静电学对AAV9体的聚合,基因组释放和自我相互作用的影响
Lily Motabar1, Veerabhadraiah Palakollu1, Hassan Shahfar1
1Department of Chemical & Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA.
Journal of pharmaceutical sciences
|July 10, 2025
概括
对腺相关病毒 (AAV) 产品的溶液状况的调查显示,静电相互作用显著影响囊的稳定性. pH 和离子强度的变化会影响聚合和基因组释放,这对配方开发至关重要.
科学领域:
- 生物化学和生物物理学
- 分子和结构生物学 分子和结构生物学
- 制药科学 制药科学
背景情况:
- 生物制剂的配方开发需要了解影响生物物理特征的溶液条件.
- 与配方中的传统治疗蛋白相比,腺相关病毒 (AAV) 产品提出了新的挑战.
- 溶液的pH值和离子强度极大地影响静电相互作用,影响体聚合.
研究的目的:
- 检查静电相互作用对腺相关病毒9 (AAV9) 囊聚合,基因组释放和自我相互作用的影响.
- 阐明溶液pH值和离子强度如何在不同的应力条件下调节AAV9体的行为.
主要方法:
- 利用静态光散射来分析不同pH值和离子强度的体-体自我相互作用.
- 采用粗粒度分子模型来预测体对离子强度变化的自我相互作用敏感性.
- 在不同pH值的温度压力下研究了聚合和基因组释放.
主要成果:
- 在pH4.5的聚合在温度应激后被空/部分体加剧,而pH7.4则通过基因组损失有利于降解.
- 从150mM降低离子强度到5mM,诱导可逆聚合物形成,pH影响聚合物反转.
- 静态光散射显示出强大的静电吸引力,在150毫米时驱动囊体-囊体自我相互作用,在pH值4.5时更强的相互作用.
- 分子建模表明,体自身相互作用对pH4.5的离子强度变化具有较高的灵敏度,而pH7.4则相比较.
结论:
- 静电相互作用对于确定腺相关病毒9 (AAV9) 囊体的稳定性至关重要.
- 溶液的pH值和离子强度是关键参数,必须在AAV配方过程中仔细控制,以防止聚合并保持产品完整性.
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