Mixed cationic liposomes for brain delivery of drugs by the intranasal route: the acetylcholinesterase reactivator 2-PAM as encapsulated drug model

TL;DR

This study develops mixed cationic liposomes for intranasal brain drug delivery, demonstrating effective encapsulation and reactivation of brain acetylcholinesterase using the model drug 2-PAM, with potential for treating organophosphorus poisoning.

Contribution

The paper introduces novel mixed cationic liposomes optimized for intranasal delivery of drugs like 2-PAM to the brain, showing improved bioavailability and therapeutic efficacy.

Findings

Intranasal liposomes increased brain bioavailability of rhodamine B.

High encapsulation efficiency (~90%) for 2-PAM in liposomes.

Liposomes reactivated brain acetylcholinesterase by 12%.

Abstract

New mixed cationic liposomes based on L-{\alpha}-phosphatidylcholine and dihexadecylmethylhydroxyethylammonium bromide (DHDHAB) were designed to overcome the BBB crossing by using the intranasal route. Synthesis and self-assembly of DHDHAB were performed. A low critical association concentration (0.01 mM), good solubilization properties toward hydrophobic dye Orange OT and antimicrobial activity against gram-positive bacteria Staphylococcus aureus (MIC=7.8 {\mu}g.mL-1) and Bacillus cereus (MIC=7.8 {\mu}g.mL-1), low hemolytic activities against human red blood cells (less than 10%) were achieved. Conditions for preparation of cationic vesicle and mixed liposomes with excellent colloidal stability at room temperature were determined. The intranasal administration of rhodamine B-loaded cationic liposomes was shown to increase bioavailability into the brain in comparison to the intravenous injection. The cholinesterase reactivator, 2-PAM, was used as model drug for the loading in cationic liposomes. 2-PAM-loaded cationic liposomes displayed high encapsulation efficiency (~ 90 %) and hydrodynamic diameter close to 100 nm. Intranasally administered 2-PAM-loaded cationic liposomes were effective against paraoxon-induced acetylcholinesterase inhibition in the brain. 2-PAM-loaded liposomes reactivated 12 +/- 1% of brain acetylcholinesterase. This promising result opens the possibility to use marketed positively charged oximes in medical countermeasures against organophosphorus poisoning for reactivation of central acetylcholinesterase by implementing a non-invasive approach, via the "nose-brain" pathway.