利用尺寸排阻色谱法和双角光散射法定量分析人血浆和血清中 mRNA 脂质纳米粒子的稳定性。

IF 4.2 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Nanomedicine : nanotechnology, biology, and medicine Pub Date : 2024-03-16 DOI:10.1016/j.nano.2024.102745
Brian Liau PhD , Li Zhang PhD , Melgious Jin Yan Ang PhD , Jian Yao Ng PhD , Suresh Babu C.V. PhD , Sonja Schneider PhD , Ravindra Gudihal PhD , Ki Hyun Bae PhD , Yi Yan Yang PhD
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摘要

了解 mRNA 脂质纳米颗粒(mRNA-LNPs)的稳定性对其临床开发至关重要。在此,我们提出使用尺寸排阻色谱-双角光散射(SEC-MALS)作为评估纯人血清和血浆中 mRNA-LNP 稳定性的新方法。通过采用双柱配置来减弱血浆成分的干扰,SEC-MALS能够阐明mRNA-LNPs的降解动力学和物理性质变化,而传统的动态光散射技术无法准确观察到这些变化。有趣的是,血清和血浆对 mRNA-LNPs 分子量和回旋半径的影响明显不同,这表明凝血因子参与了 mRNA-LNPs 脂质的解吸。我们还发现,ALC-0315 中的痕量杂质(约 1%),即其 O-叔丁氧羰基保护形式,大大降低了 mRNA-LNP 在血清中的稳定性。这些结果证明了 SEC-MALS 在 LNP 制剂的优化和质量控制方面的潜在用途。
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Quantitative analysis of mRNA-lipid nanoparticle stability in human plasma and serum by size-exclusion chromatography coupled with dual-angle light scattering

Understanding the stability of mRNA loaded lipid nanoparticles (mRNA-LNPs) is imperative for their clinical development. Herein, we propose the use of size-exclusion chromatography coupled with dual-angle light scattering (SEC-MALS) as a new approach to assessing mRNA-LNP stability in pure human serum and plasma. By applying a dual-column configuration to attenuate interference from plasma components, SEC-MALS was able to elucidate the degradation kinetics and physical property changes of mRNA-LNPs, which have not been observed accurately by conventional dynamic light scattering techniques. Interestingly, both serum and plasma had significantly different impacts on the molecular weight and radius of gyration of mRNA-LNPs, suggesting the involvement of clotting factors in desorption of lipids from mRNA-LNPs. We also discovered that a trace impurity (~1 %) in ALC-0315, identified as its O-tert-butyloxycarbonyl-protected form, greatly diminished mRNA-LNP stability in serum. These results demonstrated the potential utility of SEC-MALS for optimization and quality control of LNP formulations.

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来源期刊
CiteScore
11.10
自引率
0.00%
发文量
133
审稿时长
42 days
期刊介绍: The mission of Nanomedicine: Nanotechnology, Biology, and Medicine (Nanomedicine: NBM) is to promote the emerging interdisciplinary field of nanomedicine. Nanomedicine: NBM is an international, peer-reviewed journal presenting novel, significant, and interdisciplinary theoretical and experimental results related to nanoscience and nanotechnology in the life and health sciences. Content includes basic, translational, and clinical research addressing diagnosis, treatment, monitoring, prediction, and prevention of diseases.
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