title: Biodegradable gelatin microspheres enhance the neuroprotective potency of osteopontin via quick and sustained release in the post-ischemic brain.
abstract: Gelatin microspheres (GMSs) are widely used as drug carriers owing to their excellent biocompatibilities and toxicologically safe degradation products. The drug release profile is easily tailored by controlling the cross-linking density and surface-to-volume ratio, i.e. size, of the GMS. In this study, we employed GMSs which are 25 μm in diameter and cross-linked with 0.03125% glutaraldehyde, to enable rapid initial and a subsequent sustained release. Therapeutic potency of human recombinant osteopontin (rhOPN) with or without encapsulation into GMSs was investigated after administrating them to rat stroke model (Sprague-Dawley; middle cerebral artery occlusion, MCAO). The administration of rhOPN/GMS (100 ng/100 μg) at 1h post-MCAO reduced the mean infarct volume by 81.8% of that of the untreated MCAO control and extended the therapeutic window at least to 12h post-MCAO, demonstrating a markedly enhanced therapeutic potency for the use of OPN in the post-ischemic brain. Scanning electron microscopy micrographs revealed that GMSs maintained the three-dimensional shape for more than 5 days in normal brain but were degraded rapidly in the post-ischemic brain, presumably due to high levels of gelatinase induction. After encapsulation with GMS, the duration of OPN release was markedly extended; from the period of 2 days to 5 days in normal brain, and from 2 days to 4 days in the post-ischemic brain; these encompass the critical period for recovery processes, such as vascularization, and controlling inflammation. Together, these results indicate that GMS-mediated drug delivery has huge potential when it was used in the hyperacute period in the post-ischemic brain.
authors.affiliation: Department of Anatomy, Inha University School of Medicine, Inchon, Republic of Korea; Inha Research Institute for Medical Sciences, Inha University School of Medicine, Inchon, Republic of Korea.
authors.forename: Yinchuan
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Electrical and Computer Engineering, University of Illinois, Urbana, IL 61801, USA.
authors.forename: In-Yong
authors.initials: IY
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Inha University School of Medicine, Inchon, Republic of Korea; Inha Research Institute for Medical Sciences, Inha University School of Medicine, Inchon, Republic of Korea.
authors.forename: Il-Doo
authors.initials: ID
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Inha University School of Medicine, Inchon, Republic of Korea; Inha Research Institute for Medical Sciences, Inha University School of Medicine, Inchon, Republic of Korea.
authors.forename: Hye-Kyung
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Department of Brain and Cognitive Sciences, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Jin-Young
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Brain and Cognitive Sciences, Ewha Womans University, Seoul, Republic of Korea; Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Pyung-Lim
authors.initials: PL
authors.lastname: Han
authors.affiliation: Department of Electrical and Computer Engineering, University of Illinois, Urbana, IL 61801, USA; Micro and Nanotechnology Laboratory, University of Illinois, Urbana, IL 61801, USA; Department of Bioengineering, University of Illinois, Urbana, IL 61801, USA; Department of Material Science and Engineering, University of Illinois, Urbana, IL 61801, USA; University of Illinois Neuroscience Program, Urbana, IL 61801, USA.
authors.forename: Kyekyoon Kevin
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Department of Electrical and Computer Engineering, University of Illinois, Urbana, IL 61801, USA; Micro and Nanotechnology Laboratory, University of Illinois, Urbana, IL 61801, USA. Electronic address: hyungsoo@illinois.edu.
authors.forename: Hyungsoo
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Anatomy, Inha University School of Medicine, Inchon, Republic of Korea; Inha Research Institute for Medical Sciences, Inha University School of Medicine, Inchon, Republic of Korea. Electronic address: jklee@inha.ac.kr.
authors.forename: Ja-Kyeong
authors.initials: JK
authors.lastname: Lee
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005780:Gelatin / Q000008:administration & dosage*; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D053495:Osteopontin / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats
chemical_list: D001672:Biocompatible Materials; D018696:Neuroprotective Agents; D053495:Osteopontin; D005780:Gelatin
keywords: Cross-linking; Gelatin microsphere; MCAO; Neuroprotection; Osteopontin