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具有高效表达和良好安全性的用于mRNA递送的阴离子复合物。

Anionic Complex with Efficient Expression and Good Safety Profile for mRNA Delivery.

作者信息

Hamada Eri, Kurosaki Tomoaki, Hashizume Junya, Harasawa Hitomi, Nakagawa Hiroo, Nakamura Tadahiro, Kodama Yukinobu, Sasaki Hitoshi

机构信息

Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan.

Department of Hospital Pharmacy, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.

出版信息

Pharmaceutics. 2021 Jan 19;13(1):126. doi: 10.3390/pharmaceutics13010126.

DOI:10.3390/pharmaceutics13010126
PMID:33478077
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7835867/
Abstract

We previously found that a complex comprising plasmid DNA (pDNA), polyethylenimine (PEI), and γ-polyglutamic acid (γ-PGA) had high transgene efficiency without cytotoxicity in vitro and in vivo. However, messenger RNA (mRNA) remains an attractive alternative to pDNA. In this study, we developed a safe and effective delivery system for mRNA to prevent its degradation and efficiently deliver it into target cells. Various cationic and anionic complexes were produced containing PEI, γ-PGA, and an mRNA encoding firefly luciferase. Their physicochemical properties and cytotoxicities were analyzed and the in vitro and in vivo protein expression were determined. The cationic mRNA/PEI complex showed high in vitro protein expression with strong cytotoxicity. The anionic complex was constructed as mRNA/PEI8/γ-PGA12 complex with a theoretical charge ratio of 1:8:12 based on the phosphate groups of the mRNA, nitrogen groups of PEI, and carboxylate groups of γ-PGA. It was stable and showed high in vitro protein expression without cytotoxicity. After intravenous administration of mRNA/PEI8/γ-PGA12 complex to mice, high protein expression was observed in the spleen and liver and slight expression was observed in the lung over 24 h. Thus, the newly constructed mRNA/PEI8/γ-PGA12 complex provides a safe and effective strategy for the delivery of mRNA.

摘要

我们之前发现，一种由质粒DNA（pDNA）、聚乙烯亚胺（PEI）和γ-聚谷氨酸（γ-PGA）组成的复合物在体外和体内均具有高转基因效率且无细胞毒性。然而，信使核糖核酸（mRNA）仍然是pDNA的一种有吸引力的替代物。在本研究中，我们开发了一种安全有效的mRNA递送系统，以防止其降解并有效地将其递送至靶细胞。制备了包含PEI、γ-PGA和编码萤火虫荧光素酶的mRNA的各种阳离子和阴离子复合物。分析了它们的理化性质和细胞毒性，并测定了体外和体内的蛋白质表达。阳离子mRNA/PEI复合物在体外显示出高蛋白质表达，但具有较强的细胞毒性。阴离子复合物构建为mRNA/PEI8/γ-PGA12复合物，基于mRNA的磷酸基团、PEI的氮基团和γ-PGA的羧酸盐基团，其理论电荷比为1:8:12。它很稳定，在体外显示出高蛋白质表达且无细胞毒性。将mRNA/PEI八/γ-PGA12复合物静脉注射给小鼠后，在24小时内，脾脏和肝脏中观察到高蛋白表达，肺中观察到轻微表达。因此，新构建的mRNA/PEI8/γ-PGA12复合物为mRNA的递送提供了一种安全有效的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/1aa3fb9176d5/pharmaceutics-13-00126-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/4e06b8fa07ed/pharmaceutics-13-00126-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/9a6c7405e1aa/pharmaceutics-13-00126-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/995b4b4e6007/pharmaceutics-13-00126-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/b57acbf6eff6/pharmaceutics-13-00126-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/448c3a5eddfa/pharmaceutics-13-00126-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/78056a5c42cc/pharmaceutics-13-00126-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/595369d3ca34/pharmaceutics-13-00126-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/6f06f212f184/pharmaceutics-13-00126-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/2e58750dcf08/pharmaceutics-13-00126-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/1aa3fb9176d5/pharmaceutics-13-00126-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/4e06b8fa07ed/pharmaceutics-13-00126-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/9a6c7405e1aa/pharmaceutics-13-00126-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/995b4b4e6007/pharmaceutics-13-00126-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/b57acbf6eff6/pharmaceutics-13-00126-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/448c3a5eddfa/pharmaceutics-13-00126-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/78056a5c42cc/pharmaceutics-13-00126-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/595369d3ca34/pharmaceutics-13-00126-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/6f06f212f184/pharmaceutics-13-00126-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/2e58750dcf08/pharmaceutics-13-00126-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ccf0/7835867/1aa3fb9176d5/pharmaceutics-13-00126-g010.jpg

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