School of Pharmacy, University of Reading, Whiteknights, Post Office Box 224, Reading RG6 6DX, U.K.
Physicochemical, Ex Vivo and Invertebrate Tests and Analysis Centre (PEVITAC,www.pevitac.co.uk), University of Reading, Whiteknights, Reading RG6 6DX, U.K.
Biomacromolecules. 2024 Aug 12;25(8):4831-4842. doi: 10.1021/acs.biomac.4c00220. Epub 2024 Jul 29.
Linear polyethylenimine (L-PEI) has numerous applications, such as in pharmaceutical formulations, gene delivery, and water treatment. However, due to the presence of secondary amine groups, L-PEI shows a relatively high toxicity and low biocompatibility. Here, various organic anhydrides were used to modify L-PEI to reduce its toxicity and enhance its functionality. We selected methacrylic anhydride, crotonic anhydride, maleic anhydride, and succinic anhydride to modify L-PEI. The structure of the resulting derivatives was characterized using H NMR and FTIR spectroscopies, and their behavior in aqueous solutions was studied using turbidimetric and electrophoretic mobility measurements over a broad range of pHs. A fluorescence flow through method determined the mucoadhesive properties of the polymers to the bovine palpebral conjunctiva. Methacrylated L-PEI and crotonylated L-PEI showed strong mucoadhesive properties at pH 7.4, likely due to covalent bonding with mucin thiol groups. In contrast, maleylated and succinylated L-PEI were poorly mucoadhesive as the pH was above their isoelectric point, resulting in electrostatic repulsion between the polymers and mucin. The toxicity of these polymers was evaluated using in vivo assays with planaria and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2-tetrazolium bromide (MTT) cell viability assay in human alveolar epithelial cells. Moreover, the irritancy of polymers was assessed using a slug mucosa irritation assay. The results demonstrated that anhydride modification mitigated the adverse toxicity effects seen for parent L-PEI.
线性聚乙烯亚胺（L-PEI）具有许多应用，例如在药物制剂、基因传递和水处理中。然而，由于存在二级胺基团，L-PEI 表现出相对较高的毒性和较低的生物相容性。在这里，使用各种有机酸酐来修饰 L-PEI，以降低其毒性并增强其功能。我们选择甲基丙烯酰酐、巴豆酰酐、马来酸酐和琥珀酸酐来修饰 L-PEI。使用 H NMR 和 FTIR 光谱对所得衍生物的结构进行了表征，并使用浊度法和电泳迁移率测量法在广泛的 pH 值范围内研究了它们在水溶液中的行为。荧光流动通过法确定了聚合物对牛眼睑结膜的粘膜粘附特性。在 pH 7.4 时，甲基丙烯酰化 L-PEI 和巴豆酰化 L-PEI 表现出很强的粘膜粘附性，这可能是由于与粘蛋白硫醇基团的共价键合。相比之下，当 pH 值高于其等电点时，马来酰化和琥珀酰化 L-PEI 的粘膜粘附性较差，导致聚合物和粘蛋白之间的静电排斥。使用扁形虫体内试验和人肺泡上皮细胞中的 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基-2-四唑溴盐（MTT）细胞活力测定法评估了这些聚合物的毒性。此外，使用 slug 粘膜刺激试验评估了聚合物的刺激性。结果表明，酸酐修饰减轻了亲本 L-PEI 引起的不良毒性作用。
