**4. Conclusions**

Drug concentration plays an important role in the interaction with drug carriers affecting the kinetics of the release process and the toxicology effects. Hydrophobic drugs can be solubilized in water through CD in order to enhance their bioavailability. Solubility of PX, an important nonsteroidal anti-inflammatory drug, is enhanced by β-CDs. In the present work, MD simulation of their host–guest complexes in a 1:1 and a 2:1 stoichiometry are reported, with results in good agreement with the NMR experimental literature data. Different host–guest inclusion geometries were obtained considering both native β-CD and crosslinked β-CD nanosponges (NS). When PX interacts with an NS, at smaller concentration, the drug molecules form inclusion complexes and feature some interactions on the external NS surface, dynamically forming some H-bonds or hydrophobic interaction with the PMA crosslinker, while at larger concentrations, they also aggregate on the NS surface, forming spherical droplets. Therefore, the β-CD NS enhances the solubility of hydrophobic PX. At small drug concentration, during the MD runs, the NS shows equilibrium between an extended structure, when the NS maximizes the interactions with drug molecules exposing a larger surface area, and a more compact structure, also forming a temporary nanopore when drug/drug self-aggregation due to π–π interactions takes place on its external surface. The noncovalent interactions are favored by the great NS flexibility, enhancing solubilization and PX transport. The drug concentration plays an important role. At larger concentrations, a spherical PX nanoaggregate is observed on the external NS surface besides drug inclusion complexes, because the first layer of adsorbed PX molecules induces aggregation of other hydrophobic molecules, the NS acting as a nucleation surface. During an MD run, an equilibrium is also observed between the drugs adhered on the NS surface and the detached ones in a small aggregate that diffuses before subsequent adsorption on the NS surface. Finally, it is important to highlight that the β-CD/drug and the drug/drug interactions and association will likely also affect the kinetics of the release process, depending on the site of interaction and on the flexibility of the crosslinked β-CDs. It will be important to theoretically investigate this system at a specific concentration to model the release process in order to better understand the specific interactions and the geometry and stability of the aggregates, which may affect the kinetics of the release process. Theoretical and experimental studies of the β-CD NS/PX interaction in a specific stoichiometry and drug release are in progress and will be published in a separate paper.

**Supplementary Materials:** Supplementary data can be found in the online version.

**Author Contributions:** Conceptualization, G.R.; data curation, G.R.; formal analysis, G.R.; funding acquisition, G.R.; investigation, G.R.; methodology, G.R.; resources, G.R.; supervision, G.R. and F.G.; validation, G.R.; visualization, G.R.; writing—original draft preparation, G.R.; writing—review and editing, G.R. and F.G.; funding acquisition, G.R. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by MIUR (Ministero dell'Istruzione, dell'Università e della Ricerca)—FIRB (Fondo per gli Investimenti della Ricerca di Base) Futuro in Ricerca 2008 (Surface-Associated Selective Transfection—SAST, grant RBFR08XH0H) and by INSTM (Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali) (INSTMMIP07 project) (G.R.).

**Acknowledgments:** G. Raffaini gratefully acknowledges financial support from MIUR—FIRB 2008 (Surface-Associated Selective Transfection—SAST, grant RBFR08XH0H) and from INSTM (INSTMMIP07 project) (G.R.). Helpful discussions with Roberto Vittorio Pivato are gratefully acknowledged.

**Conflicts of Interest:** The authors declare no conflicts of interest.
