Development and characterization of a topical ferrochelatase inhibitor nanoemulsion for choroidal neovascularization therapy.
Topical nanoemulsions of the ferrochelatase inhibitor SH-17023 reduced choroidal neovascularization by over 45% in a mouse model, suggesting a potential non-invasive treatment option for age-related macular degeneration.
Where it sits
this study against the rest of the kisspeptin (kp-10) corpusSummary and findings
This study focused on developing and characterizing a topical nanoemulsion of a ferrochelatase inhibitor, SH-17023, for treating choroidal neovascularization (CNV) in a mouse model. The optimized formulation demonstrated a globule size of 32.832 ± 2.125 nm and a drug loading capacity of 7.436 ± 0.035%. The therapeutic efficacy showed a reduction in CNV by over 45% compared to blank nanoemulsions.
Abstract
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<sub>avg</sub>), 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<sub>p</sub>) = 0.050 ± 0.012 h<sup>-1</sup>.cm<sup>-2</sup>, steady-state flux (J<sub>ss</sub>) = 37.51 ± 9.29 μg.h<sup>-1</sup>.cm<sup>-2</sup>) than the drug in solution (K<sub>p</sub> = 0.002 ± 0.0004 h<sup>-1</sup>.cm<sup>-2</sup> and J<sub>ss</sub> = 1.575 ± 0.488 μg.h<sup>-1</sup>.cm<sup>-2</sup>) 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.
Background
Choroidal neovascularization (CNV) is a significant feature of neovascular age-related macular degeneration (nAMD). Previous research has identified ferrochelatase (FECH) as a potential target for therapeutic intervention. This study is relevant as it explores a novel topical approach to deliver a FECH inhibitor, potentially reducing the need for invasive treatments like intravitreal injections.
Methods
The study involved the development of topical ophthalmic nanoemulsions (NEs) of the FECH inhibitor SH-17023. The formulation was optimized using D-optimal mixture design, focusing on achieving a small globule size, low polydispersity index, and high drug loading capacity. The therapeutic efficacy was assessed in a laser-induced CNV mouse model using various imaging techniques.
Results
The optimized nanoemulsion showed a globule size of 32.832 ± 2.125 nm and a polydispersity index of 0.201 ± 0.003. The loading capacity was 7.436 ± 0.035%. The permeability coefficient for the NEs was 0.050 ± 0.012 h^-1.cm^-2, with a steady-state flux of 37.51 ± 9.29 μg.h^-1.cm^-2. The NEs significantly reduced L-CNV by >45% compared to blank NEs.
Interpretation
The findings suggest that the developed nanoemulsions may enhance drug delivery compared to the drug in solution, as indicated by the significant differences in permeability and flux. However, the clinical significance of a >45% reduction in CNV needs to be evaluated in human studies. The study's limitations, including reliance on a mouse model and lack of long-term data, may affect the generalizability of the results.
Key findings
- Globule size of 32.832 ± 2.125 nm, PDI 0.201 ± 0.003.
- Loading capacity of 7.436 ± 0.035%.
- Permeability coefficient (Kp) = 0.050 ± 0.012 h^-1.cm^-2.
- Steady-state flux (Jss) = 37.51 ± 9.29 μg.h^-1.cm^-2.
- Kp for drug in solution = 0.002 ± 0.0004 h^-1.cm^-2.
- Jss for drug in solution = 1.575 ± 0.488 μg.h^-1.cm^-2.
Limitations
- Primarily uses a mouse model, which may not fully translate to human conditions.
- No long-term follow-up data were provided.
- Small sample size in animal testing.
- Lack of clinical data to support findings.