title: Localized delivery of low-density lipoprotein docosahexaenoic acid nanoparticles to the rat brain using focused ultrasound.
abstract: Focused ultrasound exposures in the presence of microbubbles can achieve transient, non-invasive, and localized blood-brain barrier (BBB) opening, offering a method for targeted delivery of therapeutic agents into the brain. Low-density lipoprotein (LDL) nanoparticles reconstituted with docosahexaenoic acid (DHA) could have significant therapeutic value in the brain, since DHA is known to be neuroprotective. BBB opening was achieved using pulsed ultrasound exposures in a localized brain region in normal rats, after which LDL nanoparticles containing the fluorescent probe DiR (1,1'-Dioctadecyl-3,3,3',3'-Tetramethylindotricarbocyanine Iodide) or DHA were administered intravenously. Fluorescent imaging of brain tissue from rats administered LDL-DiR demonstrated strong localization of fluorescence signal in the exposed hemisphere. LDL-DHA administration produced 2 × more DHA in the exposed region of the brain, with a corresponding increase in Resolvin D1 levels, indicating DHA was incorporated into cells and metabolized. Histological evaluation did not indicate any evidence of increased tissue damage in exposed brain regions compared to normal brain. This work demonstrates that localized delivery of DHA to the brain is possible using systemically-administered LDL nanoparticles combined with pulsed focused ultrasound exposures in the brain. This technology could be used in regions of acute brain injury or as a means to target infiltrating tumor cells in the brain.
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Rohit S
authors.initials: RS
authors.lastname: Mulik
authors.affiliation: Radiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Bing
authors.affiliation: Radiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Ladouceur-Wodzak
authors.affiliation: Radiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Imalka
authors.initials: I
authors.lastname: Munaweera
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Radiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. Electronic address: ian.corbin@utsouthwestern.edu.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Corbin
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002232:Carbocyanines; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D055442:Metabolome / Q000187:drug effects; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013238:Stereotaxic Techniques; D014465:Ultrasonics
chemical_list: C574020:1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine; D002232:Carbocyanines; D008077:Lipoproteins, LDL; D004281:Docosahexaenoic Acids
keywords: Bloodbrain-barrier; Brain; Focused ultrasound; Lipoprotein; Nanoparticle; Omega-3 fatty acid