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

Elizabeth Nance, Kelsie Timbie, G. Wilson Miller, Ji Song, Cameron Louttit, Alexander L. Klibanov, Ting Yu Shih, Ganesh Swaminathan, Rafael J. Tamargo, Graeme F. Woodworth, Justin Hanes, Richard J. Price

Research output: Contribution to journalArticlepeer-review

143 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)123-132
Number of pages10
JournalJournal of Controlled Release
StatePublished - Sep 10 2014


  • Central nervous system
  • Focused ultrasound
  • Nanoparticles

ASJC Scopus subject areas

  • Pharmaceutical Science


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