title: Sustained intravitreal delivery of connexin43 mimetic peptide by poly(D,L-lactide-co-glycolide) acid micro- and nanoparticles--Closing the gap in retinal ischaemia.
abstract: Recent research has shown that transient block of connexin43 (Cx43) hemichannels by mimetic peptides (MP) after retinal ischaemia inhibits uncontrolled hemichannel opening causing blood-brain barrier permeability and endothelial cell loss, and consequently provides improved retinal ganglion cell (RGC) survival. However, the highly hydrophilic character and potentially poor stability of native peptides can limit efficient delivery in a clinical setting. The present study investigated the ability of intravitreally injected Cx43 MP encapsulated into slow-release poly(lactic-co-glycolic) acid (PLGA) nano-(Nps) and microparticles (Mps) to promote RGC survival in a retinal ischaemia-reperfusion rat model. The particle size was around 113 nm (Nps) and 9 μm (Mps), respectively, with Cx43 MP entrapment efficiencies of 70% (Nps) and 97% (Mps). A triphasic in vitro release profile was observed with an initial burst of surface-bound Cx43 MP followed by slow release due to polymer erosion and further drug release at the point of complete particle breakdown, with 100% release achieved after 63 (Nps) and 112 (Mps) days, respectively. Nps showed the most promising results on both Cx43 down-regulation and RGC rescue in this acute injury model. Mps treatment, on the other hand, was unable to down regulate the initial inflammatory response possibly due to trapping of the bigger particles in the vitreous and the much slower release of Cx43 MP from these particles, but displayed a delayed effect on Cx43 regulation and RGC preservation due to the sustained release.
authors.affiliation: Department of Ophthalmology, University of Auckland, Auckland, New Zealand.
authors.forename: Ying-Shan
authors.initials: YS
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, University of Auckland, Auckland, New Zealand.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Green
authors.affiliation: Department of Ophthalmology, University of Auckland, Auckland, New Zealand.
authors.forename: Kailun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, University of Auckland, Auckland, New Zealand.
authors.forename: Helen V
authors.initials: HV
authors.lastname: Danesh-Meyer
authors.affiliation: Department of Ophthalmology, University of Auckland, Auckland, New Zealand. Electronic address: i.rupenthal@auckland.ac.nz.
authors.forename: Ilva D
authors.initials: ID
authors.lastname: Rupenthal
mesh_terms: D000818:Animals; D018031:Connexin 43 / Q000737:chemistry* / Q000235:genetics; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D015536:Down-Regulation; D004337:Drug Carriers / Q000737:chemistry; D065546:Drug Liberation; D058449:Intravitreal Injections; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D008863:Microspheres; D053758:Nanoparticles; D010316:Particle Size; D057786:Peptidomimetics / Q000008:administration & dosage* / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017208:Rats, Wistar; D012164:Retinal Diseases / Q000188:drug therapy* / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology
chemical_list: D018031:Connexin 43; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D057786:Peptidomimetics; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: Connexin43; Intravitreal injection; Mimetic peptide; Neuroprotection; PLGA nano- and microparticles; Retinal ischaemia