A Novel Approach of Daunorubicin Application on Formation of Proliferative Retinopathy Using a Porous Silicon Controlled Delivery System: Pharmacodynamics.

PURPOSE: Proliferative vitreoretinopathy (PVR) is the most common cause of poor visual outcomes in association with retinal detachment surgeries and ocular trauma. Daunorubicin (DNR) has shown the strongest efficacy in proliferation inhibition in vitro. However, clinical studies have shown only mild effect owing to limitations of narrow therapeutic window and short vitreous half-life.

METHODS

Three milligrams of DNR-loaded particles were intravitreally injected into 18 pigmented rabbits, and vitreous samples were collected up to 84 days for analysis. Thirty-seven rabbits were used for a dose-escalation (1, 3, 6 mg) safety and efficacy study in a rabbit PVR model using a pretreatment design.

RESULTS

Loading efficiency of DNR was 108.55 ± 12 μg per 1 mg particles. Eighty-four days of follow-up did not reveal any adverse reaction. Pharmacokinetic analysis demonstrated a vitreous half-life of 29 days with a maximum DNR concentration of 178 ng/mL and a minimum concentration of 29 ng/mL at day 84. Daunorubicin-loaded porous silicon (pSi) particles were dosed 8 to 9 weeks before PVR induction, and PVR severity score was dose dependent (Spearman ρ = -0.25, P = 0.0005). Proliferative vitreoretinopathy with tractional retinal detachment was 88% in the control group, 63% in the low-dose group, 14% in the medium-dose group, and 0% in the high-dose group (Cochran-Armitage Trend Test, Z = 8.99, ρ = -0.67, P < 0.0001).

CONCLUSIONS

Daunorubicin-loaded pSi particles can safely reside in the vitreous for at least 3 months. The pSi-based delivery expanded the therapeutic window of DNR by a factor of 862 and drove down the minimum effective concentration by a factor of 175.