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

It is known that the efficiency of drug delivery based on nanoparticles (NPs) decreases due to the impact of the biological environment. Loss of targeting specificity as well as the presence of antigenicity, immunogenicity, and toxicity are common problems associated with modern nanomedicines. Each of these problems is addressed by modifying the base NPs with additional specific molecules. In this regard, cyclodextrins (CDs) are particularly attractive because they simultaneously change the physical properties of NPs in a favorable direction and provide loading and release of the host CDs with small drug molecules (guest). In order for these properties not to be lost due to suboptimal design and to be manifested in the best possible way, a preliminary assessment of the surface properties of NPs decorated with CDs, including the localization, orientation, and mobility of individual CD residues, is required. However, experimental studies of the structure and surface dynamics of NPs are challenging due to their small size and short time scales. In this paper, we used a combination of transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS), and molecular dynamics (MD) simulations to evaluate the structural and dynamic properties of core-shell micelles decorated with α- or β-CDs based on NP topographic maps. NPs are self-assembled micelles of CDs conjugated to the phospholipid DOPE through a long hydrophilic spacer. It was found that most of the CD residues adopt an unfavorable orientation and tend to clustering, which hinders the accessibility of the CD cavity. The NP surface dynamics reveals that CDs have low mobility due to their interaction with the spacer, which tends to form a static shell. A fivefold reduction in CDs and spacer density (simulating "dilution" by unconjugated phospholipid) improved accessibility for ligand hosting but did not affect the orientation or mobility of CDs. These results also suggest that the functionality of CD residues depends on the spacer structure, which, combined with the optimal CD density, opens the possibility of using the proposed NPs for the rational design of highly efficient drug delivery systems.