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

Abstract

In this study, we report the remarkable recognition and assembly characteristics of D3h symmetric basket 16- containing two adjoining and nonpolar cavities with six biocompatible GABA residues at their northern and southern termini. From the results of experimental (1H NMR, fluorescence and UV-Vis spectroscopies) and computational (MM-MC/OPLS3e) investigations, we deduced that hexaanionic 16- captured two molecules of anticancer drug doxorubicin 2+ in water and accommodated them in its two deep cavities. The formation of stable 16-⊂222+ (Ka = 3 × 1012 M-2) was accompanied by the exceptional homotopic cooperativity (α = 4K2/K1 = 112) in which K1 = 3.2 ± 0.8 × 105 M-1 and K2 = 9 ± 1 × 106 M-1. Furthermore, bolaamphiphilic 16-⊂222+ assembled into spherical nanoparticles (DLS, cryo-TEM and TEM) possessing 41% drug loading. The preorganization of abiotic receptor 16- 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 16- ⊂ 3+ complex (K1 = 2.12 ± 0.01 × 104 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.