Hsueh Pang-Yu, Edman Maria C, Sun Guoyong, Shi Pu, Xu Shi, Lin Yi-An, Cui Honggang, Hamm-Alvarez Sarah F, MacKay J Andrew
Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
Department of Chemical and Biomolecular Engineering, John Hopkins University, Baltimore, MD 21218, USA.
J Control Release. 2015 Jun 28;208:2-13. doi: 10.1016/j.jconrel.2014.12.017. Epub 2014 Dec 16.
Rapid clearance from the tears presents a formidable obstacle to the delivery of peptide drugs to the eye surface. This impedes therapies for ocular infections, wound healing, and dry-eye disease that affect the vision of millions worldwide. To overcome this challenge, this manuscript explores a novel strategy to reach the ocular surface via receptor-mediated transcytosis across the lacrimal gland (LG), which produces the bulk of human tears. The LG abundantly expresses the coxsackievirus and adenovirus receptor (CAR); furthermore, we recently reported a peptide-based nanoparticle (KSI) that targets CAR on liver cells. This manuscript reports the unexpected finding that KSI both targets and transcytoses into the LG acinar lumen, which drains to tear ducts. When followed using ex vivo live cell imaging KSI rapidly accumulates in lumen formed by LG acinar cells. LG transduction with a myosin Vb tail, which is dominant negative towards transcytosis, inhibits lumenal accumulation. Transcytosis of KSI was confirmed in vivo by confocal and TEM imaging of LG tissue following administration of KSI nanoparticles. These findings suggest that it is possible to target nanomaterials to the tears by targeting certain receptors on the LG. This design strategy represents a new opportunity to overcome barriers to ocular delivery.
泪液中的快速清除对肽类药物递送至眼表构成了巨大障碍。这阻碍了针对眼部感染、伤口愈合以及干眼症的治疗，而这些疾病影响着全球数百万人的视力。为了克服这一挑战，本文探索了一种新策略，即通过受体介导的跨细胞转运穿过泪腺（LG）到达眼表，泪腺产生了大部分的人类泪液。泪腺大量表达柯萨奇病毒和腺病毒受体（CAR）；此外，我们最近报道了一种靶向肝细胞上CAR的基于肽的纳米颗粒（KSI）。本文报道了一个意外发现，即KSI既能靶向泪腺腺泡腔，又能通过跨细胞转运进入泪腺腺泡腔，泪腺腺泡腔通向泪道。当使用离体活细胞成像进行跟踪时，KSI迅速在泪腺腺泡细胞形成的腔中积累。用对跨细胞转运呈显性负性的肌球蛋白Vb尾部转导泪腺，可抑制其在腔内的积累。在给予KSI纳米颗粒后，通过对泪腺组织进行共聚焦和透射电镜成像，在体内证实了KSI的跨细胞转运。这些发现表明，通过靶向泪腺上的某些受体，有可能将纳米材料靶向递送至泪液中。这种设计策略代表了克服眼部给药障碍的新机会。
