Tunable sustained intravitreal drug delivery system for daunorubicin using oxidized porous silicon

Daunorubicin (DNR) is an effective inhibitor of an array of proteins involved in neovascularization, including VEGF and PDGF. These growth factors are directly related to retina scar formation in many devastating retinal diseases. Due to the short vitreous half-life and narrow therapeutic window, ocular application of DNR is limited. It has been shown that a porous silicon (pSi) based delivery system can extend DNR vitreous residence from a few days to 3 months. In this study we investigated the feasibility of altering the pore size of the silicon particles to regulate the payload release. Modulation of the etching parameters allowed control of the nano-pore size from 15 nm to 95 nm. In vitro studies showed that degradation of pSi O(2) increased with increasing pore size and the degradation of pSi O(2) was approximately constant for a given particle type. The degradation of pSi O(2) with 43 nm pores was significantly greater than the other two particles with smaller pores, judged by observed and normalized mean Si concentration of the dissolution samples (44.2±8.9 vs 25.7±5.6 or 21.2±4.2 µg/mL, p<0.0001). In vitro dynamic DNR release revealed that pSiO(2)-CO(2)H:DNR (Porous silicon dioxide with covalent loading of daunorubicin) with large pores (43 nm) yielded a significantly higher DNR level than particles with 15 or 26 nm pores (13.5±6.9 ng/mL vs. 2.3±1.6 ng/mL and 1.1±0.9 ng/mL, p<0.0001). After two months of in vitro dynamic release, 54% of the pSiO(2)-CO(2)H:DNR particles still remained in the dissolution chamber by weight. In vivo drug release study demonstrated that free DNR in vitreous at post-injection day 14 was 66.52 ng/mL for 95 nm pore size pSiO(2)-CO(2)H:DNR, 10.76 ng/mL for 43 nm pSi O(2)-CO(2) H:DNR, and only 1.05 ng/mL for 15 nm pSi O(2)-CO(2) H:DNR. Pore expansion from 15 nm to 95 nm led to a 63 folds increase of DNR release (p<0.0001) and a direct correlation between the pore size and the drug levels in the living eye vitreous was confirmed. The present study demonstrates the feasibility of regulating DNR release from pSi O(2) covalently loaded with DNR by engineering the nano-pore size of pSi

Porous silicon oxide–PLGA composite microspheres for sustained ocular delivery of daunorubicin

A water-soluble anthracycline antibiotic drug (daunorubicin, DNR) was loaded into oxidized porous silicon (pSiO(2)) microparticles and then encapsulated with a layer of polymer (poly lactide-co-glycolide, PLGA) to investigate their synergistic effects in control of DNR release. Similarly fabricated PLGA-DNR microspheres without pSiO(2), and pSiO(2) microparticles without PLGA were used as control particles. The composite microparticles synthesized by a solid-in-oil-in-water (S/O/W) emulsion method have mean diameters of 52.33±16.37 μm for PLGA-pSiO(2)_21/40-DNR and the mean diameter of 49.31±8.87 μm for PLGA-pSiO(2)_6/20-DNR. The mean size, 26.00±8 μm, of PLGA-DNR was significantly smaller, compared with the other two (p<0.0001). Optical microscopy revealed that PLGA-pSiO(2)-DNR microsphere contained multiple pSiO(2) particles. In vitro release experiments determined that control PLGA-DNR microspheres completely released DNR within 38 days and control pSiO2-DNR microparticles (with no PLGA coating) released DNR within 14 days, while the PLGA-pSiO(2)-DNR microspheres released DNR for 74 days. Temporal release profiles of DNR from PLGA-pSiO(2) composite particles indicated that both PLGA and pSiO2 contribute to the sustained release of the payload. The PLGA-pSiO(2) composite displayed a more constant rate of DNR release than the pSiO(2) control formulation, and it displayed a significantly slower release of DNR than either the PLGA or pSiO(2) formulations. We conclude that this system may be useful in managing unwanted ocular proliferation when formulated with anti-proliferation compounds such as DNR

Late-Onset Retinal Findings and Complications in Untreated Retinopathy of Prematurity

PURPOSE: To investigate late retinal findings and complications of eyes with a history of retinopathy of prematurity (ROP) that did not meet treatment criteria and did not receive treatment during infancy. DESIGN: Retrospective, nonconsecutive, noncomparative, multicenter case series. PARTICIPANTS: Three hundred sixty-three eyes of 186 patients. METHODS: Data were requested from multiple providers on premature patients with a history of ROP and no treatment during infancy who demonstrated late retinal findings or complications and included age, gender, gestational age and weight, zone and stage at infancy, visual acuity, current retina vascularization status, vitreous character, presence of peripheral retinal findings such as lattice retinal tears and detachments (RDs), retinoschisis, and fluorescein findings. MAIN OUTCOME MEASURES: Rate of RDs and factors conferring a higher risk of RDs. RESULTS: The average age was 34.5 years (range, 7-76 years), average gestational age was 26.6 weeks (range, 23-34 weeks), and average birth weight was 875 g (range, 425-1590 g). Findings included lattice in 196 eyes (54.0%), atrophic holes in 126 eyes (34.7%), retinal tears in 111 eyes (30.6%), RDs in 140 eyes (38.6 %), tractional retinoschisis in 44 eyes (11.9%), and visible vitreous condensation ridge-like interface in 112 eyes (30.5%). Fluorescein angiography (FA) was performed in 113 eyes, of which 59 eyes (52.2%) showed leakage and 16 eyes (14.2%) showed neovascularization. Incomplete vascularization posterior to zone 3 was common (71.6% of eyes). Retinal detachments were more likely in patients with a gestational age of 29 weeks or less (P \u3c 0.05) and in eyes with furthest vascularization to posterior zone 2 eyes compared with zone 3 eyes (P = 0.009). CONCLUSIONS: Eyes with ROP not meeting the treatment threshold during infancy showed various late retinal findings and complications, of which RDs were the most concerning. Complications were seen in all age groups, including patients born after the Early Treatment for Retinopathy of Prematurity Study. Contributing factors to RDs included atrophic holes within peripheral avascular retina, visible vitreous condensation ridge-like interface with residual traction, and premature vitreous syneresis. We recommend regular examinations and consideration of ultra-widefield FA examinations. Prospective studies are needed to explore the frequency of complications and benefit of prophylactic treatment and if eyes treated with anti-vascular endothelial growth factor therapy are at risk of similar findings and complications