Ultrasmall Cyclodextrin-Based Nanogels as Drug Delivery Systems

Ultrasmall cyclodextrin-based nanogels (CDngs) crosslinked with ethylene glycol diglycidyl ether (EGDE) were tested as drug delivery systems for poorly water-soluble anticancer agents for the first time. Two compounds with well-established pharmacological activity but critical solubility limitations, i.e., Osthole and Combretastatin A-4 (CA-4), were selected to evaluate the encapsulation capacity and performance of the nanogel platform. After preliminary screening through experimental and docking investigation, CA-4 was chosen as the reference compound. Among the formulations developed, the CA-4/loaded nanogel displayed the highest encapsulation efficiency (EE%). Despite a less-than-ideal host-guest fit, the large cavity of γ-CD allows for efficient drug encapsulation and higher loading capacity. The optimized formulation was tested in vitro to assess both the biocompatibility of γ-CDngs, as well as the anticancer efficacy of CA-4 loaded γ-CD and γ-CDngs. We demonstrate that empty systems exhibit intrinsic biocompatibility, showing no cytotoxicity toward the A2780 cancer cell line under experimental conditions. Furthermore, the CA-4 loaded γ-CDngs retained and enhanced the cytotoxic properties of the free drug against this cell line, compared to the corresponding native γ-CD. Collectively, these findings validate CDngs as a promising and innovative platform for the delivery of hydrophobic anticancer molecules and support their potential for further therapeutic development.