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

Proliferative vitreoretinopathy (PVR) is the most common cause of poor visual outcomes in association with retinal detachment (RD) surgery and ocular trauma despite extensive advances in vitreoretinal surgical technique.1 Direct delivery of drug to the posterior segment by intravitreal injection or intravitreal implant has demonstrated benefits in treating both vitreoretinal diseases2 and experimental PVR models.1,3 It has been suggested that PVR can be prevented by inhibiting cell growth at the cell proliferation stage, which can last for approximately 6 weeks.4 Although various antiproliferative agents could be candidates for the treatment of PVR, their half-lives in the vitreous are too short (e.g., daunorubicin [DNR], 131 minutes; and 5-fluorouracil, 20 minutes).5–,7 Of those anti-PVR compounds investigated, DNR has shown the strongest efficacy.8 Owing to the narrow therapeutic window and short biological half-life in the vitreous cavity, intravitreal slow-release systems for extended drug delivery are necessary to maintain therapeutic drug levels at the disease site for longer. To meet this need, various delivery systems have been explored, such as liposomes, nanoparticles, and implantable devices. For liposomes, vitreous clarity decreases with increasing dose.9 Intravitreal injection of nanoparticles can trigger a macrophage reaction and associated vitritis.10,11 Implants involve an invasive procedure that increases the risk of developing RD, lens damage, and vitreous hemorrhage.11 We have been focusing on developing a long-lasting intravitreal drug delivery system.1,12,13 Recently, we have characterized a porous silicon (pSi)–based intravitreal drug delivery system.14,15 In these studies, we demonstrate that DNR can be covalently loaded into oxidized pSi microparticles and safely reside in rabbit vitreous for 2 to 3 months with good ocular tolerability.14 In the initial DNR loading and release study, the level of free DNR in the rabbit vitreous after 2 weeks is very low. To overcome this limitation, we engineered the pore size of the pSi and enhanced the release rate at 2 weeks from 1.05 to 66.52 ng/mL.15 Although DNR has been used for clinical and experimental treatment of PVR,7 simultaneous pharmacodynamics study with a sustained delivery system is very rare. An intravitreal bolus injection of 5 μg free DNR is the highest tolerated dose reported.16 The therapeutic window following such a single intravitreal injection is so narrow that the therapeutic concentration of the drug can be maintained for only 4 hours.17 The current study's aim was to evaluate a sustained pSi-based intravitreal DNR delivery system in a PVR rabbit eye model. We hypothesize that the minimum therapeutic concentration for a drug becomes lower when the time of drug exposure to the target tissue increases, which could be achieved by using a sustained-release system. Previous reports also suggest that inhibitory drug concentration decreases with increasing time of contact between drug and proliferating cells in vitro.18