Trehalose-releasing nanogels: A step toward a trehalose delivery vehicle for autophagy stimulation
Trehalose-releasing nanogels: A step toward a trehalose delivery vehicle for autophagy stimulation
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DOI：
10.1016/j.bioadv.2022.212969
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发表时间：
2022-06-07
影响因子：
--
通讯作者：
Wandzik, Ilona
中科院分区：
文献类型：
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作者：
Maruf, Ali;Milewska, Malgorzata;Wandzik, Ilona
海藻糖因其刺激自噬的能力而被广泛研究用于治疗各种人类疾病。然而，海藻糖在肠粘膜中的吸附和水解能力较差，口服给药需要较高剂量才能诱导自噬。本研究提出的海藻糖释放纳米凝胶的肠外注射提供了另一种递送方式。本研究旨在开发稳定的富含海藻糖的纳米凝胶分散体，并在生理相关条件下持续释放海藻糖。纳米凝胶的设计是基于6- o -丙烯酰海藻糖在聚合物网络中的共价结合。合成了一系列具有高共轭海藻糖（高达59% w/w）的9种富含海藻糖的纳米凝胶，并显示其以不依赖剂量的速率持续释放海藻糖。对纳米凝胶进行优化，使其在富含血清的细胞培养基中保持胶体稳定性。稳定的纳米凝胶对原代HUVECs无细胞毒性。选择两种具有相反表面电荷的纳米凝胶进行扩展的体外表征，包括细胞摄取研究和血液相容性测定。两种纳米凝胶都能在短时间内被HUVECs有效吸收。它们也被证明对浓度高达2.0 mg/mL的人红细胞没有溶血作用。最后，一项采用转基因斑马鱼和果蝇幼虫的体内自噬刺激研究表明，长期暴露于阳离子海藻糖释放纳米凝胶可以诱导体内系统的自噬活性，而没有任何可检测到的毒性。
Trehalose has been widely studied as a treatment for a variety of human disorders due to its ability to stimulate autophagy. Trehalose, however, is poorly adsorbed and is hydrolyzed in the intestinal mucosa, and oral delivery requires relatively high doses to induce autophagy. The parenteral injection of trehalose-releasing nanogels proposed in this study offers an alternative mode of delivery. This study aimed to develop stable colloidal dispersions of trehalose-rich nanogels that could sustainably release trehalose under physiologically relevant conditions. The nanogel design was based on the covalent incorporation of 6-O-acryloyl-trehalose within a polymer network. A series of nine trehalose-rich nanogels with highly conjugated trehalose (up to 59 % w/w) were synthesized and shown to sustainably release trehalose at a rate that is not dose dependent. The nanogels were optimized to keep colloidal stability in serum-enriched cell culture media. The stable nanogels were not cytotoxic to primary HUVECs. Two selected nanogels with opposite surface charges were subjected to extended in vitro characterization that included a cellular uptake study and a hemocompatibility assay. Both nanogels were efficiently taken up by HUVECs during a short incubation. They also proved not to be hemolytic to human RBCs in concentrations up to 2.0 mg/mL. Finally, an in vivo autophagy stimulation study employing transgenic zebrafish and Drosophila larvae demonstrated that prolonged exposure to a cationic trehalose-releasing nanogel can induce autophagic activity in in vivo systems without any detectable toxicity.