Selective disruption of early/recycling endosomes: release of disulfide-linked cargo mediated by a N-alkyl-3beta-cholesterylamine-capped peptide.
The use of endocytic uptake pathways to deliver poorly permeable molecules into mammalian cells is often plagued by entrapment and degradation of material in late endosomes and lysosomes. As a strategy to prevent the exposure of cargo to these highly hydrolytic membrane-sealed compartments, we synthesized derivatives of the membrane anchor N-alkyl-3beta-cholesterylamine that selectively target linked compounds to less hydrolytic early/recycling endosomes. By targeting a pH-dependent membrane-lytic dodecapeptide and a disulfide-linked fluorophore to these compartments in Chinese hamster ovary cells or Jurkat lymphocytes, membranes of early/recycling endosomes were selectively disrupted, resulting in cleavage of the disulfide and escape of the fluorophore into the cytosol and nucleus with low toxicity. The ability of appropriately designed N-alkyl-3beta-cholesterylamines to deliver cargo into and release disulfide-linked cargo from relatively nonhydrolytic early/recycling endosomes may be useful for the delivery of a variety of sensitive molecules into living mammalian cells.
Sun
Qi
Q
Integrative Biosciences and Chemistry Graduate Programs, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Cai
Sutang
S
Peterson
Blake R
BR
D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006224:Cricetinae; D003412:Cricetulus; D004220:Disulfides / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019169:Jurkat Cells; D010455:Peptides / Q000493:pharmacokinetics*
D004220:Disulfides; D010455:Peptides; C072855:cholesterylamine; D002784:Cholesterol