title: An intraocular drug delivery system using targeted nanocarriers attenuates retinal ganglion cell degeneration.
abstract: Glaucoma is a common blinding disease characterized by loss of retinal ganglion cells (RGCs). To date, there is no clinically available treatment directly targeting RGCs. We aim to develop an RGC-targeted intraocular drug delivery system using unimolecular micelle nanoparticles (unimNPs) to prevent RGC loss. The unimNPs were formed by single/individual multi-arm star amphiphilic block copolymer poly(amidoamine)-polyvalerolactone-poly(ethylene glycol) (PAMAM-PVL-PEG). While the hydrophobic PAMAM-PVL core can encapsulate hydrophobic drugs, the hydrophilic PEG shell provides excellent water dispersity. We conjugated unimNPs with the cholera toxin B domain (CTB) for RGC-targeting and with Cy5.5 for unimNP-tracing. To exploit RGC-protective sigma-1 receptor (S1R), we loaded unimNPs with an endogenous S1R agonist dehydroepiandrosterone (DHEA) as an FDA-approved model drug. These unimNPs produced a steady DHEA release in vitro for over two months at pH7.4. We then co-injected (mice, intraocular) unimNPs with the glutamate analog N-methyl-d-aspartate (NMDA), which is excito-toxic and induces RGC death. The CTB-conjugated unimNPs (i.e., targeted NPs) accumulated at the RGC layer and effectively preserved RGCs at least for 14days, whereas the unimNPs without CTB (i.e., non-targeted NPs) showed neither accumulation at nor protection of NMDA-treated RGCs. Consistent with S1R functions, targeted NPs relative to non-targeted NPs showed markedly better inhibitory effects on apoptosis and oxidative/inflammatory stresses in the RGC layer. Hence, the DHEA-loaded, CTB-conjugated unimNPs represent an RGC/S1R dual-targeted nanoplatform that generates an efficacious template for further development of a sustainable intraocular drug delivery system to protect RGCs, which may be applicable to treatments directed at glaucomatous pathology.
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Materials Science and Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
authors.forename: Guojun
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA; Department of Ophthalmology, The First Hospital of China Medical University, Shenyang 110001, China.; Department of Ophthalmology, The 3rd People's Hospital of Dalian, Dalian 116033, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 600 Wanping Nan Road, Shanghai 200030, China.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA.
authors.forename: Timur A
authors.initials: TA
authors.lastname: Mavlyutov
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Yao
authors.affiliation: Department of Ophthalmology and Vision Sciences, University of Wisconsin-Madison, 1300 University Ave, Madison, WI 53706, USA; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Nickells
authors.affiliation: Department of Materials Science and Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA. Electronic address: shaoqingong@wisc.edu.
authors.forename: Shaoqin
authors.initials: S
authors.lastname: Gong
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA. Electronic address: guo@surgery.wisc.edu.
authors.forename: Lian-Wang
authors.initials: LW
authors.lastname: Guo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002772:Cholera Toxin / Q000737:chemistry / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000008:administration & dosage* / Q000494:pharmacology; D050091:Dendrimers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D057927:Hydrophobic and Hydrophilic Interactions; D058449:Intravitreal Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000097605:Sigma-1 Receptor
chemical_list: D002772:Cholera Toxin; D003687:Dehydroepiandrosterone; D050091:Dendrimers; D008823:Micelles; D011092:Polyethylene Glycols; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C522249:PEG-PAMAM
keywords: Cholera toxin B domain; Excitotoxicity; Ganglion cell targeting; Retina; Sigma-1 receptor; Targeted drug delivery; Unimolecular micelles