用于有效递送 siRNA 的烷基链封端聚(β-氨基酯)的组合合成。

IF 4.4 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Macromolecular bioscience Pub Date : 2024-07-25 DOI:10.1002/mabi.202400168
Baiqiu Chen, Qidi Ren, Pingge Jiang, Qiong Wu, Qi Shuai, Yunfeng Yan
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引用次数: 0

摘要

聚(β-氨基酯)(PBAE)是一类主链中含有酯键的可生物降解聚合物,被广泛研究用作 siRNA 的阳离子聚合物载体。目前大多数 PBAE 载体都依赖于亲水性胺或带电胺的终止。在本研究中,通过连续的偶氮-迈克尔加成法,构建了一个由 168 种带有疏水烷基链末端的 PBAE 聚合物组成的聚合物平台。通过对 PBAE 平台进行体外筛选,确定了大量有效的载体,用于将 siLuc 运送到 HeLa-Luc 细胞中。其中,PA8-C6 和 PA8-C8 的基因敲除效率高达 80%,细胞毒性低。PA2 和 PA5 系列中的某些材料具有强大的 siRNA 递送能力,但细胞毒性较高。PBAE 的 pKa 值主要由亲水性胺侧链而不是端盖基团决定。PA8 系列载体的 pKa 值范围≈6.2-6.5,这可能是 PA8 系列载体具有出色递送能力的原因。PBAE载体与辅助脂质的共配制可减小siRNA多聚体NPs的尺寸和表面电荷,从而降低细胞毒性并提高siRNA的递送效果。这些发现对开发新型可降解聚合物载体递送 siRNA 具有重要意义。
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Combinatorial Synthesis of Alkyl Chain-Capped Poly(β-Amino Ester)s for Effective siRNA Delivery

Poly (β-amino ester) (PBAE) is a class of biodegradable polymers containing ester bonds in their main chain, extensively investigated as cationic polymer carriers for siRNA. Most current PBAE carriers rely on termination with hydrophilic or charged amines. In this study, a polymer platform consisting of 168 PBAE polymers with hydrophobic alkyl chain terminals is constructed through sequential aza-Michael addition. A large number of effective carriers are identified through in vitro screening of the PBAE platform for siLuc delivery to HeLa-Luc cells. Specifically, PA8-C6 and PA8-C8 achieve remarkable gene knockdown efficacies of up to 80% with low cytotoxicity. Certain materials from the PA2 and PA5 series demonstrate potent siRNA delivery capabilities associated with elevated cytotoxicity. The pKa value of PBAE is predominantly determined by the hydrophilic amine side chains rather than the end-capping groups. A pKa range of ≈6.2–6.5 may contribute to the excellent delivery capability for PA8 series carriers. The co-formulation of PBAE carriers with helper lipids leads to the reduced size and surface charges of the polyplex NPs with siRNA, consequently decreasing the cytotoxicity and enhancing siRNA delivery efficacy. These findings hold significant implications for the development of novel degradable polymer carriers for siRNA delivery.

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来源期刊
Macromolecular bioscience
Macromolecular bioscience 生物-材料科学:生物材料
CiteScore
7.90
自引率
2.20%
发文量
211
审稿时长
1.5 months
期刊介绍: Macromolecular Bioscience is a leading journal at the intersection of polymer and materials sciences with life science and medicine. With an Impact Factor of 2.895 (2018 Journal Impact Factor, Journal Citation Reports (Clarivate Analytics, 2019)), it is currently ranked among the top biomaterials and polymer journals. Macromolecular Bioscience offers an attractive mixture of high-quality Reviews, Feature Articles, Communications, and Full Papers. With average reviewing times below 30 days, publication times of 2.5 months and listing in all major indices, including Medline, Macromolecular Bioscience is the journal of choice for your best contributions at the intersection of polymer and life sciences.
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