Development and characterization of a topical ferrochelatase inhibitor nanoemulsion for choroidal neovascularization therapy

초록

Choroidal neovascularization (CNV) is a hallmark of neovascular age-related macular degeneration (nAMD). We previously identified the heme synthesis enzyme ferrochelatase (FECH) as a promising therapeutic target. This study aimed to develop and characterize topical ophthalmic nanoemulsions (NEs) of a novel FECH inhibitor, SH-17023, for CNV therapy, to avoid the intravitreal injections needed for standard-of-care anti-vascular endothelial growth factor (anti-VEGF) biologics. SH-17023-loaded NEs were prepared by spontaneous emulsification and optimized using D-optimal mixture design-based Quality-by-Design to obtain nanometric globule size (Z(avg)), low polydispersity index (PDI), and highest drug loading capacity (% LC). Therapeutic efficacy was assessed in the laser-induced CNV (L-CNV) mouse model with fundus imaging, optical coherence tomography (OCT), fluorescein angiography, and ex vivo vasculature staining. The optimized formulation was transparent with a globule size of 32.832 +/- 2.125 nm, PDI 0.201 +/- 0.003, spherical morphology, and LC of 7.436 +/- 0.035%. It showed zeta potential of -29.2 +/- 0.45 mV, sustained drug release, and robust accelerated and kinetic stability. Attenuated total reflectance-Fourier transform infrared spectroscopy and X-ray diffraction revealed excellent drug-excipient compatibility. Ex vivo goat cornea permeation of NEs showed significantly higher drug transport (permeability coefficient (K-p) = 0.050 +/- 0.012 h(-1).cm(-2), steady-state flux (J(ss)) = 37.51 +/- 9.29 mu g.h(-1).cm(-2)) than the drug in solution (K-p = 0.002 +/- 0.0004 h(-1).cm(-2) and J(ss) = 1.575 +/- 0.488 mu g.h(-1).cm(-2)) with an enhancement ratio of 23.815. Optimized NEs significantly reduced L-CNV assessed by OCT and ex vivo staining by >45% compared to blank NEs, without ocular irritation or toxicity, indicating their promise for nAMD therapy.

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