Cross-Linked Cyclodextrin-Based Nanoparticles as Drug Delivery Vehicles: Synthesis Strategy and Degradation Studies

In this work, we report on the synthesis and characterization of cyclodextrin-based nanocarriers, intended as new biogenic and biodegradable drug-delivery agents. Specifically, β-cyclodextrins were covalently cross-linked by carbonyl linkages using carbonyldiimidazole (CDI) and were colloidally stabilized via PEGylation to form β-CD-CO-PEG nanoparticles termed CD-CO NPs. The optimized synthesis results in size-controlled nanoparticles with a narrow particle size distribution and a hydrodynamic diameter around 200-300 nm in water and 100-160 nm as dried powder as observed by scanning electron microscopy. CD-CO nanoparticles are promising drug delivery carriers as they offer an intrinsic pore system originating from the β-cyclodextrin building units and an additional intraparticle pore space created by cross-linking these β-cyclodextrin units. We demonstrate the biodegradability of these materials and show exemplarily their drug delivery potential using two different model cargos. Time-based fluorescence release measurements in cuvette established a stable cargoretention of the fluorescent dye Hoechst at neutral pH, and in contrast, an efficient stimuli-responsive release at pH 5, accompanied by a fast nanoparticle degradation. This cargo-release behavior at low pH is further observed with a small drug molecule, the hydrophobic necrosulfonamide, when followed with infrared spectroscopy. Finally, the drug-delivery potential of these new nanoparticles was established by following the cell uptake of covalently labeled CD-CO nanoparticles into HeLa cells with in vitro fluorescence microscopy, whereby the membrane-permeable Hoechst dye was delivered time-delayed in comparison to free Hoechst dye. In summary, our work aims to contribute to the design and understanding of cyclodextrin-based nanocarriers as a promising drug delivery platform.