Targeted Shiga toxin-drug conjugates prepared via Cu-free click chemistry.
The main drawback of the anticancer chemotherapy consists in the lack of drug selectivity causing severe side effects. The targeted drug delivery appears to be a very promising strategy for controlling the biodistribution of the cytotoxic agent only on malignant tissues by linking it to tumor-targeting moiety. Here we exploit the natural characteristics of Shiga toxin B sub-unit (STxB) as targeting carrier on Gb3-positive cancer cells. Two cytotoxic conjugates STxB-doxorubicin (STxB-Doxo) and STxB-monomethyl auristatin F (STxB-MMAF) were synthesised using copper-free 'click' chemistry. Both conjugates were obtained in very high yield and demonstrated strong tumor inhibition activity in a nanomolar range on Gb3-positive cells.
Institut Curie, CNRS, UMR 3666/INSERM U1143, 26 rue d'Ulm, 75248 Cedex 05 Paris, France.
Vesela
V
Kostova
Institut Curie, CNRS, UMR 3666/INSERM U1143, 26 rue d'Ulm, 75248 Cedex 05 Paris, France.
Estelle
E
Dransart
Institut Curie, CNRS, UMR 3666/INSERM U1143, 26 rue d'Ulm, 75248 Cedex 05 Paris, France.
Michel
M
Azoulay
Institut Curie, CNRS, UMR 3666/INSERM U1143, 26 rue d'Ulm, 75248 Cedex 05 Paris, France.
Laura
L
Brulle
Institut Curie, CNRS, UMR 3666/INSERM U1143, 26 rue d'Ulm, 75248 Cedex 05 Paris, France.
Siau-Kun
SK
Bai
Institut Curie, CNRS, UMR 3666/INSERM U1143, 26 rue d'Ulm, 75248 Cedex 05 Paris, France.
Jean-Claude
JC
Florent
Institut Curie, CNRS, UMR 3666/INSERM U1143, 26 rue d'Ulm, 75248 Cedex 05 Paris, France.
Ludger
L
Johannes
Institut Curie, CNRS, UMR 3666/INSERM U1143, 26 rue d'Ulm, 75248 Cedex 05 Paris, France. Electronic address: Frederic.Schmidt@curie.fr.
Frédéric
F
Schmidt
D000906:Antibodies / Q000276:immunology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001692:Biological Transport; D002470:Cell Survival / Q000187:drug effects; D057930:Click Chemistry; D003300:Copper / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry* / Q000633:toxicity; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D015195:Drug Design; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D009842:Oligopeptides / Q000737:chemistry* / Q000633:toxicity; D022621:Shiga Toxin / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D000970:Antineoplastic Agents; D004337:Drug Carriers; D009842:Oligopeptides; C513576:monomethylauristatin F; D022621:Shiga Toxin; D003300:Copper; D004317:Doxorubicin
Auristatin; Copper-free click; Doxorubicin; Shiga toxin; Targeted drug delivery