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 1 ^6- 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 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 × 10¹² M^-2) was accompanied by the exceptional homotopic cooperativity (? = 4K ₂/K ₁ = 112) in which K ₁ = 3.2 ± 0.8 × 10⁵ M^-1 and K ₂ = 9 ± 1 × 10⁶ 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···? and ?-? 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 × 10⁴ M^-1) and the negative homotopic allostery (? ? 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.

SUBMITTER: Wang W 

PROVIDER: S-EPMC6566385 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature