Cellular uptake of substrate-initiated cell-penetrating poly(disulfide)s

Giulio Gasparini, Eun Kyoung Bang, Guillaume Molinard, David V. Tulumello, Sandra Ward, Shana O. Kelley, Aurelien Roux, Naomi Sakai, Stefan Matile*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

175 Scopus citations


Substrate-initiated, self-inactivating, cell-penetrating poly(disulfide)s (siCPDs) are introduced as general transporters for the covalent delivery of unmodified substrates of free choice. With ring-opening disulfide-exchange polymerization, we show that guanidinium-rich siCPDs grow on fluorescent substrates within minutes under the mildest conditions. The most active siCPD transporters reach the cytosol of HeLa cells within 5 min and depolymerize in less than 1 min to release the native substrate. Depolymerized right after use, the best siCPDs are nontoxic under conditions where cell-penetrating peptides (CPPs) are cytotoxic. Intracellular localization (cytosol, nucleoli, endosomes) is independent of the substrate and can be varied on demand, through choice of polymer composition. Insensitivity to endocytosis inhibitors and classical structural variations (hydrophobicity, aromaticity, branching, boronic acids) suggest that the best siCPDs act differently. Supported by experimental evidence, a unique combination of the counterion-mediated translocation of CPPs with the underexplored, thiol-mediated covalent translocation is considered to account for this decisive difference.

Original languageEnglish (US)
Pages (from-to)6069-6074
Number of pages6
JournalJournal of the American Chemical Society
Issue number16
StatePublished - Apr 23 2014
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry


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