Dual aptamer modified dendrigraft poly-L-lysine nanoparticles for overcoming multi-drug resistance through mitochondrial targeting

A smart dendrigraft poly-L-lysine (DGL) nanoplatform for mitochondria-targeted chemotherapy was devised, which aims to achieve enhanced efficacy against drug resistant tumor cells. In this system, doxorubicin (Dox) was intercalated into the DNA duplex containing an ATP aptamer, which was subsequently condensed by DGL to form a nanoscaled controlled-release system. A nucleolin-specific binding aptamer, AS1411, and a cytochrome c aptamer were then incorporated into the system to give the nanoparticles (Dox/Mito-DGL) for biological evaluations. This dual modified system has been shown to selectively accumulate in the mitochondria of cancer cells and promptly release the loaded Dox in virtue of the high concentrations of ATP in mitochondria. The mitochondria-specific and spatiotemporally controlled release of Dox led to enhanced therapeutic outcomes both in vitro and in vivo. More significantly, Dox/Mito-DGL was successfully applied to improve the efficacy towards multi-drug resistant cancer cells by altering the mitochondrial membrane potential and bypassing the P-glycoprotein-mediated drug efflux. This work presents a paradigm for mitochondria-targeting therapy against mitochondria-associated diseases and provides a potential avenue for overcoming MDR in the treatment of solid tumors.