Disulfide-functional poly(amido amine)s with tunable degradability for gene delivery
Disulfide-functional poly(amido amine)s with tunable degradability for gene delivery
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DOI：
10.1016/j.jconrel.2016.08.021
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发表时间：
2016-12-28
影响因子：
10.8
通讯作者：
Paulusse, Jos M. J.
中科院分区：
文献类型：
--
作者：
Elzes, M. Rachel;Akeroyd, Niels;Paulusse, Jos M. J.
响应于局部环境的受控降解性是实现基因从聚合物载体时空释放的最有效策略之一。利用细胞外和细胞内环境之间还原电位的差异，二硫化物经常被掺入聚合物药物递送剂的主链中以确保有效载荷的有效细胞内释放。然而，尽管程度较低，二硫化物的还原也可能发生在细胞外环境中，应加以防止，以避免过早释放。对二硫键稳定性的精确控制使得能够优化用于有效药物递送的聚合物载体。制备了在二硫键附近具有不同空间位阻程度（0、2或4个甲基）的生物可还原聚（酰胺基胺）（PAA），以获得具有可控稳定性的载体。在不同的还原条件下，这些PAA-聚合物的降解行为进行了评估，并在体外毒性和转染效率进行了评估。降解的PAA为基础的复合物始终需要更高的还原强度的空间位阻附近的二硫键增加。基于2-甲基胱胺二硫化物的PAA聚合物（PAA（2 m））的聚合复合物在细胞外谷胱甘肽浓度（0.001- 0.01mM）下保持稳定，而在与细胞内环境（1- 10 mM谷胱甘肽）中的还原条件类似的还原条件下在1小时内降解。该聚合物表现出优异的转染能力，转染细胞的效率高达90%。PAA（0 m）显示出与PAA（2 m）相比略微降低的转染性质，这可能是由于过早降解。然而，严重受阻的PAA（4 m）显示出增加的毒性，伴随着降低的转染效率，这是其异常稳定性的结果。这些结果证明了在二硫键附近引入空间位阻来调节复合物对生物还原的稳定性的可行性，并表明PAA（2 m）是一种有前途的用于基因治疗的聚合物。(C)2016爱思唯尔B. V.保留所有权利。
Controlled degradability in response to the local environment is one of the most effective strategies to achieve spatiotemporal release of genes from a polymeric carrier. Exploiting the differences in reduction potential between the extracellular and intracellular environment, disulfides are frequently incorporated into the backbone of polymeric drug delivery agents to ensure efficient intracellular release of the payload. However, although to a lesser extent, reduction of disulfides may also occur in the extracellular environment and should be prevented to avoid premature release. Accurate control over the stability of disulfide linkages enables the optimization of polymeric carriers for efficient drug delivery. Bioreducible poly(amido amine)s (PAAs) with varying degrees of steric hindrance adjacent to the disulfide bonds (0, 2 or 4 methyl groups) were prepared in order to obtain carriers with controlled stability. The degradation behavior of these PAA-polymers was evaluated under different reducing conditions and their in vitro toxicities and transfection efficiencies were assessed. Degradation of the PAA-based polyplexes consistently required higher reducing strengths as the steric hindrance near the disulfide bonds increased. Polyplexes based on 2-methyl cystamine disulfide based PAA polymer (PAA(2m)) remained stable under extracellular glutathione concentrations (0.001-0.01 mM), while degrading within 1 h under reducing conditions similar to those in the intracellular environment (1- 10 mM glutathione). This polymer exhibited excellent transfection capabilities, with efficiencies up to 90% of transfected cells. PAA(0m) showed slightly reduced transfection properties compared to PAA(2m), likely due to premature degradation. The severely hindered PAA(4m), however, displayed increased toxicity, accompanied by reduced transfection efficiency, as a result of its exceptional stability. These results demonstrate the feasibility of introducing steric hindrance near the disulfide moiety to tune polyplex stability against bioreduction, and showthat PAA(2m) is a promising polymer to be further developed for gene therapy. (C) 2016 Elsevier B.V. All rights reserved.