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Lianwang Guo, Lei Zhao, Guojun Chen, Jun Li, Yingmei Fu, Timur Mavlyutov, Annie Yao, Robert W Nickells, Shaoqin Gong; A Retinal Ganglion Cell Targting and Protecting Intraocular Drug Delivery System Using Unimolecular Nanoparticles. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4109. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
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 pH 7.4. We then intraocularly co-injected unimNPs in mice 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 14 days, 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.
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.*Lei Zhao and Guojun Chen contributed equally to this work; Lian-Wang Guo and Shaoqin Gong are co-coresponding authors.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
Schematic: RGC-targeted nanoparticles accumulate at the RGC layer
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