Guanidinylated neomycin delivers large, bioactive cargo into cells through a heparan sulfate-dependent pathway

  • Elson-Schwab L
  • Garner O
  • Schuksz M
 et al. 
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Facilitating the uptake of molecules into living cells is of substantial
interest for basic research and drug delivery applications. Arginine-rich
peptides have been shown to facilitate uptake of high molecular mass
cargos into cells, but the mechanism of uptake is complex and may
involve multiple receptors. In this report, we show that a derivative
of the aminoglycoside antibiotic neomycin, in which all of the ammonium
groups have been converted into guanidinium groups, can carry large
(>300 kDa) bioactive molecules across cell membranes. Delivery occurs
at nanomolar transporter concentrations and under these conditions
depends entirely on cell surface heparan sulfate proteoglycans. Conjugation
of guanidinoneomycin to the plant toxin saporin, a ribosome-inactivating
agent, results in proteoglycan-dependent cell toxicity. In contrast,
an arginine-rich peptide shows both heparan sulfate-dependent and
-independent cellular uptake. The high selectivity of guanidinoneomycin
for heparan sulfate suggests the possibility of exploiting differences
in proteoglycan compositions to target delivery to different cell

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  • Lev Elson-Schwab

  • Omai B. Garner

  • Manuela Schuksz

  • Brett E. Crawford

  • Jeffrey D. Esko

  • Yitzhak Tor

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