In this work, a library of amphiphilic cyclodextrin derivatives was synthesized by conjugating aliphatic chains of different lengths to native β-cyclodextrin via thioether or ester bonds. Upon nanoprecipitation, the synthesized amphiphilic cyclodextrin derivatives spontaneously self-assembled into nanosized supramolecular structures with a monodisperse size distribution. The authors systematically investigated the relationship between the molecular structure of the amphiphilic cyclodextrin derivatives and the corresponding self-assembly into nanosystems as well as the encapsulation of model drugs with different physicochemical properties. Encapsulation efficiencies up to 97% and pH-dependent release profiles were achieved. It was found that both the aliphatic chain length and the linker molecule determine the respective self-assembly and drug encapsulation mechanism of the individual system. The colloidal stability and biocompatibility with human cells of all derivatives were proven. Consequently, amphiphilic cyclodextrin conjugates provide a drug delivery platform with tailor-made control over physicochemical properties and high drug encapsulation efficiency for a broad range of drug molecules, thus offering great potential for the development of future therapeutics with improved therapeutic efficiency.
The syntheses of the ester derivatives heptakis-6-O-hexanoyl-β-cyclodextrin (CDOC6) and heptakis-6-O-lauroyl-β-cyclodextrin (CDOC12) were carried out in one-step conjugations of hexanoyl chloride or lauroyl chloride to the primary hydroxyl groups of native β-CD. The thioether derivative heptakis-(6-deoxy-6-hexylthio)-β-cyclodextrin (CDSC6, Scheme 1, 3) was obtained from native β-CD by bromination and subsequent nucleophilic substitution with 1-hexanethiol.
It was demonstrated that all nanocarrier formulations exhibit excellent colloidal stability in physiologically relevant fluids and are biocompatible with human epithelial as well as immune cells. Thus, amphiphilic CD derivatives pose a high potential to become a potent drug delivery platform for intracellular delivery of a wide variety of drugs exhibiting different physicochemical profiles as well as molecular weights.
Felix E. B. Brettner, Jonas Schreiner, Sarah Vogel-Kindgen,* and Maike Windbergs: Engineered Self-Assembly of Amphiphilic Cyclodextrin Conjugates for Drug Encapsulation. ACS Biomater. Sci. Eng. 2024, 10, 115−128. https://doi.org/10.1021/acsbiomaterials.2c01023