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5 years ago

Memantine-Loaded PEGylated Biodegradable Nanoparticles for the Treatment of Glaucoma

Memantine-Loaded PEGylated Biodegradable Nanoparticles for the Treatment of Glaucoma
Li Guo, Maria Luisa García, Maria Francesca Cordeiro, Nivedita Ravindran, Ana Cristina Calpena, Marta Espina, Miren Ettcheto, Amelia Maria Silva, Elena Sánchez-López, Eliana Maria Barbosa Souto, Antonio Camins, Benjamin Michael Davis, Maria Antonia Egea
Glaucoma is a multifactorial neurodegenerative disease associated with retinal ganglion cells (RGC) loss. Increasing reports of similarities in glaucoma and other neurodegenerative conditions have led to speculation that therapies for brain neurodegenerative disorders may also have potential as glaucoma therapies. Memantine is an N-methyl-d-aspartate (NMDA) antagonist approved for Alzheimer's disease treatment. Glutamate-induced excitotoxicity is implicated in glaucoma and NMDA receptor antagonism is advocated as a potential strategy for RGC preservation. This study describes the development of a topical formulation of memantine-loaded PLGA-PEG nanoparticles (MEM-NP) and investigates the efficacy of this formulation using a well-established glaucoma model. MEM-NPs <200 nm in diameter and incorporating 4 mg mL−1 of memantine were prepared with 0.35 mg mL−1 localized to the aqueous interior. In vitro assessment indicated sustained release from MEM-NPs and ex vivo ocular permeation studies demonstrated enhanced delivery. MEM-NPs were additionally found to be well tolerated in vitro (human retinoblastoma cells) and in vivo (Draize test). Finally, when applied topically in a rodent model of ocular hypertension for three weeks, MEM-NP eye drops were found to significantly (p < 0.0001) reduce RGC loss. These results suggest that topical MEM-NP is safe, well tolerated, and, most promisingly, neuroprotective in an experimental glaucoma model. Memantine, a clinically used neuroprotectant, significantly prolongs retinal ganglion cell survival in a well-established rodent glaucoma model after daily topical instillation when formulated as PLGA-PEG nanoparticles (MEM-NP). MEM-NPs are prepared using the double emulsion method from which memantine exhibits a two-phase release: a rapid release fraction from the lipophilic phase and a slow fraction from the entrapped aqueous phase.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/smll.201701808

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