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

Abstract

Promoting nerve regeneration involves not only modulating the post-injury 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.

Self-Assembled Tat Nanofibers as Effective Drug Carrier and Transporter

“…Coumarin-6 was selected as a model drug because of its hydrophobicity, strong green fluorescence, and wide application in the in vitro and in vivo evaluation of drug delivery system. 82,83 Flutax-2 was also employed because of its similarity to PTX in the structure, 64,65 and previous successful application as a model drug in drug delivery. 66–68 Coumarin-6 or Flutax-2 and qC 8 -Tat were dissolved in HFIP at a ratio of 1 to 10 (mol/mol), and dried using rotary evaporator under vacuum to give a thin film.…”

Use of biomaterials for sustained delivery of anti-VEGF to treat retinal diseases

“…One of the challenges associated with PLGA-based NP/MP systems is creating a particle with an ideal size that balances the above-mentioned characteristics. Particle size controls the rate at which the encapsulated drug is released [66]. In general, with smaller particles, less drug can be loaded.…”

Nanotechnology—novel therapeutics for CNS disorders

“…To achieve similar local delivery in a minimally invasive manner, nanospheres composed of poly(lactic-co-glycolic acid)—also known as PLGA—were loaded with the EGFR kinase inhibitor AG1478 and delivered via the eye to rats after an optic nerve crush injury. 68 AG1478-containing nanospheres potentiated axon regeneration beyond the site of injury at 4 weeks. Importantly, this result was not achieved when the AG1478 was encapsulated in PLGA microspheres, suggesting that nanoscale encapsulation of the drug directly contributed to its efficacy, perhaps owing to the constant rate of release of the drug from nanospheres, as opposed to an initial burst then decreased release as observed with microspheres.…”

“…Importantly, this result was not achieved when the AG1478 was encapsulated in PLGA microspheres, suggesting that nanoscale encapsulation of the drug directly contributed to its efficacy, perhaps owing to the constant rate of release of the drug from nanospheres, as opposed to an initial burst then decreased release as observed with microspheres. 68 …”