Nishida Shogo, Takashima Yuuki, Udagawa Ryotaro, Ibaraki Hisako, Seta Yasuo, Ishihara Hiroshi
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Pharmaceutics. 2023 Feb 11;15(2):611. doi: 10.3390/pharmaceutics15020611.
Drug therapy for retinal diseases (e.g., age-related macular degeneration, the leading cause of blindness) is generally performed by invasive intravitreal injection because of poor drug delivery caused by the blood-retinal barrier (BRB). This study aimed to develop a nanocarrier for the non-invasive delivery of small interfering RNA (siRNA) to the posterior segment of the eye (i.e., the retina) by eyedrops. To this end, we prepared a hybrid nanocarrier based on a multifunctional peptide and liposomes, and the composition was optimized. A cytoplasm-responsive stearylated peptide (STR-CH2R4H2C) was used as the multifunctional peptide because of its superior ability to enhance the complexation, cell permeation, and intracellular dynamics of siRNA. By adding STR-CH2R4H2C to the surface of liposomes, intracellular uptake increased regardless of the liposome surface charge. The STR-CH2R4H2C-modified cationic nanocarrier demonstrated significant siRNA transfection efficiency with no cytotoxicity, enhanced siRNA release from endosomes, and effectively suppressed vascular endothelial growth factor expression in rat retinal pigment epithelium cells. The 2.0 mol% STR-CH2R4H2C-modified cationic nanocarrier enhanced intraocular migration into the retina after instillation into rat eyes.
视网膜疾病（如年龄相关性黄斑变性，失明的主要原因）的药物治疗通常通过有创玻璃体内注射进行，因为血视网膜屏障（BRB）导致药物递送不佳。本研究旨在开发一种纳米载体，通过滴眼液将小干扰RNA（siRNA）无创递送至眼后段（即视网膜）。为此，我们制备了一种基于多功能肽和脂质体的混合纳米载体，并对其组成进行了优化。由于其在增强siRNA的络合、细胞渗透和细胞内动力学方面具有卓越能力，一种细胞质响应性硬脂酰化肽（STR-CH2R4H2C）被用作多功能肽。通过将STR-CH2R4H2C添加到脂质体表面，无论脂质体表面电荷如何，细胞内摄取均增加。STR-CH2R4H2C修饰的阳离子纳米载体显示出显著的siRNA转染效率，无细胞毒性，增强了siRNA从内涵体的释放，并有效抑制了大鼠视网膜色素上皮细胞中血管内皮生长因子的表达。2.0 mol% STR-CH2R4H2C修饰的阳离子纳米载体在滴入大鼠眼睛后增强了向视网膜的眼内迁移。
