Synthesis and Biological Evaluation of Ionizable Lipid Materials for the In Vivo Delivery of Messenger RNA to B Lymphocytes.

Autor:	Fenton OS; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Kauffman KJ; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA., Kaczmarek JC; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA., McClellan RL; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA., Jhunjhunwala S; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA., Tibbitt MW; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA., Zeng MD; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA., Appel EA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA., Dorkin JR; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Mir FF; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA., Yang JH; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA., Oberli MA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA., Heartlein MW; Shire Pharmaceuticals, Lexington, MA, 02421, USA., DeRosa F; Shire Pharmaceuticals, Lexington, MA, 02421, USA., Langer R; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Anderson DG; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Jazyk:	angličtina
Zdroj:	Advanced materials (Deerfield Beach, Fla.) [Adv Mater] 2017 Sep; Vol. 29 (33). Date of Electronic Publication: 2017 Jul 06.
DOI:	10.1002/adma.201606944
Abstrakt:	B lymphocytes regulate several aspects of immunity including antibody production, cytokine secretion, and T-cell activation; moreover, B cell misregulation is implicated in autoimmune disorders and cancers such as multiple sclerosis and non-Hodgkin's lymphomas. The delivery of messenger RNA (mRNA) into B cells can be used to modulate and study these biological functions by means of inducing functional protein expression in a dose-dependent and time-controlled manner. However, current in vivo mRNA delivery systems fail to transfect B lymphocytes and instead primarily target hepatocytes and dendritic cells. Here, the design, synthesis, and biological evaluation of a lipid nanoparticle (LNP) system that can encapsulate mRNA, navigate to the spleen, transfect B lymphocytes, and induce more than 60 pg of protein expression per million B cells within the spleen is described. Importantly, this LNP induces more than 85% of total protein production in the spleen, despite LNPs being observed transiently in the liver and other organs. These results demonstrate that LNP composition alone can be used to modulate the site of protein induction in vivo, highlighting the critical importance of designing and synthesizing new nanomaterials for nucleic acid delivery. (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze:	MEDLINE
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