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Molecular Pharmaceutics: Hydrophobic Domain Structure of Linear-Dendritic Poly(ethylene glycol) Lipids Affects RNA Delivery of Lipid Nanoparticles
作者:Kejin Zhou, Lindsay T. Johnson, Hu Xiong, Sergio Barrios, Jonathan T. Minnig, Yunfeng Yan, Bethanie
關(guān)鍵字:linear-dendritic PEGylated lipids, lipid nanoparticles, RNA delivery, linear-dendritic block copolymers
論文來源:期刊
具體來源:Molecular Pharmaceutics
發(fā)表時(shí)間:2020年

In this work, a series of linear-dendritic poly-

(ethylene glycol) (PEG) lipids (PEG-GnCm) were synthesized

through a strategy using sequential aza- and sulfa-Michael addition

reactions. The effect of modulating the hydrophobic domain of

linear-dendritic PEG lipids was systematically investigated for in

vitro and in vivo small RNA delivery as the surface-stabilizing

component of 5A2-SC8 dendrimer lipid-based nanoparticles

(DLNPs). The lipid alkyl lengths (C8, C12, and C16) and

dendrimer generations (G1, G2, and G3) were altered to create

PEG-GnCm with different physical properties and anchoring

potential. The tail chemical structure of PEG-GnCm did not affect

the formulation of 5A2-SC8 DLNPs, including the nanoparticle

size, RNA encapsulation, and stability. However, the tail chemical structure did dramatically affect the RNA delivery efficacy of the

formed 5A2-SC8 DLNPs with different PEG-GnCm. First-generation PEG lipids (PEG-G1C8, PEG-G1C12, and PEG-G1C16) and

a second-generation PEG lipid (PEG-G2C8) formed 5A2-SC8 DLNPs that could deliver siRNAs effectively in vitro and in vivo. 5A2-

SC8 DLNPs formulated with second-generation PEG lipids (PEG-G2C12 and PEG-G2C16) and all three third-generation PEG

lipids (PEG-G3C8, PEG-G3C12, and PEG-G3C16) lost the ability to deliver siRNA effectively in vitro and in vivo. Overall, we

determined that the hydrophobic domain chemical structure of linear-dendritic poly(ethylene glycol) lipids affected the RNA

delivery of DLNPs by impacting the escape of 5A2-SC8 DLNPs from endosomes at early cell incubation times, thereby indicating

how PEG lipid anchoring and chemical structure can modulate in vitro and in vivo siRNA delivery efficacies.



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