On the encapsulation and assembly of anticancer drugs in a cooperative fashion

摘要

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 = 4 K _(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.