Kwon Kiyoon, Hwang Youngmin, Jung Junyoung, Tae Giyoong
School of Materials Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea.
Pharmaceutics. 2021 Mar 29;13(4):463. doi: 10.3390/pharmaceutics13040463.
The outer part of the retina pigment epithelium (RPE) in the retina is the main site of neovascularization associated with retinal diseases. However, various obstacles interrupt the delivery of medicines across the RPE, mainly due to the well-developed tight junctions in the RPE. Currently, there is no practical formulation to overcome this issue. In this study, we demonstrated that simple mixing with adenosine tetraphosphate (ATP) has the potential to greatly enhance the transport and permeation of a polymeric nanocarrier across the retina via intravitreal administration. Chitosan-functionalized, pluronic-based nanocarrier (NC), which can deliver various biomolecules efficiently, was used as a polymeric nanocarrier. Mixing with ATP facilitated the diffusion of the nanocarrier in the vitreous humor by reducing the electrostatic interaction between NC and negatively charged glycosaminoglycans (GAGs) in the vitreous humor. Mixing with ATP also allowed the penetration of NC across the whole retina, and it resulted in a great increase (approximately nine times) in the transport of NC across the retina, as well as spreading it throughout the whole retina upon intravitreal administration in a mouse model. This enhanced permeation across the retina was specific to ATP but not to GTP, suggesting the possibility of P2Y receptor-mediated tight junction disruption by ATP.
视网膜色素上皮（RPE）的外层是视网膜疾病相关新生血管形成的主要部位。然而，多种障碍阻碍了药物穿过RPE的递送，这主要是由于RPE中紧密连接发达。目前，尚无切实可行的制剂来克服这一问题。在本研究中，我们证明与四磷酸腺苷（ATP）简单混合有潜力通过玻璃体内给药极大地增强聚合物纳米载体在视网膜上的转运和渗透。壳聚糖功能化的、基于普朗尼克的纳米载体（NC）可有效递送各种生物分子，被用作聚合物纳米载体。与ATP混合通过减少NC与玻璃体内带负电荷的糖胺聚糖（GAGs）之间的静电相互作用促进了纳米载体在玻璃体内的扩散。与ATP混合还使NC能够穿透整个视网膜，并且在小鼠模型中玻璃体内给药后，导致NC在视网膜上的转运大幅增加（约九倍），并使其在整个视网膜中扩散。这种跨视网膜的增强渗透对ATP具有特异性，而对GTP不具有特异性，提示ATP介导P2Y受体破坏紧密连接的可能性。
