Our strategy: To engineer a drug that would spare sNMDARs and exclusively inhibit eNMDARs, we took into consideration geometrical parameters of their respective subcellular locations and constructed a nanodrug that, due to its dimensions, would interact with one receptor sub-type, but not the other.
We reasoned that a nanostructure larger than the synaptic cleft (~25 nm) should not be able to access receptors inside the synapse, but would reach receptors located elsewhere. To implement our rational drug design, we engineered a nanostructure comprised of memantine tethered to the ends of a thiol-PEG-carboxyl PEG that is centrally attached to an inert spherical 13-nm Au nanoparticle core. Additionally, we used a shorter inert thiol-PEG-methoxy diluent PEG to passivate the remaining Au surface and form a dense monolayer. The final hybrid nanostructure, dubbed AuM, contained ~50 memantine molecules per nanoparticle and exhibited a hydrodynamic size of ~35 nm.