Hou Huiyuan, Huffman Kristyn, Rios Sandy, Freeman William R, Sailor Michael J, Cheng Lingyun
Department of Ophthalmology Jacobs Retina Center at Shiley Eye Institute, University of California San Diego, La Jolla, California, United States.
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States.
Invest Ophthalmol Vis Sci. 2015 Apr;56(4):2755-63. doi: 10.1167/iovs.15-16526.
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.
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.
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).
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.
增殖性玻璃体视网膜病变（PVR）是与视网膜脱离手术和眼外伤相关的视力不良结局的最常见原因。柔红霉素（DNR）在体外增殖抑制方面显示出最强的疗效。然而，由于治疗窗窄和玻璃体半衰期短的限制，临床研究仅显示出轻微效果。
将3毫克载有DNR的颗粒玻璃体内注射到18只色素兔中，并在长达84天的时间内收集玻璃体样本进行分析。37只兔子用于采用预处理设计的兔PVR模型中的剂量递增（1、3、6毫克）安全性和疗效研究。
每1毫克颗粒的DNR负载效率为108.55±12微克。84天的随访未发现任何不良反应。药代动力学分析表明，玻璃体半衰期为29天，在第84天时DNR的最大浓度为178纳克/毫升，最小浓度为29纳克/毫升。在诱导PVR前8至9周给予载有柔红霉素的多孔硅（pSi）颗粒，PVR严重程度评分呈剂量依赖性（Spearman ρ=-0.25，P=0.0005）。对照组中伴有牵拉性视网膜脱离的增殖性玻璃体视网膜病变发生率为88%，低剂量组为63%，中剂量组为14%，高剂量组为0%（ Cochr an-Armitage趋势检验，Z=8.99，ρ=-0.67，P<0.0001）。
载有柔红霉素的pSi颗粒可在玻璃体内安全存留至少3个月。基于pSi的递送将DNR的治疗窗扩大了862倍，并将最低有效浓度降低了175倍。
