Osswald Christian R, Guthrie Micah J, Avila Abigail, Valio Joseph A, Mieler William F, Kang-Mieler Jennifer J
a Department of Biomedical Engineering , Illinois Institute of Technology , Chicago , IL , USA.
b Department of Ophthalmology and Visual Sciences , University of Illinois at Chicago , Chicago , IL , USA.
Curr Eye Res. 2017 Sep;42(9):1293-1301. doi: 10.1080/02713683.2017.1302590. Epub 2017 May 30.
Demonstrate in vivo that controlled and extended release of a low dose of anti-vascular endothelial growth factor (anti-VEGF) from a microsphere-hydrogel drug delivery system (DDS) has a therapeutic effect in a laser-induced rat model of choroidal neovascularization (CNV).
Anti-VEGF (ranibizumab or aflibercept) was loaded into poly(lactic-co-glycolic acid) microspheres that were then suspended within an injectable poly(N-isopropylacrylamide)-based thermo-responsive hydrogel DDS.The DDS was shown previously to release bioactive anti-VEGF for ~200 days. CNV was induced using an Ar-green laser. The four experimental groups were as follows: (i) non-treated, (ii) drug-free DDS, (iii) anti-VEGF-loaded DDS, and (iv) bolus injection of anti-VEGF. CNV lesion areas were measured based on fluorescein angiograms and quantified using a multi-Otsu thresholding technique. Intraocular pressure (IOP) and dark-adapted electroretinogram (ERG) were also obtained pre- and post-treatment (1, 2, 4, 8, and 12 weeks).
The anti-VEGF-loaded DDS group had significantly smaller (60%) CNV lesion areas than non-treated animals throughout the study. A small transient increase in IOP was seen immediately after injection; however, all IOP measurements at all time points were within the normal range. There were no significant changes in ERG maximal response compared to pre-treatment measurements for the drug-loaded DDS, which suggests no adverse effects on retinal cellular function.
The current study demonstrates that the DDS can effectively decrease laser-induced CNV lesions in a murine model. Controlled and extended release from our DDS achieved greater treatment efficacy using an order of magnitude less drug than what is required with bolus administration. This suggests that our DDS may provide a significant advantage in the treatment of posterior segment eye diseases.
在体内证明，从微球 - 水凝胶药物递送系统（DDS）中控制释放低剂量抗血管内皮生长因子（anti - VEGF）对激光诱导的大鼠脉络膜新生血管（CNV）模型具有治疗效果。
将抗VEGF（雷珠单抗或阿柏西普）负载到聚乳酸 - 乙醇酸共聚物微球中，然后将其悬浮在基于聚（N - 异丙基丙烯酰胺）的可注射热响应水凝胶DDS中。先前已证明该DDS可释放生物活性抗VEGF约200天。使用氩绿激光诱导CNV。四个实验组如下：（i）未治疗组，（ii）无药物DDS组，（iii）负载抗VEGF的DDS组，和（iv）抗VEGF推注组。基于荧光血管造影测量CNV病变面积，并使用多Otsu阈值技术进行量化。还在治疗前和治疗后（1、2、4、8和12周）测量眼内压（IOP）和暗适应视网膜电图（ERG）。
在整个研究过程中，负载抗VEGF的DDS组的CNV病变面积比未治疗的动物显著小（60％）。注射后立即观察到IOP有小的短暂升高；然而，所有时间点的所有IOP测量值均在正常范围内。与负载药物的DDS治疗前测量值相比，ERG最大反应没有显著变化，这表明对视网膜细胞功能没有不良影响。
当前研究表明，该DDS可有效减少小鼠模型中激光诱导的CNV病变。与推注给药所需药物量相比，我们的DDS控制和延长释放使用的药物量少一个数量级，却实现了更高的治疗效果。这表明我们的DDS在治疗后段眼部疾病方面可能具有显著优势。
