
authors: Rafael J
authors: RJ
authors: Tamargo
authors: Department of Neurosurgery, University of Maryland, Baltimore, MD 21201 (USA).
authors: Graeme F
authors: GF
authors: Woodworth
authors: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231 (USA).|Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218 (USA).|Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231 (USA).
authors: Justin
authors: J
authors: Hanes
authors: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908 (USA).
authors: Richard J
authors: RJ
authors: Price
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002232:Carbocyanines / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000737:chemistry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D045423:Microbubbles; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D014465:Ultrasonics / Q000379:methods*
chemical_list: C569686:Alexa Fluor 647; D002232:Carbocyanines; D005456:Fluorescent Dyes; D011108:Polymers
keywords: Central nervous system; Focused ultrasound; Nanoparticles