Biodegradable Covalent Beta-Cyclodextrin Nanocages for Acidic and Reductive-Responsive Drug Delivery in Enhanced Tumor Therapy

Traditional beta-cyclodextrin (beta-CD) in biomedical applications faces challenges due to its inherent physical and biochemical limitations. One of the most effective strategies to enhance the properties of beta-CD for drug delivery is the synthesis of supramolecular polycyclodextrins. In this study, we designed a novel beta-CD nanocage-like structure for drug delivery, incorporating imine and disulfide bonds through Schiff base reactions. Aldehyde group-functionalized beta-CD units were used to construct the main backbone of the nanocage, forming dual-dynamic covalent bonds. The chemical structure of the beta-CD nanocage was confirmed using ¹H nuclear magnetic resonance (¹H NMR) and Fourier transform infrared spectroscopy (FTIR). Additionally, atomic force microscopy (AFM) and dynamic light scattering (DLS) revealed that varying amounts of beta-CD crosslinked with cystamine resulted in nanocages approximately 200 nm in size. In vitro drug release experiments demonstrated that doxorubicin (DOX)-loaded beta-CD nanocages exhibited accelerated DOX release in acidic and reductive environments compared to normal physiological conditions, owing to the pH-sensitive imine bond and the glutathione (GSH)-cleavable disulfide bond. The DOX-loaded beta-CD nanocages showed exceptional tumor-killing effects, particularly in acid/reduction-enhanced tumor cells. Both cellular fluorescence imaging and flow cytometry confirmed the potential of the beta-CD nanocages for acid/reduction-specific drug release. Consequently, this precision medicine model using imine/disulfide-linked beta-CD nanocage structures as acidity/reduction-sensitive drug carriers promises to improve oncotherapy through more targeted drug delivery and release, supporting individualized treatment approaches.