Adamantoid Scaffolds for Multiple Cargo Loading and Cellular Delivery as β-Cyclodextrin Inclusion Complexes.

Area of Science:

• Supramolecular Chemistry
• Materials Science
• Nanotechnology

Background:

• Developing efficient cellular delivery systems for therapeutics is crucial.
• Cyclodextrins (CDs) are widely used for drug encapsulation and delivery.
• There is a need for guests that can conjugate multiple cargos for enhanced cellular delivery.

Purpose of the Study:

• To synthesize and characterize trioxaadamantane derivatives as guests for beta-cyclodextrin (β-CD).
• To evaluate the binding affinity and complex formation between these guests and β-CD.
• To assess the biocompatibility, cellular uptake, and therapeutic efficacy of the β-CD-guest inclusion complexes for drug delivery.

Main Methods:

• Synthesis of trioxaadamantane derivatives.
• 1H NMR titration and isothermal titration calorimetry (ITC) for binding studies.
• Single-crystal X-ray diffraction for structural analysis.
• MTT assays for biocompatibility assessment.
• Confocal laser scanning microscopy (CLSM) and fluorescence-activated cell sorting (FACS) for cellular delivery studies.

Main Results:

• Trioxaadamantane derivatives formed 1:1 inclusion complexes with β-CD with association constants of ~10^3 M⁻¹.
• X-ray diffraction confirmed the inclusion complex structure with the adamantane core in the β-CD cavity.
• Biocompatibility was established for representative guest G4 and its β-CD complex (β-CD⊂G4).
• Cellular delivery of rhodamine-conjugated G4 was confirmed.
• β-CD inclusion complexes of G4-derived prodrugs (G6 and G7) showed efficient cellular internalization and cargo distribution.
• β-CD⊂G7, carrying three camptothecin units, exhibited superior cytotoxicity compared to other formulations.

Conclusions:

• Trioxaadamantane derivatives are effective guests for β-CD, enabling high-density cargo conjugation.
• These supramolecular complexes facilitate efficient cellular uptake and delivery of therapeutic agents.
• The developed adamantoid-β-CD system holds promise for advanced drug delivery applications, particularly with high drug loading.