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 D_3h 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⁺ (K_a = 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.