Сalixresorcine cavitands bearing lipophilic cationic fragments in the construction of mitochondrial-targeting supramolecular nanoparticles

Abstract

The development of mitochondrial-targeting therapeutic nanoparticles is one of the crucial tasks of nanotechnology and nanomedicine. Here the study of supramolecular macrocycles decorated by lipophilic cationic mitochondrial-targeting fragments in the formation of supramolecular nanoparticles with the potential mitochondria-dependent apoptosis ability is described. Four cavitands based on tetrapentyl- and tetraundecylcalix[4]resorcines were functionalized with pyridinium (С5-Pyr and C11-Pyr, respectively) and triethylammonium groups (С5-NEt3 and C11-NEt3, respectively). Cavitands demonstrate amphiphilic character with critical association concentration values of 1.21, 1.20, 0.27 and 0.13 mM for С5-Pyr, С5-NEt3, C11-Pyr, and C11-NEt3, respectively (DMSO/Н2О 5/95 v/v, conductometry), and form small self-associates (D2O, DMSO-d6/D2О 5/95 v/v, FT-PGSE NMR method). The supramolecular modification of cavitands self-associates by the formation of polymer complexes with biocompatible polymer alginate sodium (AlgNa) was carried out. It was found that the size and stability of polymer complexes depends on the cavitand choice; the average hydrodynamic diameter of particles is 142 nm for С5-Pyr + AlgNa, 122 nm for С5-NEt3 + AlgNa and C11-NEt3 + AlgNa, and 615 nm for C11-Pyr + AlgNa complexes (DLS method). The formation of polymer complexes mainly is the result of electrostatic interaction and leads to the binding of cavitands by alginate in the form of self-associates (electrophoretic light scattering method, IR, fluorimetry). It was shown that pentylcavitands С5-Pyr and С5-NEt3 show higher hemotoxicity and cytotoxicity against normal (Chang liver cells) and tumor cells (M-HeLa cells) than undecylcavitands C11-Pyr and С11-NEt3. It was found that cavitand С5-NEt3 reduces the mitochondrial membrane potential and leads to the increase of ROS in M-HeLa cells (Flow cytometry analysis). However С5-NEt3 + AlgNa complex loses the ability to reduce the membrane potential of mitochondria, the possible reason of which is discussed.