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Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches
Wang, Wei1,2; Deng, Shiwei1,2; Lin, Jinzhong3,4,5; Ouyang, Defang1,2
2024-10
Source PublicationActa Pharmaceutica Sinica B
ISSN2211-3835
Volume14Issue:10Pages:4591-4607
Abstract

The lipid nanoparticle (LNP) has been so far proven as a strongly effective delivery system for mRNA and siRNA. However, the mechanisms of LNP's distribution, metabolism, and elimination are complicated, while the transportation and pharmacokinetics (PK) of LNP are just sparsely investigated and simply described. This study aimed to build a model for the transportation of RNA-LNP in Hela cells, rats, mice, and humans by physiologically based pharmacokinetic (PBPK) and quantum mechanics (QM) models with integrated multi-source data. LNPs with different ionizable lipids, particle sizes, and doses were modeled and compared by recognizing their critical parameters dominating PK. Some interesting results were found by the models. For example, the metabolism of ionizable lipids was first limited by the LNP disassembly rate instead of the hydrolyzation of ionizable lipids; the ability of RNA release from endosomes for three ionizable lipids was quantitively derived and can predict the probability of RNA release. Moreover, the biodegradability of three ionizable lipids was estimated by the QM method and the is generally consistent with the result of PBPK result. In summary, the transportation model of RNA LNP among various species for the first time was successfully constructed. Various in vitro and in vivo pieces of evidence were integrated through QM/PBPK multi-level modeling. The resulting new understandings are related to biodegradability, safety, and RNA release ability which are highly concerned issues of the formulation. This would benefit the design and research of RNA-LNP in the future.

KeywordLipid Nanoparticle Rna Ionizable Lipid In Vivo Transportation Endosomal Escape Metabolism Quantum Mechanics Physiologically-based Pharmacokinetics
DOI10.1016/j.apsb.2024.06.011
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:001343922600001
PublisherINST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES, C/O EDITORIAL BOARD OF ACTA PHARMACEUTICA SINICA, 1 XIANNONGTAN ST, BEIJING 100050, PEOPLES R CHINA
Scopus ID2-s2.0-85200234033
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Citation statistics
Document TypeJournal article
CollectionFaculty of Health Sciences
Institute of Chinese Medical Sciences
THE STATE KEY LABORATORY OF QUALITY RESEARCH IN CHINESE MEDICINE (UNIVERSITY OF MACAU)
Corresponding AuthorOuyang, Defang
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, 999078, China
2.Faculty of Health Sciences, University of Macau, Macau, 999078, China
3.State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China
4.Center for mRNA Translational Research, Fudan University, Shanghai, 200438, China
5.Zhangjiang mRNA Innovation and Translation Center, Fudan University, Shanghai, 200438, China
First Author AffilicationInstitute of Chinese Medical Sciences;  Faculty of Health Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences;  Faculty of Health Sciences
Recommended Citation
GB/T 7714
Wang, Wei,Deng, Shiwei,Lin, Jinzhong,et al. Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches[J]. Acta Pharmaceutica Sinica B, 2024, 14(10), 4591-4607.
APA Wang, Wei., Deng, Shiwei., Lin, Jinzhong., & Ouyang, Defang (2024). Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches. Acta Pharmaceutica Sinica B, 14(10), 4591-4607.
MLA Wang, Wei,et al."Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches".Acta Pharmaceutica Sinica B 14.10(2024):4591-4607.
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