Investigating histidinylated highly branched poly(lysine) for siRNA delivery.
Investigating histidinylated highly branched poly(lysine) for siRNA delivery.
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研究用于 siRNA 递送的组氨酸化高度支化聚赖氨酸。
DOI：
10.1039/d1tb01793d
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Alazzo A
中科院分区：
文献类型：
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作者：
Alazzo A
利用短干扰RNA（siRNA）暂时沉默疾病相关基因是解决广泛的生命限制性疾病的有效和选择性途径。然而，少数临床批准的siRNA疗法依赖于基于脂质的制剂，其虽然有效，但提供有限的化学空间来调节稳定性、功效和组织选择性。在这项研究中，我们调查的作用，摩尔质量和组氨酸的聚（赖氨酸）为基础的非病毒载体，通过一个完全水热缩聚合成。制剂和体外研究显示，较高摩尔质量的衍生物产生较小的聚合复合物，这归因于在较低N/P比下对siRNA的较大亲和力，产生较大的转染效率，尽管具有一些细胞毒性。组氨酸化对制剂大小的影响可忽略不计，但赋予了生物相容性的适度改善，但与非组氨酸化衍生物相比，没有提供任何有意义的沉默效率改善。这归因于非组氨酸化类似物的细胞内化程度更高，这在较高摩尔质量的材料中得到增强。
The temporary silencing of disease-associated genes utilising short interfering RNA (siRNA) is a potent and selective route for addressing a wide range of life limiting disorders. However, the few clinically approved siRNA therapies rely on lipid based formulations, which although potent, provide limited chemical space to tune the stability, efficacy and tissue selectivity. In this study, we investigated the role of molar mass and histidinylation for poly(lysine) based non-viral vectors, synthesised through a fully aqueous thermal condensation polymerisation. Formulation and in vitro studies revealed that higher molar mass derivatives yielded smaller polyplexes attributed to a greater affinity for siRNA at lower N/P ratios yielding greater transfection efficiency, albeit with some cytotoxicity. Histidinylation had a negligible effect on formulation size, yet imparted a moderate improvement in biocompatibility, but did not provide any meaningful improvement over silencing efficiency compared to non-histidinylated derivatives. This was attributed to a greater degree of cellular internalisation for non-histidinylated analogues, which was enhanced with the higher molar mass material.