TY - JOUR
T1 - Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood - Brain barrier using MRI-guided focused ultrasound
AU - Nance, Elizabeth
AU - Timbie, Kelsie
AU - Miller, G. Wilson
AU - Song, Ji
AU - Louttit, Cameron
AU - Klibanov, Alexander L.
AU - Shih, Ting Yu
AU - Swaminathan, Ganesh
AU - Tamargo, Rafael J.
AU - Woodworth, Graeme F.
AU - Hanes, Justin
AU - Price, Richard J.
N1 - Funding Information:
Supported by NIH RO1 CA164789 .
PY - 2014/9/10
Y1 - 2014/9/10
N2 - 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 60 nm 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.
AB - 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 60 nm 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.
KW - Central nervous system
KW - Focused ultrasound
KW - Nanoparticles
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UR - http://www.scopus.com/inward/citedby.url?scp=84904282240&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2014.06.031
DO - 10.1016/j.jconrel.2014.06.031
M3 - Article
C2 - 24979210
AN - SCOPUS:84904282240
SN - 0168-3659
VL - 189
SP - 123
EP - 132
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -