Synthesis and properties of a mitochondrial peripheral benzodiazepine receptor conjugate.
Peripheral benzodiazepine receptors are potential targets for cancer therapeutics through the use of specific ligands such as the pro-apoptotic benzodiazepine RO5-4864. However, the poor water solubility of this compound has been a limitation to its application in vivo. Herein we describe an efficient synthesis for the conjugation, via a cleavable linker arm, of RO5-4864 to a novel tumour-delivery tool, the B-subunit of Shiga toxin (STxB). The conjugate is water soluble and specifically targets cancer cells that overexpress the glycolipid Gb3, the cellular Shiga toxin receptor that is found on several human tumours. After internalisation via retrograde transport, the prodrug is cleaved inside cells to release the active principle. Delivery by STxB therefore increases the cytotoxic activity of RO5-4864 and its tumour specificity.
El Alaoui
Abdessamad
A
Institut Curie, Centre de Recherche, Conception, Synthèse et Vectorisation de Biomolécules, 26 rue d'Ulm, 75248 Paris, France.
Schmidt
Frédéric
F
Sarr
Marianne
M
Decaudin
Didier
D
Florent
Jean-Claude
JC
Johannes
Ludger
L
D017209:Apoptosis; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D016503:Drug Delivery Systems; D015195:Drug Design; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006017:Glycolipids / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism*; D008956:Models, Chemical; D011963:Receptors, GABA-A / Q000737:chemistry*; D022621:Shiga Toxin / Q000737:chemistry; D013107:Sphingolipids / Q000737:chemistry
D006017:Glycolipids; D011963:Receptors, GABA-A; D013107:Sphingolipids; C063288:globotriaosyl lysosphingolipid; D022621:Shiga Toxin