Xiao Ying, Choi Kyung Seek, Warther David, Huffman Kristyn, Landeros Stephanie, 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, CA, USA.
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA.
Drug Deliv. 2020 Dec;27(1):1461-1473. doi: 10.1080/10717544.2020.1833382.
Proliferative vitreoretinopathy (PVR) is a significant threat for vision recovery from retinal detachment or ocular trauma. Currently, no approved pharmacological intervention to prevent PVR. Daunorubicin (DNR) and dexamethasone (DEX) were sequentially loaded into oxidized porous silicon (pSiO) particles by covalent conjugation. The DNR + DEX-loaded particles, and control particles loaded with DNR only and DEX only were incubated with RPE-populated collagen for daily gel surface quantitation. Toxicity was monitored by ophthalmic examinations and histological evaluation 21 days after injection. At 3rd week following intravitreal injection, a localized retinal detachment (RD) was created by subretinal injection of Healon in all pretreated eyes in addition to 3 non-interventional control eyes. 10 µg of bromodeoxyuridine (BrdU) was injected into the vitreous 4 h before sacrifice on day 3 after RD induction. Retinal sections were stained for glial fibrillary green protein (GFAP) and BrdU to identify activated glial cells and retinal cell proliferation. The studies demonstrated that all three pSiO particle types were well tolerated in vivo. DNR alone and DNR + DEX combination formulations demonstrated equally strong suppression on gel contraction (least square mean area of the gel: control = 1.71 vs. 30DNR = 1.85 or 30/40Dual = 1.83, < .05). Eyes pretreated with pSiO-DNR + DEX exhibited the least GFAP activation (least square mean intensity mm: Dual = 4.03, DNR = 7.76, Dex = 16.23, control = 29.11, < .05) and BrdU expression (Mean number of BrdU positive cells per mm of retina: Dual = 2.77, DNR = 4.58, Dex = 4.01, control = 6.16, < .05). The synergistic effect of a sustained release pSiO-DNR/DEX showed promise for the prevention of PVR development while reducing the necessary therapeutic concentration of each drug.
增殖性玻璃体视网膜病变（PVR）是视网膜脱离或眼外伤后视力恢复的重大威胁。目前，尚无获批的预防PVR的药物干预措施。通过共价结合将柔红霉素（DNR）和地塞米松（DEX）依次载入氧化多孔硅（pSiO）颗粒中。将载有DNR + DEX的颗粒、仅载有DNR的对照颗粒和仅载有DEX的对照颗粒与含视网膜色素上皮细胞的胶原蛋白一起孵育，用于每日凝胶表面定量分析。在注射后21天通过眼科检查和组织学评估监测毒性。在玻璃体内注射后的第3周，除3只非干预对照眼外，对所有预处理眼通过视网膜下注射Healon造成局限性视网膜脱离（RD）。在RD诱导后第3天处死前4小时，向玻璃体内注射10μg溴脱氧尿苷（BrdU）。对视网膜切片进行胶质纤维酸性蛋白（GFAP）和BrdU染色，以识别活化的神经胶质细胞和视网膜细胞增殖。研究表明，所有三种类型的pSiO颗粒在体内耐受性良好。单独使用DNR和DNR + DEX联合制剂对凝胶收缩的抑制作用同样强烈（凝胶的最小二乘平均面积：对照 = 1.71，30DNR = 1.85或30/40双药 = 1.83，P < 0.05）。用pSiO-DNR + DEX预处理的眼GFAP活化程度最低（最小二乘平均强度mm：双药 = 4.03，DNR = 7.76，地塞米松 = 16.23，对照 = 29.11，P < 0.05），BrdU表达也最低（每毫米视网膜BrdU阳性细胞的平均数：双药 = 2.77，DNR = 4.58，地塞米松 = 4.01，对照 = 6.16，P < 0.05）。持续释放的pSiO-DNR/DEX的协同作用显示出预防PVR发展的前景，同时降低了每种药物所需的治疗浓度。
