Development of a Tau-Targeted Drug Delivery System Using a Multifunctional Nanoscale Metal–Organic Framework for Alzheimer’s Disease Therapy

Alzheimer’s disease (AD) is a widespread and burdensome neurodegenerative disease; effective diagnostic methods are lacking, and it remains incurable. The clinical applications of nanoscale metal–organic frameworks (NMOFs) have mainly focused on disease diagnosis and treatment of cancer. A multifunctional NMOF-based nanoplatform was successfully developed for the application in AD diagnosis and therapy. The magnetic nanomaterial Fe-MIL-88B-NH2 was selected to encapsulate methylene blue (MB, a tau aggregation inhibitor) and used as a magnetic resonance contrast material. Subsequently, the targeting reagent 5-amino-3-(pyrrolo­[2,3-c]­pyridin-1-yl)­isoquinoline (defluorinated MK6240, DMK6240) was connected to the surface of Fe-MIL-88B-NH2 via 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) to enhance hyperphosphorylated tau targeting, resulting in the formation of an advanced drug delivery system, Fe-MIL-88B-NH2-NOTA-DMK6240/MB. The surface properties of Fe-MIL-88B-NH2-NOTA-DMK6240/MB enable outstanding magnetic resonance imaging capability, as well as amelioration of AD symptoms in vitro and in vivo via the inhibition of hyperphosphorylated tau aggregation and impediment of neuronal death. In conclusion, a tau-targeted drug delivery platform with both disease diagnostics and treatment functions was developed in order to promote new applications of MOFs in the fields of AD and has potential applications in other neurodegenerative diseases.