We report here a novel and personalized strategy of selenium/ruthenium nanoparticles modified metal organic frameworks MIL-101(Fe) for delivering pooled small interfering RNAs (siRNAs) to enhance therapy efficacy by silencing multidrug resistance (MDR) genes and interfere with microtubule (MT) dynamics in MCF-7/T (Taxol-resistance) cell. The existence of coordinatively unsaturated metal sites in MIL-101(Fe) can strongly interact with the electron-rich functional groups of cysteine, which can be regarded as the linkage between selenium/ruthenium nanoparticles and MIL-101(Fe). Se@MIL-101 and Ru@MIL-101 loaded with MDR gene-silencing siRNAs via surface coordination can significantly enhance protection of siRNAs against nuclease degradation, increase siRNA cellular uptake, and promote siRNA escape from endosomes/lysosome to silence MDR genes in MCF-7/T cell, resulting in enhanced cytotoxicity through the induction of apoptosis with the signaling pathways of phosphorylation of p53, MAPK, and PI3K/Akt and the dynamic instability of MTs and disrupting normal mitotic spindle formation. Furthermore, in vivo investigation of the nanoparticles on nude mice bearing MCF-7/T cancer xenografts confirmed that Se@MIL-101-(P+V)siRNA nanoparticles can significantly enhance cancer therapeutic efficacy and decrease systemic toxicity in vivo.
Keywords: MOF surface modifications; multidrug resistance cancer therapy; selenium/ruthenium nanoparticle; siRNA delivery systems; tubulin polymerization.