Dataset Information

Safe and Effective Delivery of mRNA Using Modified PEI-Based Lipopolymers.

ABSTRACT: Chemically modified mRNA (modRNA) has proven to be a versatile tool for the treatment of various cancers and infectious diseases due to recent technological advancements. However, a safe and effective delivery system to overcome the complex extracellular and intracellular barriers is required in order to achieve higher therapeutic efficacy and broaden clinical applications. Here, we explored All-Fect and Leu-Fect C as novel transfection reagents derived from lipopolymers, which demonstrated excellent biocompatibility, efficient delivery capabilities, and a robust ability to escape the lysosomes. These properties directly increase mRNA stability by preventing mRNA degradation by nucleases and simultaneously promote efficient gene translation in vitro and in vivo. The modRNA delivered with lipopolymer vectors sustained effective transfection in mouse hearts following direct intramyocardial injection, as well as in major organs (liver and spleen) after systemic administration. No observable immune reactions or systemic toxicity were detected following the systemic administration of lipopolymer-mRNA complexes to additional solid organs. This study identified commercial reagents for the effective delivery of modRNA and may help facilitate the advancement of gene-based interventions involving the safe and effective delivery of nucleic acid drug substances.

SUBMITTER: Wang H

PROVIDER: S-EPMC9967631 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Safe and Effective Delivery of mRNA Using Modified PEI-Based Lipopolymers.

Wang Huijing H Liu Xin X Ai Xuefeng X Remant-Bahadur K C KC Dick Teo A TA Yan Bingqian B Lu Tingting T Zhou Xingliang X Luo Runjiao R Liu Minglu M Wang Xiangying X Li Kaixiang K Wang Wei W Uludag Hasan H Fu Wei W

Pharmaceutics 20230126 2

Chemically modified mRNA (modRNA) has proven to be a versatile tool for the treatment of various cancers and infectious diseases due to recent technological advancements. However, a safe and effective delivery system to overcome the complex extracellular and intracellular barriers is required in order to achieve higher therapeutic efficacy and broaden clinical applications. Here, we explored All-Fect and Leu-Fect C as novel transfection reagents derived from lipopolymers, which demonstrated exce ...[more]

PMID: 36839732

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Project description:Previously, it was reported that mRNA/cationic liposome complexes (mRNA lipoplexes) composed of the cationic triacyl lipid, 11-((1,3-bis(dodecanoyloxy)-2-((dodecanoyloxy)methyl)propan-2-yl)amino)-N,N,N- trimethyl-11-oxoundecan-1-aminium bromide (TC-1-12), with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine and poly(ethylene glycol) cholesteryl ether, induce high protein expression in human cervical carcinoma HeLa cells. In the present study, the authors aimed to optimize mRNA transfection using TC-1-12-based mRNA lipoplexes. mRNA lipoplexes were prepared at various charge ratios (+:-) using modified ethanol injection (MEI) and thin-film hydration (TFH) methods and compared the protein expression efficiency after transfection of HeLa cells with the developed mRNA lipoplexes. Firefly luciferase (FLuc) and enhanced green fluorescent protein (EGFP) mRNA lipoplexes prepared using the MEI method exhibited higher Luc and EGFP expression levels in cells than those prepared using the TFH method. Moreover, FLuc mRNA lipoplexes prepared using the MEI and TFH methods at charge ratios of 3:1 and 4:1, respectively, exhibited the highest Luc expression in cells. However, transfection with mRNA lipoplexes using the MEI and TFH methods induced moderate cytotoxicity in HeLa cells (46 and 57% cell viability, respectively). Furthermore, Cy5-labeled mRNA lipoplexes, which were prepared using the MEI method, showed higher cellular uptake of mRNA than those prepared using the TFH method. In the transfection of FLuc mRNA lipoplexes prepared using the MEI method, the storage of the lipid-ethanol solution at 37˚C for 4 months did not decrease Luc expression in HeLa cells. Additionally, FLuc mRNA lipoplexes prepared using the MEI method, induced relatively high Luc expression in human prostate carcinoma PC-3 and human liver cancer HepG2 cells with low cytotoxicity (103 and 81% cell viability, respectively). Overall, the results highlighted the potential of TC-1-12-based mRNA lipoplexes prepared using the MEI method for efficient mRNA delivery to cells.

Dataset Information

Safe and Effective Delivery of mRNA Using Modified PEI-Based Lipopolymers.

Publications

Safe and Effective Delivery of mRNA Using Modified PEI-Based Lipopolymers.

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