A Bolaamphiphilic and Nanoparticulate Pillar[6]arene for Noncovalent/Inclusion Complexation of Doxorubicin and Mitoxantrone in Water.

Pillar-[6]-arene 1 2- is a dianionic and accessible host, possessing a cylindrical cavity composed of six benzene rings with ten ethoxy and two carboxylic acid groups at the top/bottom portals. The results from 1H NMR spectroscopy, dynamic light scattering (DLS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) measurements of bolaamphiphilic 1 2- in 30 mM phosphate buffer (PBS) at pH = 7.4 are in line with its self-association into spherical nanoparticles at concentrations up to 200 μM. At lower concentrations (<25 μM), nanoparticles of 1 2- are smaller (D = 150 nm, DLS), while at the 25-100 μM concentration range, they grow bigger (D = 330 nm, DLS). With computational studies (molecular mechanics) revealing the electronic and shape complementarity of the cavity of 1 2- and anticancer drugs mitoxantrone (MTO2+) and doxorubicin (DOX+), 1H NMR spectra of equimolar drug/pillararene mixtures resulted in a severe broadening of all signals. The formation of drug/pillararene noncovalent complexes was further confirmed by the pH-triggered precipitation of both drugs and pillararene from their mixtures. The results from UV-vis supramolecular titrations were in line with two equilibria characterizing noncovalent complexations and corresponding to the formation of (a) multimeric [drug x ⊂ y ] complexes (x > y) along with (b) binary and inclusion [drug⊂pillararene] complexes. The existence of the latter was corroborated with mass spectrometry (ESI/TOF MS). Importantly, multimeric [drug x ⊂pillararene y ] and binary [drug⊂pillararene] complexes constitute sizable and spherical nanoparticles (600 nm-1 μm; DLS and TEM). With the biocompatibility of nanoparticulate 1 2- toward HeLa cells and its capacity to capture toxic anticancer agents used in clinics thereby forming larger nanoparticles, we reason that the nanosystem described here could be developed into a platform for effective sequestration or delivery of anticancer drugs.