Single vehicular delivery system with combination inhibition

27 Jul 2015 Scientists in NUS have developed a single vehicular system, based on mesoporous silica nanoparticles to achieve the combination inhibition of endogenous miR-122.

The liver-specific, highly abundant miR-122 is implicated in many human diseases including cancer. Its inhibition has been found to result in a dramatic loss in the ability of Hepatitis C virus (HCV) to infect host cells. Both antisense technology and small molecules have been used to independently inhibit endogenous miR-122 function, but not in combination. Intracellular stability, efficient delivery, hydrophobicity and controlled release are some of the current challenges associated with these novel therapeutic methods.

A team led by Prof YAO Shao Qin from the Department of Chemistry in NUS has reported the first single vehicular system, based on mesoporous silica nanoparticles (MSNs), for simultaneous cellular delivery of miR-122 antagomir and small molecule inhibitorsto achieve efficient combination inhibition of its targeted mRNAs in Huh7 cells (see Figure).

The system is demonstrated the following key features: 1) simultaneous delivery of antagomir-122 and the hydrophobic small molecule inhibitors to the same Huh7 liver cells, thereby achieving combination inhibition of endogenous miR-122 function; 2) controlled release of both inhibitors in amounts that depend proportionally upon the expression levels of endogenous miR-122; 3) highly specific and efficient inhibition by targeting the same miRNA with two mechanistically different agents along the same miRNA functional pathway,and 4) the possibility ofencapsulating a variety of other small molecule inhibitors to achieve dual inhibition of miR-122 function and its downstream targeted enzymes.

This research has been published in Angew. Chem. Int. Ed. (2015),DOI: 10.1002/anie.201504913


This scheme shows the endocytosis by endosome/lysosome pathways, endosomal/lysosomal escape, controlled release of antagomir-122 and small molecule inhibitors via antagomir-122/endogenous miR-122 hybridization, combination inhibition of miR-122 function by antagomir-122 and small molecule inhibitors. [Image credit: YU Changmin]



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