Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University, 3-3-35 Yamate, Suita, Osaka 564-8680, Japan.
Organization for Research and Development of Innovative Science and Technology (ORDIST), Kansai University, 3-3-35 Yamate, Suita, Osaka 564-8680, Japan.
Int J Mol Sci. 2018 May 30;19(6):1606. doi: 10.3390/ijms19061606.
Nanogels, nanometer-sized hydrogel particles, have great potential as drug delivery carriers. To achieve effective drug delivery to the active sites in a cell, control of intracellular traffic is important. In this study, we prepared nanogels composed of dextran with oligolactide (OLA) chains attached via disulfide bonds (Dex--SS-OLA) that collapse under the reductive conditions of the cytosol to achieve efficient drug delivery. In addition, we introduced galactose (Gal) residues on the nanogels, to enhance cellular uptake by receptor-mediated endocytosis, and secondary oligo-amine (tetraethylenepentamine) groups, to aid in escape from endosomes via proton sponge effects. The obtained Dex--SS-OLA with attached Gal residues and tetraethylenepentamine (EI₄) groups, EI₄/Gal-Dex--SS-OLA, formed a nanogel with a hydrodynamic diameter of ca. 203 nm in phosphate-buffered solution. The collapse of the EI₄/Gal-Dex--SS-OLA nanogels under reductive conditions was confirmed by a decrease in the hydrodynamic diameter in the presence of reductive agents. The specific uptake of the hydrogels into HepG2 cells and their intercellular behavior were investigated by flow cytometry and confocal laser scanning microscopy using fluorescence dye-labeled nanogels. Escape from the endosome and subsequent collapse in the cytosol of the EI₄/Gal-Dex--SS-OLA were observed. These biodegradable nanogels that collapse under reductive conditions in the cytosol should have great potential as efficient drug carriers in, for example, cancer chemotherapy.
纳米凝胶是一种纳米级水凝胶颗粒，作为药物传递载体具有很大的潜力。为了实现药物向细胞内活性部位的有效传递，控制细胞内运输非常重要。在本研究中，我们制备了通过二硫键（Dex--SS-OLA）连接到带有低聚丙交酯（OLA）链的葡聚糖（Dex--SS-OLA）纳米凝胶，这些二硫键在细胞质的还原条件下会发生坍塌，从而实现有效的药物传递。此外，我们在纳米凝胶上引入了半乳糖（Gal）残基，以增强通过受体介导的内吞作用的细胞摄取，以及二级寡胺（四亚乙基五胺）基团，以通过质子海绵效应帮助从内涵体中逃逸。所得的带有 Gal 残基和四亚乙基五胺（EI₄）基团的 Dex--SS-OLA，EI₄/Gal-Dex--SS-OLA，在磷酸盐缓冲溶液中形成了一种水动力学直径约为 203nm 的纳米凝胶。在还原剂存在下，EI₄/Gal-Dex--SS-OLA 纳米凝胶的水动力学直径减小，证实了纳米凝胶的坍塌。通过用荧光染料标记的纳米凝胶进行流式细胞术和共聚焦激光扫描显微镜研究，证实了水凝胶对 HepG2 细胞的特异性摄取及其细胞内行为。观察到了 EI₄/Gal-Dex--SS-OLA 从内涵体中逃逸和随后在细胞质中坍塌。这些在细胞质中还原条件下发生坍塌的可生物降解纳米凝胶有望成为癌症化疗等高效药物载体。
