Delivery nanosystems based on sterically hindered phenol derivatives containing a quaternary ammonium moiety: Synthesis, cholinesterase inhibition and antioxidant activity

Abstract

Multitarget ligands (MTL) based on sterically hindered phenol and containing a quaternary ammonium moiety (SHP-n-Q) were synthesized. These compounds are inhibitors of cholinesterases with antioxidant properties. The inhibitory selectivity is 10-fold potent for BChE than for AChE. IC50 of SHP-n-Q for BChE is 20 μM. SHP-n-Q and their nanosystems exhibit more pronounced antioxidant properties than the synthetic antioxidant (hindered phenol, butylated hydroxytoluene). These compounds display a low hemolytic activity against human red blood cells. The nanotechnological approach was used to increase the bioavailability of SHP-n-Q derivatives. For water soluble SHP-n-Q derivative, the self-assembled structures have a size close to 100 nm at critical association concentration (0.01 M). Mixed cationic liposomes based on l-α-phosphatidylcholine and SHP-n-Q of 100 nm diameter were prepared. The stability, encapsulation efficacy and release from liposomes of a model drug, Rhodamine B, depend on the structure of SHP-n-Q. Cationic liposomes based on l-α-phosphatidylcholine and SHP-3-Q show a good stability in time (1year) and a sustained release (>65 h). They are promising templates for the development of anti-Alzheimer MT-drug delivery systems.