Ocular Inserts for Sustained Release of the Angiotensin-Converting Enzyme 2 Activator, Diminazene Aceturate, to Treat Glaucoma in Rats.
Ocular Inserts for Sustained Release of the Angiotensin-Converting Enzyme 2 Activator, Diminazene Aceturate, to Treat Glaucoma in Rats.
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DOI：
10.1371/journal.pone.0133149
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Ferreira AJ
中科院分区：
文献类型：
--
作者：
Foureaux G;Franca JR;Nogueira JC;Fulgêncio Gde O;Ribeiro TG;Castilho RO;Yoshida MI;Fuscaldi LL;Fernandes SO;Cardoso VN;Cronemberger S;Faraco AA;Ferreira AJ
本研究的目的是开发和评价壳聚糖插入物在实验性青光眼中持续释放血管紧张素转换酶2（ACE 2）激活剂，醋酸二氮烯（DIZE）的作用。制备了载DIZE的单层插入物（D+I），并通过溶胀、衰减全反射傅里叶变换红外光谱（ATR-FTIR）、差示扫描量热法（DSC）和体外药物释放进行表征。在功能上，在昏迷大鼠中测试D+I的作用。通过每周向前房注射透明质酸（HA）诱导青光眼，并进行眼内压（IOP）测量。视网膜神经节细胞（RGC）和视神经乳头杯在组织切片进行了评价。通过放射成像和离体放射计数评估药物的生物分布。我们发现，DIZE增加了插入物的溶胀指数。此外，其作为游离碱分子分散并散布在聚合物基质中。DIZE在装入衬垫时未丧失其化学完整性和活性。功能评价表明，D+I降低了IOP，并维持IOP降低长达一个月（上周：11.0±0.7 mmHg）。D+I的这种作用防止了RGC的丢失和视神经的变性。未观察到与衬垫应用相关的眼部毒性作用。此外，生物分布研究表明，D+I延长了DIZE在角膜部位的保留。我们得出结论，D+I提供了持续的DIZE体内输送，从而证明了基于聚合物的DIZE插入物在青光眼管理中的潜在应用。
The aim of this study was to develop and evaluate the effects of chitosan inserts for sustained release of the angiotensin-converting enzyme 2 (ACE2) activator, diminazene aceturate (DIZE), in experimental glaucoma. Monolayer DIZE loaded inserts (D+I) were prepared and characterized through swelling, attenuated total reflectance Fourier transformed infrared spectroscopy (ATR-FTIR), differential scanning calorimetry (DSC) and in vitro drug release. Functionally, the effects of D+I were tested in glaucomatous rats. Glaucoma was induced by weekly injections of hyaluronic acid (HA) into the anterior chamber and intraocular pressure (IOP) measurements were performed. Retinal ganglion cells (RGC) and optic nerve head cupping were evaluated in histological sections. Biodistribution of the drug was accessed by scintigraphic images and ex vivo radiation counting. We found that DIZE increased the swelling index of the inserts. Also, it was molecularly dispersed and interspersed in the polymeric matrix as a freebase. DIZE did not lose its chemical integrity and activity when loaded in the inserts. The functional evaluation demonstrated that D+I decreased the IOP and maintained the IOP lowered for up to one month (last week: 11.0±0.7 mmHg). This effect of D+I prevented the loss of RGC and degeneration of the optic nerve. No toxic effects in the eyes related to application of the inserts were observed. Moreover, biodistribution studies showed that D+I prolonged the retention of DIZE in the corneal site. We concluded that D+I provided sustained DIZE delivery in vivo, thereby evidencing the potential application of polymeric-based DIZE inserts for glaucoma management.