Arrangement and dynamics of individual cyclodextrins on the surface of core-shell micelles

Efficient site-specific drug delivery systems (DDS) would require sophisticated surface structure to overcome challenges arising from currently inevitable interactions with components of complex biological environment. One way to endow nanoparticles (NPs) with the designed surface properties is to use excipients that enable appropriate multivalent surface modifications. In this respect, cyclodextrins (CDs) is a versatile building block that can be used to provide NPs various surface modifications as well as drug loading capacity by means of host-guest interactions. On the other hand, structural properties of CD-decorated NPs including localization, orientation, and mobility of individual CDs should be assessed for rational design of DDS and control over its surface properties. In this paper, we used combination of transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS) and molecular dynamics(MD) to assess these structural and dynamical properties of α- and β-CD-decorated core-shell micelles based on NPs topography maps. Micelles self-assemble from function-spacer-lipid (FSL) constructs that are conjugates of CDs, phospholipid DOPE and hydrophylic N-carboxymethyloligoglycine spacer. It was found that most of CD residues lose their functionality because of their clustering and unfavorable orientation, that results in CD cavity becomes inaccessible for binding. Dynamics of NPs surface structure reveals that CDs have low mobility, due to their interactions with oligoglycine spacer that prone to form static shell. Reducing the density of CD and spacer by 5 times prevents clusterization suggesting optimal density of CD residues, but does not affect CDs orientations and mobility. These findings indicate that the functionality of CD residues depends on the type of spacer and CD and their junction, and simple conjugation may not be enough to properly orient CDs on the surface. The combination of oligoglycine spacer with CD can be used as an excipient that turn hydrophobic core into stable multivalent scaffold to which various functional compounds can be attached through guest-host interactions. Obtained insights could be useful in development of CD-based NPs surface modifications towards rational design of smart next generation drug delivery systems.