Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood - brain barrier using MRI-guided focused ultrasound

被引：195

作者：

Nance, Elizabeth ^{[1
,2
]}

Timbie, Kelsie ^{[3
]}

Miller, G. Wilson ^{[4
]}

Song, Ji ^{[3
]}

Louttit, Cameron ^{[3
]}

Klibanov, Alexander L. ^{[5
]}

Shih, Ting-Yu ^{[2
]}

Swaminathan, Ganesh ^{[2
]}

Tamargo, Rafael J. ^{[1
]}

Woodworth, Graeme F. ^{[6
]}

Hanes, Justin ^{[1
,2
,7
]}

Price, Richard J. ^{[3
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Ctr Nanomed, Baltimore, MD 21231 USA

[2] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21231 USA

[3] Univ Virginia, Dept Biomed Engn, Charlottesville, VA 22908 USA

[4] Univ Virginia, Dept Radiol, Charlottesville, VA 22908 USA

[5] Univ Virginia, Dept Internal Med, Div Cardiovasc, Charlottesville, VA 22908 USA

[6] Univ Maryland, Dept Neurosurg, Baltimore, MD 21201 USA

[7] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Dept Ophthalmol, Baltimore, MD 21231 USA

来源：

JOURNAL OF CONTROLLED RELEASE | 2014年 / 189卷

关键词：

Nanoparticles; Focused ultrasound; Central nervous system; POLY(BUTYL CYANOACRYLATE) NANOPARTICLES; CONTRAST AGENT; BIODEGRADABLE NANOPARTICLES; TARGETED DELIVERY; MICROBUBBLE SIZE; IN-VIVO; DISRUPTION; DOXORUBICIN; TEMOZOLOMIDE; DIFFUSION;

D O I：

10.1016/j.jconrel.2014.06.031

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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. (C) 2014 Elsevier B.V. All rights reserved.

引用

页码：123 / 132

页数：10

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