Effects of a novel pH-sensitive liposome with cleavable esterase-catalyzed and pH-responsive double smart mPEG lipid derivative on ABC phenomenon

Abstract

Daquan Chen1,2, Wanhui Liu1,2, Yan Shen3, Hongjie Mu1,2, Yanchun Zhang4 , Rongcai Liang1,2, Aiping Wang1,2, Kaoxiang Sun1,2, Fenghua Fu1,2 1School of Pharmacy, Yantai University, Yantai, People’s Republic of China; 2State Key Laboratory of Long-acting and Targeting Drug Delivery System, Yantai, People’s Republic of China; 3College of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 4College of Pharmacy, Anhui University of Traditional Chinese Medicine, Hefei, People’s Republic of China Background: The ABC phenomenon is described as a syndrome of accelerated clearance of polyethylene glycol (PEG)-modified liposomes from the bloodstream when repeatedly injected, with their increased accumulation in the liver and spleen. Methods: To clarify this immune response phenomenon, we evaluated a novel modified pH-sensitive liposome with a cleavable double smart PEG-lipid derivative (mPEG-Hz-CHEMS). Results: The ABC phenomenon in mice was brought about by repeated injection of conventional PEG-PE liposomes and was accompanied by a greatly increased uptake in the liver. However, a slight ABC phenomenon was brought about by repeated injection of mPEG-CHEMS liposomes and was accompanied by only a slightly increased uptake in the liver, and repeated injection of mPEG-Hz-CHEMS liposomes did not induce the ABC phenomenon and there was no increase in liver accumulation. This finding indicates that the cleavable mPEG-Hz-CHEMS derivative could lessen or eliminate the ABC phenomenon induced by repeated injection of PEGylated liposomes. Conclusion: This research has shed some light on a solution to the ABC phenomenon using a cleavable PEG-Hz-CHEMS derivative encapsulated in nanoparticles. Keywords: accelerated blood clearance, double smart, cleavable, mPEG-lipid derivates, pH-sensitive liposome