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

Pillar[6]arene 12– 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 12– 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 12– 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 12– 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 [drugx⊂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 [drugx⊂pillarareney] and binary [drug⊂pillararene] complexes constitute sizable and spherical nanoparticles (600 nm–1 μm; DLS and TEM). With the biocompatibility of nanoparticulate 12– 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.