Zhao Lei, Chen Guojun, Li Jun, Fu Yingmei, Mavlyutov Timur A, Yao Annie, Nickells Robert W, Gong Shaoqin, Guo Lian-Wang
Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA.
Department of Materials Science and Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
J Control Release. 2017 Feb 10;247:153-166. doi: 10.1016/j.jconrel.2016.12.038. Epub 2017 Jan 4.
Glaucoma is a common blinding disease characterized by loss of retinal ganglion cells (RGCs). To date, there is no clinically available treatment directly targeting RGCs. We aim to develop an RGC-targeted intraocular drug delivery system using unimolecular micelle nanoparticles (unimNPs) to prevent RGC loss. The unimNPs were formed by single/individual multi-arm star amphiphilic block copolymer poly(amidoamine)-polyvalerolactone-poly(ethylene glycol) (PAMAM-PVL-PEG). While the hydrophobic PAMAM-PVL core can encapsulate hydrophobic drugs, the hydrophilic PEG shell provides excellent water dispersity. We conjugated unimNPs with the cholera toxin B domain (CTB) for RGC-targeting and with Cy5.5 for unimNP-tracing. To exploit RGC-protective sigma-1 receptor (S1R), we loaded unimNPs with an endogenous S1R agonist dehydroepiandrosterone (DHEA) as an FDA-approved model drug. These unimNPs produced a steady DHEA release in vitro for over two months at pH7.4. We then co-injected (mice, intraocular) unimNPs with the glutamate analog N-methyl-d-aspartate (NMDA), which is excito-toxic and induces RGC death. The CTB-conjugated unimNPs (i.e., targeted NPs) accumulated at the RGC layer and effectively preserved RGCs at least for 14days, whereas the unimNPs without CTB (i.e., non-targeted NPs) showed neither accumulation at nor protection of NMDA-treated RGCs. Consistent with S1R functions, targeted NPs relative to non-targeted NPs showed markedly better inhibitory effects on apoptosis and oxidative/inflammatory stresses in the RGC layer. Hence, the DHEA-loaded, CTB-conjugated unimNPs represent an RGC/S1R dual-targeted nanoplatform that generates an efficacious template for further development of a sustainable intraocular drug delivery system to protect RGCs, which may be applicable to treatments directed at glaucomatous pathology.
青光眼是一种常见的致盲性疾病，其特征是视网膜神经节细胞（RGCs）丧失。迄今为止，尚无直接针对RGCs的临床可用治疗方法。我们旨在开发一种使用单分子胶束纳米颗粒（unimNPs）的RGC靶向眼内药物递送系统，以防止RGCs丧失。unimNPs由单/个体多臂星形两亲性嵌段共聚物聚（酰胺胺）-聚戊内酯-聚（乙二醇）（PAMAM-PVL-PEG）形成。疏水性的PAMAM-PVL核心可以包裹疏水性药物，而亲水性的PEG外壳提供了出色的水分散性。我们将unimNPs与霍乱毒素B结构域（CTB）偶联用于RGC靶向，并与Cy5.5偶联用于unimNP追踪。为了利用RGC保护的sigma-1受体（S1R），我们将unimNPs装载了内源性S1R激动剂脱氢表雄酮（DHEA）作为FDA批准的模型药物。这些unimNPs在体外pH7.4条件下持续释放DHEA超过两个月。然后，我们将unimNPs与谷氨酸类似物N-甲基-D-天冬氨酸（NMDA）共同注射（小鼠，眼内），NMDA具有兴奋性毒性并诱导RGC死亡。CTB偶联的unimNPs（即靶向纳米颗粒）在RGC层积累，并至少有效保存RGCs 14天，而没有CTB的unimNPs（即非靶向纳米颗粒）在NMDA处理的RGCs中既没有积累也没有保护作用。与S1R功能一致，相对于非靶向纳米颗粒，靶向纳米颗粒对RGC层中的细胞凋亡和氧化/炎症应激显示出明显更好的抑制作用。因此，装载DHEA、CTB偶联的unimNPs代表了一种RGC/S1R双靶向纳米平台，为进一步开发可持续的眼内药物递送系统以保护RGCs产生了有效的模板，这可能适用于针对青光眼病理的治疗。
