title: Optical barcoding of PLGA for multispectral analysis of nanoparticle fate in vivo.
abstract: Understanding of the mechanisms by which systemically administered nanoparticles achieve delivery across biological barriers remains incomplete, due in part to the challenge of tracking nanoparticle fate in the body. Here, we develop a new approach for "barcoding" nanoparticles composed of poly(lactic-co-glycolic acid) (PLGA) with bright, spectrally defined quantum dots (QDs) to enable direct, fluorescent detection of nanoparticle fate with subcellular resolution. We show that QD labeling does not affect major biophysical properties of nanoparticles or their interaction with cells and tissues. Live cell imaging enabled simultaneous visualization of the interaction of control and targeted nanoparticles with bEnd.3 cells in a flow chamber, providing direct evidence that surface modification of nanoparticles with the cell-penetrating peptide TAT increases their biophysical association with cell surfaces over very short time periods under convective current. We next developed this technique for quantitative biodistribution analysis in vivo. These studies demonstrate that nanoparticle surface modification with the cell penetrating peptide TAT facilitates brain-specific delivery that is restricted to brain vasculature. Although nanoparticle entry into the healthy brain parenchyma is minimal, with no evidence for movement of nanoparticles across the blood-brain barrier (BBB), we observed that nanoparticles are able to enter to the central nervous system (CNS) through regions of altered BBB permeability - for example, into circumventricular organs in the brain or leaky vasculature of late-stage intracranial tumors. In sum, these data demonstrate a new, multispectral approach for barcoding PLGA, which enables simultaneous, quantitative analysis of the fate of multiple nanoparticle formulations in vivo.
authors.affiliation: Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ 85013, USA.
authors.forename: David X
authors.initials: DX
authors.lastname: Medina
authors.affiliation: Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ 85013, USA; School of Biological and Health Systems Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287, USA.
authors.forename: Kyle T
authors.initials: KT
authors.lastname: Householder
authors.affiliation: Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ 85013, USA; School of Biological and Health Systems Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287, USA.
authors.forename: Ricki
authors.initials: R
authors.lastname: Ceton
authors.affiliation: Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ 85013, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Kovalik
authors.affiliation: Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ 85013, USA; School of Biological and Health Systems Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Heffernan
authors.affiliation: School of Biological and Health Systems Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287, USA.
authors.forename: Rohini V
authors.initials: RV
authors.lastname: Shankar
authors.affiliation: Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ 85013, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Bowser
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wechsler-Reya
authors.affiliation: Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ 85013, USA; School of Biological and Health Systems Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287, USA. Electronic address: rachael.sirianni@dignityhealth.org.
authors.forename: Rachael W
authors.initials: RW
authors.lastname: Sirianni
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D015696:Gene Products, tat; D057809:HEK293 Cells; D006801:Humans; D019344:Lactic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D055620:Optical Phenomena; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D014018:Tissue Distribution
chemical_list: D057846:Cell-Penetrating Peptides; D015696:Gene Products, tat; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: Cell-penetrating peptide; Imaging and tracking; Multispectral; PLGA nanoparticles; Quantum-dots; Targeting