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

Abstract

AbstractThere is huge demand for developing guests that bind β‐CD and can conjugate multiple cargos for cellular delivery. We synthesized trioxaadamantane derivatives, which can conjugate up to three cargos per guest. 1H NMR titration and isothermal titration calorimetry revealed these guests form 1 : 1 inclusion complexes with β‐CD with association constants in the order of 103 M−1. Co‐crystallization of β‐CD with guests yielded crystals of their 1 : 1 inclusion complexes as determined by single‐crystal X‐ray diffraction. In all cases, trioxaadamantane core is buried within the hydrophobic cavity of β‐CD and three hydroxyl groups are exposed outside. We established biocompatibility using representative candidate G4 and its inclusion complex with β‐CD (β‐CD⊂G4), by MTT assay using HeLa cells. We incubated HeLa cells with rhodamine‐conjugated G4 and established cellular cargo delivery using confocal laser scanning microscopy (CLSM) and fluorescence‐activated cell sorting (FACS) analysis. For functional assay, we incubated HeLa cells with β‐CD‐inclusion complexes of G4‐derived prodrugs G6 and G7, containing one and three units of the antitumor drug (S)‐(+)‐camptothecin, respectively. Cells incubated with β‐CD⊂G7 displayed the highest internalization and uniform distribution of camptothecin. β‐CD⊂G7 showed higher cytotoxicity than G7, camptothecin, G6 and β‐CD⊂G6, affirming the efficiency of adamantoid derivatives in high‐density loading and cargo delivery.