Abstract
In this study, we report the remarkable recognition and assembly characteristics of D (3h) symmetric basket 1 (6-) containing two adjoining and nonpolar cavities with six biocompatible GABA residues at their northern and southern termini. From the results of experimental ((1)H NMR, fluorescence and UV-Vis spectroscopies) and computational (MM-MC/OPLS3e) investigations, we deduced that hexaanionic 1 (6-) captured two molecules of anticancer drug doxorubicin 2 (+) in water and accommodated them in its two deep cavities. The formation of stable 1 (6-)⊂2 (2) (2+) (K (a) = 3 × 10(12) M(-2)) was accompanied by the exceptional homotopic cooperativity (α = 4K (2)/K (1) = 112) in which K (1) = 3.2 ± 0.8 × 10(5) M(-1) and K (2) = 9 ± 1 × 10(6) M(-1). Furthermore, bolaamphiphilic 1 (6-)⊂2 (2) (2+) assembled into spherical nanoparticles (DLS, cryo-TEM and TEM) possessing 41% drug loading. The preorganization of abiotic receptor 1 (6-) and its complementarity to 2 (+) have been proposed to play a part in the positive cooperativity in which ten favorable noncovalent contacts (i.e. hydrogen bonds, salt bridges, C-H···π and π-π contacts) are formed between doxorubicin and the dual-cavity host. In the case of topotecan 3 (+), however, the absence of multiple and favorable basket⊂drug interactions resulted in the predominant formation of a binary 1 (6-) ⊂ 3 (+) complex (K (1) = 2.12 ± 0.01 × 10(4) M(-1)) and the negative homotopic allostery (α ≪ 1). To summarize, our study lays out a roadmap for creating a family of novel, accessible and multivalent hosts capable of complexing anticancer agents in a cooperative manner. As basket⊂drug complexes organize into highly loaded nanoparticles, the reported soft material is amenable to the bottom-up construction of stimuli-responsive nanomedicine capable of effective scavenging and/or delivery of drugs.