Enhanced cellular uptake of maleimide-modified liposomes via thiol-mediated transport

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

With a small amount of maleimide modification on the liposome surface, enhanced cellular uptake of liposomes and drug-delivery efficiency can be obtained both in vitro and in vivo. Herein, we describe the mechanisms underlying this enhanced cellular uptake. Suppression of the cellular uptake of maleimide-modified liposomes (M-GGLG, composed of 1,5-dihexadecyl N,N-diglutamyl-lysyl-L-glutamate [GGLG]/cholesterol/poly(ethylene glycol) - 1,2-distearoyl-sn-glycero-3-phosphoethanolamine [PEG5000-DSPE]/maleimide [M]-PEG5000-Glu2C18 at a molar ratio of 5:5:0.03:0.03) caused by temperature block and addition of serum was alleviated compared with that of liposomes without maleimide modification (GGLG liposomes, composed of GGLG/cholesterol/PEG5000-DSPE/PEG5000-Glu2C18 at a molar ratio of 5:5:0.03:0.03). When 0.01 nM N-ethylmaleimide was used to pre-block cellular thiols, the cellular uptake of M-GGLG liposomes was decreased to approximately 70% in HeLa, HCC1954, MDA-MB-468, and COS-7 cell lines. Moreover, inhibition of a thiol-related reductase such as protein disulfide isomerase resulted in a 15%-45% inhibition of the cellular uptake of M-GGLG liposomes, whereas GGLG liposomes were not influenced. Further, single and mixed inhibitors of clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis did not efficiently inhibit the cellular uptake of M-GGLG liposomes. Using confocal microscopy, we verified that M-GGLG liposomes were localized partially in lysosomes after inhibition of the mentioned conventional endocytic pathways. Therefore, it was hypothesized that the mechanisms underlying the enhanced cellular uptake of liposomes by maleimide modification was thiol-mediated membrane trafficking, including endocytosis and energy-independent transport.

Original languageEnglish
Pages (from-to)2849-2861
Number of pages13
JournalInternational Journal of Nanomedicine
Volume9
Issue number1
DOIs
Publication statusPublished - 2014 Jun 5

Fingerprint

Liposomes
Sulfhydryl Compounds
Endocytosis
Cholesterol
maleimide
Protein Disulfide-Isomerases
Caveolae
Clathrin
Ethylmaleimide
Ethylene Glycol
Confocal microscopy
COS Cells
Lysosomes
Drug delivery
Confocal Microscopy
Polyethylene glycols
Glutamic Acid
Oxidoreductases
Cells
Proteins

Keywords

  • Endocytosis
  • Energy-independent transport
  • Liposome
  • Maleimide
  • Protein disulfide isomerase
  • Thiol reactive

ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Biomaterials
  • Organic Chemistry
  • Drug Discovery
  • Medicine(all)

Cite this

Enhanced cellular uptake of maleimide-modified liposomes via thiol-mediated transport. / Li, Tianshu; Takeoka, Shinji.

In: International Journal of Nanomedicine, Vol. 9, No. 1, 05.06.2014, p. 2849-2861.

Research output: Contribution to journalArticle

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