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Journal of controlled release : official journal of the Controlled Release Society v.247, 2017년, pp.153 - 166   SCI SCIE
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An intraocular drug delivery system using targeted nanocarriers attenuates retinal ganglion cell degeneration

Zhao, Lei (Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA ); Chen, Guojun (Department of Materials Science and Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA ); Li, Jun (Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA ); Fu, Yingmei (Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA ); Mavlyutov, Timur A. (Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA ); Yao, Annie (Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA ); Nickells, Robert W. (Department of Ophthalmology and Vision Sciences, University of Wisconsin-Madison, 1300 University Ave, Madison, WI 53706, U ); Gong, Shaoqin ( ); Guo, Lian-Wang ( );
  • 초록  

    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.


    Graphical abstract Schematic: Intraocular drug delivery system using nanoparticles targeting retinal ganglion cells (RGCs). CTB: non-toxic cholera toxin B domain. unimNP: unimolecular micelle nanoparticle. [DISPLAY OMISSION]


  • 주제어

    Targeted drug delivery .   Unimolecular micelles .   Retina .   Ganglion cell targeting .   Excitotoxicity .   Sigma-1 receptor .   Cholera toxin B domain.  

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