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Promoting nerve regeneration involves not only modulating the postinjury microenvironment but also ensuring survival of injured neurons. Sustained delivery of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been shown to promote the survival and regeneration of neurons, but systemic administration is associated with significant side effects. We fabricated poly(lactic-co-glycolic acid) (PLGA) microspheres and nanospheres containing the EGFR TKI 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) for intravitreal administration in a rat optic nerve crush injury model. Upon administration, less backflow from the injection site was observed when injecting nanospheres compared to microspheres. Two weeks after intravitreal delivery, we were able to detect microspheres and nanospheres in the vitreous using coumarin-6 fluorescence, but fewer microspheres were observed compared to the nanospheres. At four weeks only nanospheres could be detected. AG1478 microspheres and nanospheres promoted optic nerve regeneration at two weeks, and at four weeks evidence of regeneration was found only in the nanosphere-injected animals. This observation could be attributed to the ease of administration of the nanospheres versus the microspheres, which in turn led to an increased amount of spheres delivered to the vitreous in the nanosphere group compared to the microsphere group. These data provide evidence for use of PLGA nanospheres to deliver AG1478 intravitreally in a single administration to promote nerve regeneration.

Nanospheres Delivering the EGFR TKI AG1478 Promote Optic Nerve Regeneration: The Role of Size for Intraocular Drug Delivery