Hydrophobic Domain Structure of Linear-Dendritic Poly(ethylene glycol) Lipids Affects RNA Delivery of Lipid Nanoparticles

Kejin Zhou, Lindsay T. Johnson, Hu Xiong, Sergio Barrios, Jonathan T. Minnig, Yunfeng Yan, Bethanie Abram, Xueliang Yu, Daniel J. Siegwart

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1575-1585
Number of pages11
JournalMolecular Pharmaceutics
Volume17
Issue number5
DOIs
StatePublished - May 4 2020
Externally publishedYes

Keywords

  • RNA delivery
  • linear-dendritic PEGylated lipids
  • linear-dendritic block copolymers
  • lipid nanoparticles

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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