序列对功能性siRNA传递和基因淘汰与循环两性传递剂的序列的影响
Melissa L Jagrosse1, Uday K Baliga2, Christopher W Jones1
1Department of Chemistry, University of Rochester, Rochester, New York 14627-0216, United States.
Molecular pharmaceutics
|November 14, 2023
概括
修改的细胞透 (CAPs) 增强短干扰RNA (siRNA) 传递用于基因沉默. 循环,带有芳香残留的阴离子CAP显示了较好的siRNA结合和细胞吸收,从而通过内细胞分裂有效地降低了基因.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药物运输 药物运输 药物运输
背景情况:
- 短干扰RNA (siRNA) 疗法通过通过RNA干扰 (RNAi) 调节基因表达来治疗疾病.
- siRNA的临床应用受到有效和安全的细胞输送方面的挑战所阻碍.
- 细胞透 (CAPs) 被研究为核酸治疗药物的载体.
研究的目的:
- 为了研究修改的循环两性细胞透 (CAPs) 的结构-功能关系,用于siRNA传递.
- 确定CAP序列如何影响siRNA结合,细胞传递,基因淘汰效率和吸收机制.
- 为优化基于CAP的siRNA传递系统建立设计原则.
主要方法:
- 合成和表征9个周期性CAPs (Ac-C[XZ]4CG-NH2) 和一个非周期性CAP (Ac-(WR) 4G-NH2) 与不同的疏水性/芳香性 (X) 和充电性/水性 (Z) 残留物.
- 使用结合分析评估siRNA结合亲和力.
- 在体外细胞传递和基因淘汰效率的评估.
- 使用小分子抑制剂和蛋白质淘汰来研究内细胞吸收机制.
主要成果:
- CAP-siRNA的结合亲和力随着阴阳性和芳香残留含量 (Trp > Tyr > Phe > His) 的增加.
- 循环和CAPs的阴离子电荷显著增强了siRNA的吸收和输送在体外.
- 所有测试的CAP实现了至少50%的基因淘汰,最佳CAP超过80%;淘汰效率与结合亲和力相对应适度,与内化不强.
- CAP-siRNA纳米颗粒主要通过克拉特林和卡韦林介导的内细胞酶内化.
结论:
- 具有特定芳香残留的循环,阴离子CAPs是siRNA传递的有效载体.
- -siRNA结合亲和力和CAP结构影响细胞传递和基因沉默功效.
- 了解结合,输送和敲击之间的相互作用对于设计下一代寡核酸输送材料至关重要.
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