Tumor microenvironment responsive nanocarriers for efficient antisense DNA delivery and enhanced chemodynamic therapy

Abstract

Cancer is undoubtedly one of the major threats to mankind. Herein, we demonstrate a supramolecular approach for the design of tumour microenvironment sensitive nanoparticles composed of artemisinin, glutathione-responsive and redox-active ferrocene and antisense DNA via a single-step assembly. Assembly between the antisense DNA and ferrocene derivative results in the noncovalent tethering of the latter along the backbone of antisense DNA and leads to the formation of the corresponding supramolecular amphiphile. The addition of hydrophobic artemisinin during the assembly of the supramolecular amphiphile permits the encapsulation of artemisinin and leads to the formation of glutathione-responsive NPs composed of antisense DNA, ferrocene derivative and artemisinin. The most remarkable feature of our design strategy is the glutathione-triggered cascade reactions of the NPs inside the cancer cell in a cooperative fashion. Cleavage of disulfide bonds of the NPs by the overexpressed glutathione in the tumour microenvironment leads to the following cascade chemodynamic therapy reactions: (i) glutathione-triggered uncaging of the ferrocene derivative to release amino ferrocene, which then undergoes reaction with endogenous hydrogen peroxide to produce ˙OH radicals and Fe³⁺ and (ii) the in situ reduction of Fe³⁺ by glutathione to form Fe²⁺ and the subsequent Fe²⁺-triggered cleavage of the peroxide bond of artemisinin to form carbon-centered free radicals. Furthermore, disassembly of NPs releases antisense DNA, which efficiently downregulates the translation of Bcl-2 mRNA and thereby causes cell apoptosis. Excellent anticancer efficacy is demonstrated by using HeLa cells as a representative example and the enhanced therapeutic efficacy of our approach is attributed to the co-operative cascade CDT and antisense therapy.