Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
Bioconjug Chem. 2020 May 20;31(5):1320-1326. doi: 10.1021/acs.bioconjchem.0c00238. Epub 2020 May 3.
Whereas small siRNA nanocarriers with a size of 10-20 nm exert high tissue-permeability, they encounter the challenge of inefficient adsorption on the cell surface, resulting in poor cellular uptake of siRNA. To solve this dilemma, this study aims to control the hydrophobicity of a small siRNA nanocarrier, unimer polyion complex (uPIC), with a size of ∼10 nm. The uPICs are fabricated to consist of a single pair between siRNA and a smart triblock copolymer comprising hydrophilic poly(2-ethyl-2-oxazoline) (PEtOx), thermoswitchable poly(2--propyl-2-oxazoline) (PnPrOx), and cationic poly(l-lysine) (PLL). The PnPrOx segment is dehydrated at 37 °C (>lower critical solution temperature) to enhance the hydrophobicity of uPICs. The uPICs with a hydrophobic domain facilitates cellular uptake of the siRNA payload through stronger binding to the cell surface, compared with control uPICs without a PnPrOx segment, leading to a significantly enhanced gene silencing effect in cultured cancer cells.
虽然尺寸为 10-20nm 的小 siRNA 纳米载体具有很高的组织通透性，但它们在细胞表面的吸附效率不高，导致 siRNA 的细胞摄取率较差。为了解决这一难题，本研究旨在控制小 siRNA 纳米载体，即尺寸约为 10nm 的单聚体聚离子复合物（uPIC）的疏水性。uPIC 由 siRNA 和一种智能三嵌段共聚物组成，该共聚物包含亲水性聚（2-乙基-2-恶唑啉）（PEtOx）、温度响应性聚（2-异丙基-2-恶唑啉）（PnPrOx）和阳离子聚（L-赖氨酸）（PLL）。在 37°C（>低临界溶液温度）下，PnPrOx 段脱水以增强 uPIC 的疏水性。与没有 PnPrOx 段的对照 uPIC 相比，具有疏水区的 uPIC 更有利于 siRNA 有效负载的细胞摄取，通过与细胞表面更强的结合，导致培养的癌细胞中的基因沉默效果显著增强。
