Ilhami Fasih Bintang, Bayle Enyew Alemayehu, Cheng Chih-Chia
Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 10607, Taiwan.
Advanced Membrane Materials Research Center, National Taiwan University of Science and Technology, Taipei 10607, Taiwan.
Pharmaceutics. 2021 Nov 15;13(11):1929. doi: 10.3390/pharmaceutics13111929.
A new concept in cooperative adenine-uracil (A-U) hydrogen bonding interactions between anticancer drugs and nanocarrier complexes was successfully demonstrated by invoking the co-assembly of water soluble, uracil end-capped polyethylene glycol polymer (BU-PEG) upon association with the hydrophobic drug adenine-modified rhodamine (A-R6G). This concept holds promise as a smart and versatile drug delivery system for the achievement of targeted, more efficient cancer chemotherapy. Due to A-U base pairing between BU-PEG and A-R6G, BU-PEG has high tendency to interact with A-R6G, which leads to the formation of self-assembled A-R6G/BU-PEG nanogels in aqueous solution. The resulting nanogels exhibit a number of unique physical properties, including extremely high A-R6G-loading capacity, well-controlled, pH-triggered A-R6G release behavior, and excellent structural stability in biological media. Importantly, a series of in vitro cellular experiments clearly demonstrated that A-R6G/BU-PEG nanogels improved the selective uptake of A-R6G by cancer cells via endocytosis and promoted the intracellular release of A-R6G to subsequently induce apoptotic cell death, while control rhodamine/BU-PEG nanogels did not exert selective toxicity in cancer or normal cell lines. Overall, these results indicate that cooperative A-U base pairing within nanogels is a critical factor that improves selective drug uptake and effectively promotes apoptotic programmed cell death in cancer cells.
通过水溶性尿嘧啶封端的聚乙二醇聚合物（BU-PEG）与疏水性药物腺嘌呤修饰的罗丹明（A-R6G）缔合时的共组装，成功证明了抗癌药物与纳米载体复合物之间新型的腺嘌呤-尿嘧啶（A-U）氢键协同相互作用概念。这一概念有望成为一种智能且通用的药物递送系统，以实现靶向性更强、效率更高的癌症化疗。由于BU-PEG与A-R6G之间存在A-U碱基配对，BU-PEG与A-R6G相互作用的倾向很高，这导致在水溶液中形成自组装的A-R6G/BU-PEG纳米凝胶。所得纳米凝胶具有许多独特的物理性质，包括极高的A-R6G负载能力、可控的、pH触发的A-R6G释放行为以及在生物介质中出色的结构稳定性。重要的是，一系列体外细胞实验清楚地表明，A-R6G/BU-PEG纳米凝胶通过内吞作用提高了癌细胞对A-R6G的选择性摄取，并促进了A-R6G在细胞内的释放，随后诱导细胞凋亡死亡，而对照罗丹明/BU-PEG纳米凝胶在癌细胞或正常细胞系中未表现出选择性毒性。总体而言，这些结果表明纳米凝胶内的A-U碱基配对协同作用是改善药物选择性摄取并有效促进癌细胞凋亡程序性细胞死亡的关键因素。
