title: Noninvasive targeting delivery and in vivo magnetic resonance tracking method for live apoptotic cells in cerebral ischemia with functional Fe2O3 magnetic nanoparticles.
abstract: BACKGROUND
  Apoptotic neuronal death is known as programmed cell death. Inhibition of this progression might contribute to a new treatment strategy. However, methods for in vivo detection of live apoptotic cells are in need to be developed and established.
  
  
  OBJECTIVE
  The purpose of this study is to develop a new method for in vivo brain imaging for live apoptotic lesions using magnetic resonance imaging (MRI). We focused on the specific accumulation of our recently developed functional magnetic nanoparticles (FMNPs) into apoptotic cells using a rat cerebral ischemia model. Sulphorhodamine B, fluorescent dye was linked to valylalanylaspartic acid fluoromethyl ketone as a pan-caspase inhibitor to form SR-FLIVO. SR-FLIVO was bound with FMNPs to develop SR-FLIVO-FMNP probe. Ischemic rat brains were scanned by 7T MRI before and after intravenous injection of SR-FLIVO-FMNP and the distribution was evaluated by subtraction images of T2* colored mapping. SR-FLIVO, intracellular FMNPs, and T2* reduction area were histologically analyzed. The distribution of SR-FLIVO-FMNP was evaluated by subtracting the T2* signal images and was significantly correlated with the histological findings by TUNEL staining.
  
  
  RESULTS
  Our experimental results revealed several findings where our newly developed probe SR-FLIVO-FMNP was intravenously administered into ischemic rats and FLIVO expression was tracked and found in apoptotic cells in rat brains after cerebral ischemia. A remarkable T2* reduction within the ischemic lesion was recorded using MRI based SR-FLIVO-FMNP probe as a contrasting agent due to the specific probe accumulation in apoptotic cells whereas, no observation of T2* reduction within the non-ischemic lesion due to no probe accumulation in non-apoptotic cells. Histological analysis based on the correlation between FLIVO and TUNEL staining showed that almost all FLIVO-positive cells were positive for TUNEL staining. These findings suggest the possibility for establishment of in vivo targeting delivery methods to live apoptotic cells based on conjugation of magnetic and fluorescent dual functional probes.
  
  
  CONCLUSIONS
  A newly developed probe SR-FLIVO-FMNP might be considered as a useful probe for in vivo apoptotic detection, and FMNPs might be a strong platform for noninvasive imaging and targeting delivery.
authors.affiliation: Department of Neurosurgery, Aomori Prefectural Central Hospital, 2-1-1 Higashitsukurimichi, Aomori, 030-8553, Japan. satsushi2002@yahoo.co.jp.|Department of Neurosurgery, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. satsushi2002@yahoo.co.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Saito
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. moataz_mekawy@yahoo.com.|National Institute for Materials Science, 1-Chome-2-1 Sengen, Tsukuba, Ibaraki Prefecture, 305-0047, Japan. moataz_mekawy@yahoo.com.
authors.forename: Moataz M
authors.initials: MM
authors.lastname: Mekawy
authors.affiliation: Department of Functional Brain Imaging, Institute of Development, Aging and Cancer, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Sumiyoshi
authors.affiliation: Department of Functional Brain Imaging, Institute of Development, Aging and Cancer, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
authors.forename: Jorge J
authors.initials: JJ
authors.lastname: Riera
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of Functional Brain Imaging, Institute of Development, Aging and Cancer, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Kawashima
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology*; D003287:Contrast Media / Q000008:administration & dosage; D005290:Ferric Compounds / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging / Q000379:methods; D058185:Magnetite Nanoparticles / Q000008:administration & dosage*; D008297:Male; D051381:Rats; D013194:Staining and Labeling / Q000379:methods
chemical_list: D003287:Contrast Media; D005290:Ferric Compounds; D058185:Magnetite Nanoparticles
keywords: Apoptosis; Fluorescently-labeled poly-caspase inhibitor (SR-FLIVO); Functionalized magnetic nanoparticles (FMNPs); Magnetic resonance imaging (MRI)