title: Enabling dual cellular destinations of polymeric nanoparticles for treatment following partial injury to the central nervous system.
abstract: Following neurotrauma, oxidative stress is spread via the astrocytic syncytium and is associated with increased aquaporin 4 (AQP4), inflammatory cell infiltration, loss of neurons and glia and functional deficits. Herein we evaluate multimodal polymeric nanoparticles functionalized with an antibody to an extracellular epitope of AQP4, for targeted delivery of an anti-oxidant as a therapeutic strategy following partial optic nerve transection. Using fluorescence microscopy, spectrophotometry, correlative nanoscale secondary ion mass spectrometry (NanoSIMS) and transmission electron microscopy, in vitro and in vivo, we demonstrate that functionalized nanoparticles are coated with serum proteins such as albumin and enter both macrophages and astrocytes when administered to the site of a partial optic nerve transection in rat. Antibody functionalized nanoparticles synthesized to deliver the antioxidant resveratrol are effective in reducing oxidative damage to DNA, AQP4 immunoreactivity and preserving visual function. Non-functionalized nanoparticles evade macrophages more effectively and are found more diffusely, including in astrocytes, however they do not preserve the optic nerve from oxidative damage or functional loss following injury. Our study highlights the need to comprehensively investigate nanoparticle location, interactions and effects, both in vitro and in vivo, in order to fully understand functional outcomes.
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia; Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia.
authors.forename: I
authors.initials: I
authors.lastname: Lozić
authors.affiliation: Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia.
authors.forename: R V
authors.initials: RV
authors.lastname: Hartz
authors.affiliation: Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia.
authors.forename: C A
authors.initials: CA
authors.lastname: Bartlett
authors.affiliation: Centre for Microscopy, Characterisation and Analysis, The University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Shaw
authors.affiliation: Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Archer
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia; Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia.
authors.forename: P S R
authors.initials: PS
authors.lastname: Naidu
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia; Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia.
authors.forename: N M
authors.initials: NM
authors.lastname: Smith
authors.affiliation: Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia.
authors.forename: S A
authors.initials: SA
authors.lastname: Dunlop
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia.
authors.forename: K Swaminathan
authors.initials: KS
authors.lastname: Iyer
authors.affiliation: Centre for Microscopy, Characterisation and Analysis, The University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia.
authors.forename: M R
authors.initials: MR
authors.lastname: Kilburn
authors.affiliation: Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia. Electronic address: lindy.fitzgerald@uwa.edu.au.
authors.forename: M
authors.initials: M
authors.lastname: Fitzgerald
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics; D002493:Central Nervous System Diseases / Q000188:drug therapy*; D005260:Female; D053758:Nanoparticles; D011108:Polymers / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats
chemical_list: C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D011108:Polymers
keywords: Central nervous system injury; Macrophages; Nanoscale secondary ion mass spectroscopy (NanoSIMS); Oxidative stress and aquaporin 4; Polymer nanoparticles; Targeted drug delivery of antioxidants