Non-invasive Delivery of Stealth, Brain-Penetrating Nanoparticles Across the Blood-Brain Barrier Using MRI-guided Focused Ultrasound

J Control Release. 2014 Sep 10;189:123-132. doi: 10.1016/j.jconrel.2014.06.031. Epub 2014 Jun 28.

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.

Keywords: Central nervous system; Focused ultrasound; Nanoparticles.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism*
  • Carbocyanines / administration & dosage
  • Carbocyanines / chemistry
  • Drug Delivery Systems*
  • Fluorescent Dyes / administration & dosage
  • Fluorescent Dyes / chemistry
  • Magnetic Resonance Imaging / methods*
  • Microbubbles
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Polymers / administration & dosage
  • Polymers / chemistry
  • Rats, Sprague-Dawley
  • Ultrasonics / methods*

Substances

  • Alexa Fluor 647
  • Carbocyanines
  • Fluorescent Dyes
  • Polymers