Hydrophobic Optimization of Functional Poly(TPAE-co-suberoyl chloride) for Extrahepatic mRNA Delivery following Intravenous Administration

Messenger RNA (mRNA) has generated great attention due to its broad potential therapeutic applications, including vaccines, protein replacement therapy, and immunotherapy. Compared to other nucleic acids (e.g., siRNA and pDNA), there are more opportunities to improve the delivery efficacy of mRNA th...

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Autores principales:	Xueliang Yu, Shuai Liu, Qiang Cheng, Sang M. Lee, Tuo Wei, Di Zhang, Lukas Farbiak, Lindsay T. Johnson, Xu Wang, Daniel John Siegwart
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	polyesters nanoparticles polyplex mRNA delivery luciferase mRNA Cre recombinase mRNA Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/d4c84e7de6404a5fad7c36abe82adb46
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spelling	oai:doaj.org-article:d4c84e7de6404a5fad7c36abe82adb462021-11-25T18:41:45ZHydrophobic Optimization of Functional Poly(TPAE-co-suberoyl chloride) for Extrahepatic mRNA Delivery following Intravenous Administration10.3390/pharmaceutics131119141999-4923https://doaj.org/article/d4c84e7de6404a5fad7c36abe82adb462021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1914https://doaj.org/toc/1999-4923Messenger RNA (mRNA) has generated great attention due to its broad potential therapeutic applications, including vaccines, protein replacement therapy, and immunotherapy. Compared to other nucleic acids (e.g., siRNA and pDNA), there are more opportunities to improve the delivery efficacy of mRNA through systematic optimization. In this report, we studied a high-throughput library of 1200 functional polyesters for systemic mRNA delivery. We focused on the chemical investigation of hydrophobic optimization as a method to adjust mRNA polyplex stability, diameter, pKa, and efficacy. Focusing on a region of the library heatmap (PE4K-A17), we further explored the delivery of luciferase mRNA to IGROV1 ovarian cancer cells in vitro and to C57BL/6 mice in vivo following intravenous administration. PE4K-A17-0.2C8 was identified as an efficacious carrier for delivering mRNA to mouse lungs. The delivery selectivity between organs (lungs versus spleen) was found to be tunable through chemical modification of polyesters (both alkyl chain length and molar ratio in the formulation). Cre recombinase mRNA was delivered to the Lox-stop-lox tdTomato mouse model to study potential application in gene editing. Overall, we identified a series of polymer-mRNA polyplexes stabilized with Pluronic F-127 for safe and effective delivery to mouse lungs and spleens. Structure–activity relationships between alkyl side chains and in vivo delivery were elucidated, which may be informative for the continued development of polymer-based mRNA delivery.Xueliang YuShuai LiuQiang ChengSang M. LeeTuo WeiDi ZhangLukas FarbiakLindsay T. JohnsonXu WangDaniel John SiegwartMDPI AGarticlepolyestersnanoparticlespolyplexmRNA deliveryluciferase mRNACre recombinase mRNAPharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1914, p 1914 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	polyesters nanoparticles polyplex mRNA delivery luciferase mRNA Cre recombinase mRNA Pharmacy and materia medica RS1-441
spellingShingle	polyesters nanoparticles polyplex mRNA delivery luciferase mRNA Cre recombinase mRNA Pharmacy and materia medica RS1-441 Xueliang Yu Shuai Liu Qiang Cheng Sang M. Lee Tuo Wei Di Zhang Lukas Farbiak Lindsay T. Johnson Xu Wang Daniel John Siegwart Hydrophobic Optimization of Functional Poly(TPAE-co-suberoyl chloride) for Extrahepatic mRNA Delivery following Intravenous Administration
description	Messenger RNA (mRNA) has generated great attention due to its broad potential therapeutic applications, including vaccines, protein replacement therapy, and immunotherapy. Compared to other nucleic acids (e.g., siRNA and pDNA), there are more opportunities to improve the delivery efficacy of mRNA through systematic optimization. In this report, we studied a high-throughput library of 1200 functional polyesters for systemic mRNA delivery. We focused on the chemical investigation of hydrophobic optimization as a method to adjust mRNA polyplex stability, diameter, pKa, and efficacy. Focusing on a region of the library heatmap (PE4K-A17), we further explored the delivery of luciferase mRNA to IGROV1 ovarian cancer cells in vitro and to C57BL/6 mice in vivo following intravenous administration. PE4K-A17-0.2C8 was identified as an efficacious carrier for delivering mRNA to mouse lungs. The delivery selectivity between organs (lungs versus spleen) was found to be tunable through chemical modification of polyesters (both alkyl chain length and molar ratio in the formulation). Cre recombinase mRNA was delivered to the Lox-stop-lox tdTomato mouse model to study potential application in gene editing. Overall, we identified a series of polymer-mRNA polyplexes stabilized with Pluronic F-127 for safe and effective delivery to mouse lungs and spleens. Structure–activity relationships between alkyl side chains and in vivo delivery were elucidated, which may be informative for the continued development of polymer-based mRNA delivery.
format	article
author	Xueliang Yu Shuai Liu Qiang Cheng Sang M. Lee Tuo Wei Di Zhang Lukas Farbiak Lindsay T. Johnson Xu Wang Daniel John Siegwart
author_facet	Xueliang Yu Shuai Liu Qiang Cheng Sang M. Lee Tuo Wei Di Zhang Lukas Farbiak Lindsay T. Johnson Xu Wang Daniel John Siegwart
author_sort	Xueliang Yu
title	Hydrophobic Optimization of Functional Poly(TPAE-co-suberoyl chloride) for Extrahepatic mRNA Delivery following Intravenous Administration
title_short	Hydrophobic Optimization of Functional Poly(TPAE-co-suberoyl chloride) for Extrahepatic mRNA Delivery following Intravenous Administration
title_full	Hydrophobic Optimization of Functional Poly(TPAE-co-suberoyl chloride) for Extrahepatic mRNA Delivery following Intravenous Administration
title_fullStr	Hydrophobic Optimization of Functional Poly(TPAE-co-suberoyl chloride) for Extrahepatic mRNA Delivery following Intravenous Administration
title_full_unstemmed	Hydrophobic Optimization of Functional Poly(TPAE-co-suberoyl chloride) for Extrahepatic mRNA Delivery following Intravenous Administration
title_sort	hydrophobic optimization of functional poly(tpae-co-suberoyl chloride) for extrahepatic mrna delivery following intravenous administration
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/d4c84e7de6404a5fad7c36abe82adb46
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Hydrophobic Optimization of Functional Poly(TPAE-co-suberoyl chloride) for Extrahepatic mRNA Delivery following Intravenous Administration

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