On the Encapsulation and Assembly of Anticancer Drugs in a Cooperative Fashion
In this study, we report on the remarkable recognition and assembly characteristics of D3hsymmetric 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-Ì222+(Ka= 3 · 1012M-2) was accompanied with the exceptional homotopic cooperativity (a= 4K2/K1= 112) in which K1= 3.2 ± 0.8 · 105M-1and K2= 9 ± 1 · 106M-1. Furthermore, bolaamphiphilic 16-Ì222+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---pand p-pcontacts) are formed between doxorubicin and dual-cavity host. In the case of topotecan 3+, however, the absence of multiple and favorable basketÌdrug interactions resulted in the predominant formation of binary 16-Ì3+complex (K1= 2.12 ± 0.01 · 104M-1) and the negative homotopic allostery (a<<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 basketÌdrug 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 delivering of drugs.