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The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.

Optimization of Lipid Nanoparticle Formulations for mRNA Delivery in Vivo with Fractional Factorial and Definitive Screening Designs

Kauffman, Kevin J., Dorkin, J. Robert, Yang, Jung H., Heartlein, Michael W., DeRosa, Frank, Mir, Faryal F., Fenton, Owen S., Anderson, Daniel G.·2015·Nano Letters
DOI 10.1021/acs.nanolett.5b02497
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Abstract

Intracellular delivery of messenger RNA (mRNA) has the potential to induce protein production for many therapeutic applications. Although lipid nanoparticles have shown considerable promise for the delivery of small interfering RNAs (siRNA), their utility as agents for mRNA delivery has only recently been investigated. The most common siRNA formulations contain four components: an amine-containing lipid or lipid-like material, phospholipid, cholesterol, and lipid-anchored polyethylene glycol, the relative ratios of which can have profound effects on the formulation potency. Here, we develop a generalized strategy to optimize lipid nanoparticle formulations for mRNA delivery to the liver in vivo using Design of Experiment (DOE) methodologies including Definitive Screening and Fractional Factorial Designs. By simultaneously varying lipid ratios and structures, we developed an optimized formulation which increased the potency of erythropoietin-mRNA-loaded C12-200 lipid nanoparticles 7-fold relative to formulations previously used for siRNA delivery. Key features of this optimized formulation were the incorporation of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and increased ionizable lipid:mRNA weight ratios. Interestingly, the optimized lipid nanoparticle formulation did not improve siRNA delivery, indicating differences in optimized formulation parameter design spaces for siRNA and mRNA. We believe the general method described here can accelerate in vivo screening and…

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Metadata

Authors
Kauffman, K. J., Dorkin, J. R., Yang, J. H., Heartlein, M. W., DeRosa, F., Mir, F. F., Fenton, O. S., & Anderson, D. G.
Affiliations
Shire Pharmaceuticals, Lexington, Massachusetts 02421, United States
Venue
Nano Letters
Publisher
American Chemical Society (ACS)
Published
2015-10-20
Volume
15
Issue
11
Pages
7300-7306
ISSN
  • 1530-6984
  • 1530-6992
DOI
10.1021/acs.nanolett.5b02497
Cited by
796
References
11
Language
en
Funders
  • Shire
  • Skolkovo Institute of Science and Technology, Massachusetts Institute of Technology

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