Genome-Free Viral Capsids for Targeted Drug Delivery to Breast Cancer.

摘要

A targeted drug delivery vehicle based on the bacteriophage MS2 viral capsid was constructed using site-selective bioconjugation reactions. A palladium-catalyzed tyrosine allylation reaction was evaluated for interior modification of intact MS2 capsids with water-insoluble drug molecules. Ultimately, a tri-functional linker was synthesized and used to attach multiple copies of the chemotherapeutic agent taxol to the interior surface of an MS2 mutant containing a uniquely modifiable cysteine. This virus-based vehicle was able to deliver and release taxol to breast cancer cells in vitro and effect cytotoxicity at comparable levels to that of the drug alone. We next utilized a sodium periodate mediated oxidative coupling reaction to attach multiple types of targeting groups to the exterior of the MS2 capsids. Targeting groups we evaluated include short peptides, DNA aptamers, and engineered proteins. The most effective of these targeting groups proved to be a class of engineered binding proteins called designed ankyrin repeat proteins (DARPins). MS2 capsids modified with anti-HER2 DARPins were found to preferentially bind in vitro to several breast cancer cell lines overexpressing HER2.