1. Effect of Kupffer cells depletion on ABC phenomenon induced by Kupffer cells-targeted liposomes
- Author
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Ling Hu, Yihui Deng, Qiujun Qiu, Cong Li, Xinrong Liu, Chaoyang Lai, Yanzhi Song, Xiang Luo, and Mengyang Liu
- Subjects
Biodistribution ,Pharmaceutical Science ,Spleen ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Depletion ,In vivo ,medicine ,Kupffer cells ,Secretion ,Pharmacology ,Liposome ,Chemistry ,lcsh:RM1-950 ,021001 nanoscience & nanotechnology ,In vitro ,eye diseases ,0104 chemical sciences ,Cell biology ,Alendronate Sodium ,medicine.anatomical_structure ,lcsh:Therapeutics. Pharmacology ,Liposomes ,Bio-distribution ,Nanocarriers ,0210 nano-technology ,Accelerated blood clearance (ABC) phenomenon ,Research Article - Abstract
Accelerated blood clearance (ABC) phenomenon is common in many PEGylated nanocarriers, whose mechanism has not been completely elucidated yet. In this study, the correlation between Kupffer cells (KCs) and ABC phenomenon has been studied by KCs-targeted liposomes inducing ABC phenomenon and KCs depletion. In other words, the 4-aminophenyl-α-D-mannopyranoside (APM) lipid derivative DSPE-PEG2000-APM (DPM), and 4-aminophenyl-β-L-fucopyranoside (APF) lipid derivative DSPE-PEG2000-APF (DPF) were conjugated and modified on alendronate sodium (AD) liposomes to specifically target and deplete KCs. The dual-ligand modified PEGylated liposomes (MFPL) showed stronger ability to damage KCs in vitro and in vivo, which also could indirectly illustrate that dual-ligand modification could better target KCs. Besides, the hepatic biodistribution and pharmacokinetics could directly prove that MFPL had a stronger targeting ability to KCs. In addition, in depletion rats, plasma concentration and splenic biodistribution of MFPL and PEGylated liposomes (PL) were significantly elevated and hepatic biodistribution was significantly reduced, which demonstrated that KCs played an important role on elimination of nanoparticles. What's more, ABC phenomenon of the secondary injection of PL was stronger in KCs depletion rats than that in normal rats, which indicated that depletion of KCs prolonged the circulation of PL in the first injection repeatedly stimulating B-cells in the marginal region of the spleen and causing it to secrete more IgM antibodies. This could also illustrate that anti-PEG IgM takes up a major station compared with KCs. Most important of all, KCs-targeted liposomes could induce a stronger ABC phenomenon than PL in normal rats, which declared that based on the same IgM concentration, the more the KCs were stimulated, the stronger ABC phenomenon was induced. However, in depletion rats, this difference of ABC phenomenon between PL and MFPL could no more exist, further demonstrating that KCs could participate and play a certain role in the ABC phenomenon., Graphical abstract Mannose and fucose derivatives were conjugated and modified on AD liposomes to specifically target and deplete KCs. Effect of Kupffer depletion on accelerated blood clearance (ABC) phenomenon induced by PEGylated liposomes (PL) and Kupffer cells-targeted liposomes (MFPL) respectively was evaluated by pharmacokinetics and biodistribution of liposomes, which demonstrated that the clearance function of KCs to PL and KCs could participate in the happening of ABC phenomenon.Image, graphical abstract
- Published
- 2019