Molecules, Vol. 25, Pages 2714: Conjugation of Doxorubicin to siRNA Through Disulfide-based Self-immolative Linkers

Molecules, Vol. 25, Pages 2714: Conjugation of Doxorubicin to siRNA Through Disulfide-based Self-immolative Linkers Molecules doi: 10.3390/molecules25112714 Authors: Florian Gauthier Jean-Rémi Bertrand Jean-Jacques Vasseur Christelle Dupouy Françoise Debart Co-delivery systems of siRNA and chemotherapeutic drugs have been developed as an attractive strategy to optimize the efficacy of chemotherapy towards cancer cells with multidrug resistance. In these typical systems, siRNAs are usually associated to drugs within a carrier but without covalent interactions with the risk of a premature release and degradation of the drugs inside the cells. To address this issue, we propose a covalent approach to co-deliver a siRNA-drug conjugate with a redox-responsive self-immolative linker prone to intracellular glutathione-mediated disulfide cleavage. Herein, we report the use of two disulfide bonds connected by a pentane spacer or a p-xylene spacer as self-immolative linker between the primary amine of the anticancer drug doxorubicin (Dox) and the 2′-position of one or two ribonucleotides in RNA. Five Dox-RNA conjugates were successfully synthesized using two successive thiol-disulfide exchange reactions. The Dox-RNA conjugates were annealed with their complementary strands and the duplexes were shown to form an A-helix sufficiently stable under physiological conditions. The enzymatic stability of Dox-siRNAs in human serum was enhanced compared to the unmo...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research