Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA; College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China.
Int J Pharm. 2020 Jan 5;573:118894. doi: 10.1016/j.ijpharm.2019.118894. Epub 2019 Nov 23.
Uveal melanoma (UM) is rare yet the most common and malignant primary intraocular tumor in adults. Due to the lack of effective treatment, the mortality rate of UM has remained high over the past few decades. In the present study, hyaluronic acid (HA) coated chitosan (Chi)/siRNA ternary complexes have been developed and characterized as a novel therapeutic strategy molecularly targeting hypoxia-inducible factor 1α (HIF-1α) pathway for the treatment of UM. The cytotoxicity, cellular uptake, and siRNA silencing effect of the developed siRNA complexes were evaluated. In addition, whether the developed ternary complexes can inhibit UM migration and invasion was investigated. Results showed that the developed ternary siRNA complexes were negatively charged and with a particle size below 190 nm. The ternary siRNA complexes showed excellent cellular uptake and lysosome escape ability with low cytotoxicity. In addition, the ternary complexes were able to downregulate both HIF-1α and VEGF expression in UM cells, and successfully inhibit UM migration and invasion. These results demonstrated that the biocompatible ternary siRNA complexes are promising for local treatment of UM in the posterior segment with future clinical application potential.
葡萄膜黑色素瘤（UM）是罕见但最常见和恶性的成人眼内原发性肿瘤。由于缺乏有效的治疗方法，UM 的死亡率在过去几十年中一直居高不下。在本研究中，开发了透明质酸（HA）包覆壳聚糖（Chi）/siRNA 三元复合物，并将其作为一种新型治疗策略，通过靶向缺氧诱导因子 1α（HIF-1α）通路来治疗 UM。评估了所开发的 siRNA 复合物的细胞毒性、细胞摄取和 siRNA 沉默效果。此外，还研究了所开发的三元复合物是否可以抑制 UM 的迁移和侵袭。结果表明，所开发的三元 siRNA 复合物带负电荷，粒径小于 190nm。三元 siRNA 复合物具有优异的细胞摄取和溶酶体逃逸能力，细胞毒性低。此外，三元复合物能够下调 UM 细胞中的 HIF-1α 和 VEGF 表达，并成功抑制 UM 的迁移和侵袭。这些结果表明，生物相容性三元 siRNA 复合物具有在后部段局部治疗 UM 的潜力，具有未来的临床应用前景。
