Abstract
Purpose :
Choroidal neovascularization (CNV) is a key pathobiological feature of neovascular age-related macular degeneration (nAMD). Current anti-vascular endothelial growth factor (VEGF) treatments are poorly effective in a significant fraction of patients and must be intravitreally injected frequently. We previously identified the heme synthesis enzyme ferrochelatase (FECH) as a promising alternative therapeutic target for CNV. FECH can be inhibited by a metabolite of griseofulvin, an antifungal drug. We developed a long-acting microparticle formulation for sustained delivery of griseofulvin and showed release and antiangiogenic activity over one month in vitro. Here, we tested this formulation for therapeutic effects in vivo.
Methods :
Griseofulvin was incorporated in poly(lactic-co-glycolide) (PLGA) microparticles along with 2% Mg(OH)2. Therapeutic efficacy was assessed in the murine laser-induced choroidal neovascularization model (L-CNV). Treatments included vehicle, “empty” microparticles, griseofulvin microparticles, and equimolar free griseofulvin. Each was given by intravitreal injection at 28 or 14 days prior to, or at time of induction of L-CNV, to assess duration of therapeutic effect. Fundus imaging, optical coherence tomography, fluorescein angiography, and ex vivo agglutinin staining were performed to evaluate CNV.
Results :
In vivo imaging of L-CNV in the three time cohorts suggested a reduction in lesion volume by griseofulvin microparticles, with effect still seen even 42 days after injection (28 days prior to laser plus 14 days after) without obvious signs of toxicity. Confocal image analysis showed that griseofulvin microparticles significantly reduced lesion volume at all time points (but free griseofulvin was effective only when it was given at the time of laser), indicating that the microparticles provided a sustained effect in reducing CNV volume, unlike free griseofulvin. Lesions in “empty” microparticle-treated eyes did not differ from those in vehicle-treated eyes.
Conclusions :
Griseofulvin-loaded PLGA microparticles not only show sustained release of drug over a multi-week period but are also therapeutically effective against L-CNV at least 6 weeks after intravitreal injection. With further optimization, griseofulvin microparticles may offer an appealing adjunct or alternative to anti-VEGF therapies.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.