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Cytosolic delivery of macromolecules: I. Synthesis and characterization of pH-sensitive acyloxyalkylimidazoles.

Publication ,  Journal Article
Chen, F-J; Asokan, A; Cho, MJ
Published in: Biochim Biophys Acta
April 1, 2003

A series of 1-(acyloxyalkyl)imidazoles (AAI) were synthesized by nucleophilic substitution of chloroalkyl esters of fatty acids with imidazole. The former was prepared from fatty acid chloride and an aldehyde. When incorporated into liposomes, these lipids show an apparent pK(a) value ranging from 5.12 for 1-(palmitoyloxymethyl)imidazole (PMI) to 5.29 for 1-[(alpha-myristoyloxy)ethyl]imidazole (alpha-MEI) as determined by a fluorescence assay. When the imidazole moiety was protonated, the lipids were surface-active, as demonstrated by hemolytic activity towards red blood cells. As expected, AAI were hydrolyzed in serum as well as in cell homogenate. They were significantly less toxic than biochemically stable N-dodecylimidazole (NDI) towards Chinese hamster ovary (CHO) and RAW 264.7 (RAW) cells as determined by MTT assay. When fed to RAW cells, fluorescein-labeled oligonucleotides encapsulated in liposomes containing 20 mol% 1-(stearoyloxymethyl)imidazole (SMI) resulted in punctate as well as partially diffuse fluorescence. In a functional assay involving down-regulation of luciferase in CV-1 cells, neutral liposomes containing imidazole lipids showed suboptimal delivery of antisense phosphorothioate oligomers. Taken together, the results suggest that AAI are of potential use in developing nontoxic, pH-sensitive liposomes. However, these liposomal formulations need to be optimized to achieve higher concentrations of pH-sensitive detergents within the endosome to facilitate efficient cytosolic release of liposome-entrapped contents.

Duke Scholars

Published In

Biochim Biophys Acta

DOI

ISSN

0006-3002

Publication Date

April 1, 2003

Volume

1611

Issue

1-2

Start / End Page

140 / 150

Location

Netherlands

Related Subject Headings

  • Surface-Active Agents
  • Molecular Structure
  • Macromolecular Substances
  • Liposomes
  • Imidazoles
  • Hydrogen-Ion Concentration
  • Fatty Acids
  • Endosomes
  • Drug Stability
  • Drug Carriers
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Chen, F.-J., Asokan, A., & Cho, M. J. (2003). Cytosolic delivery of macromolecules: I. Synthesis and characterization of pH-sensitive acyloxyalkylimidazoles. Biochim Biophys Acta, 1611(1–2), 140–150. https://doi.org/10.1016/s0005-2736(03)00049-x
Chen, Feng-Jing, Aravind Asokan, and Moo J. Cho. “Cytosolic delivery of macromolecules: I. Synthesis and characterization of pH-sensitive acyloxyalkylimidazoles.Biochim Biophys Acta 1611, no. 1–2 (April 1, 2003): 140–50. https://doi.org/10.1016/s0005-2736(03)00049-x.
Chen F-J, Asokan A, Cho MJ. Cytosolic delivery of macromolecules: I. Synthesis and characterization of pH-sensitive acyloxyalkylimidazoles. Biochim Biophys Acta. 2003 Apr 1;1611(1–2):140–50.
Chen, Feng-Jing, et al. “Cytosolic delivery of macromolecules: I. Synthesis and characterization of pH-sensitive acyloxyalkylimidazoles.Biochim Biophys Acta, vol. 1611, no. 1–2, Apr. 2003, pp. 140–50. Pubmed, doi:10.1016/s0005-2736(03)00049-x.
Chen F-J, Asokan A, Cho MJ. Cytosolic delivery of macromolecules: I. Synthesis and characterization of pH-sensitive acyloxyalkylimidazoles. Biochim Biophys Acta. 2003 Apr 1;1611(1–2):140–150.

Published In

Biochim Biophys Acta

DOI

ISSN

0006-3002

Publication Date

April 1, 2003

Volume

1611

Issue

1-2

Start / End Page

140 / 150

Location

Netherlands

Related Subject Headings

  • Surface-Active Agents
  • Molecular Structure
  • Macromolecular Substances
  • Liposomes
  • Imidazoles
  • Hydrogen-Ion Concentration
  • Fatty Acids
  • Endosomes
  • Drug Stability
  • Drug Carriers