Amitriptyline overdose treatment by pegylated anionic liposomes

Liposomes composed of DOPG, 50:50 DMPC:DOPG, 95:5 and 85:15 DOPG:DPPE-mPEG-2000, and 55:15:30 DMPC:DPPE-mPEG-2000:CH were studied for their ability to sequester amitriptyline in human serum. The effects of lipid type and loading, liposome size, PEG inclusion, protein interaction and storage were considered. Liposome size had no effect on drug uptake, as 40, 100, and 284 nm liposomes bound similar amounts of drug in buffer. The optimal amount of PEG-modified lipid incorporated into liposomes was found to be 5%. 95:5 DOPG:DPPE-mPEG-2000 liposomes loaded at 1.44 mg lipid/mL were most effective at shielding protein interactions while still allowing amitriptyline to diffuse to the bilayer surface and bind. Absolute reductions of 99% in buffer and human serum samples were observed, while the free drug concentration reduction relative to binding in serum without liposomes was nearly 90% across a drug concentration range of 1-20 muM. With such reductions, serum drug concentrations could be rapidly reduced from toxic to therapeutic levels. Furthermore, storage tests revealed that such liposomes may be stored for at least one month without a change in drug binding ability. These findings strongly suggest that predominantly anionic liposomes incorporated with PEG are excellent candidates for amitriptyline overdose treatment.