Abstract
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 unmodified siRNA, especially when two Dox are attached to siRNA. The release of native Dox and RNA from the bioconjugate was demonstrated under reducing conditions suggesting efficient linker disintegration. These results demonstrate the feasibility of making siRNA-drug conjugates via disulfide-based self-immolative linkers for potential therapeutic applications.
Highlights
Successful chemotherapy of cancer using small-molecule drugs has to overcome a major obstacle that is the multidrug resistance of cancer cells [1]
The objective of this work was to conjugate Dox to the sense strand of a siRNA targeting the production of the EWS/Fli-1 protein involved in Ewing’s sarcoma [29] through a disulfide-based self-immolative linker
UGA-3′) on in thetwo biophysical properties the of several conjugates have been synthesized steps following retrosynthetic conjugates, one Dox was attached either at 2′-position of guanosine G1 at 5′-end of the RNA sequence depicted in Scheme 2
Summary
Successful chemotherapy of cancer using small-molecule drugs has to overcome a major obstacle that is the multidrug resistance of cancer cells [1]. Great research efforts have been provided to circumvent the resistance and to improve chemotherapy. In this aim, combination therapy of nucleic acids and anticancer drugs was proposed to increase therapeutic efficacy and prevent side effects [2,3]. The anthracyclines and doxorubicin (Dox) are efficient anticancer molecules acting as DNA intercalating agents and DNA topoisomerase II inhibitors for the treatment of leukemia, lymphoma or breast cancer [4,5]. Despite Dox efficacy, high doses of Dox are toxic for organs and result in heart damage [6]. The association of several therapeutic agents with different cellular targets was proposed to decrease their dose and their toxicity
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