title: Repeated injections of PEGylated liposomal topotecan induces accelerated blood clearance phenomenon in rats.
abstract: The "accelerated blood clearance (ABC) phenomenon" of PEGylated liposomes following multiple injections has been reported recently. This immunogenicity poses a problem for research into liposomes and hinders their clinical application. However, since doxorubicin liposomes and mitoxantrone liposomes have been reported to fail to induce the ABC phenomenon, some people believe that cytotoxic drugs loaded liposomes will not produce this ABC phenomenon under multiple-dosing regimens. Nevertheless, in the present study, we report that a first injection of the PEGylated liposomal topotecan (a cell cycle-specific drug for the S phase) still produced a strong ABC phenomenon. Likewise, when the first dose of "empty" PEGylated liposomes or topotecan liposomes was increased, the ABC phenomenon of the subsequent dose was accordingly attenuated. Unlike doxorubicin and mitoxantrone, the blood clearance rate of topotecan was dramatically rapid, and the hepatic and splenic accumulations of topotecan liposomes were anomalous because of the ABC phenomenon. These findings may present new challenges to the clinical application of formulations of cytotoxic drugs loaded liposomes that require repeated administrations.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Ma
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yang
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.forename: Xinyu
authors.initials: X
authors.lastname: Zhou
authors.forename: Yongxue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yihui
authors.initials: Y
authors.lastname: Deng
mesh_terms: D000818:Animals; D004317:Doxorubicin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D007075:Immunoglobulin M / Q000097:blood / Q000378:metabolism; D008081:Liposomes / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008942:Mitoxantrone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D010743:Phospholipids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D019772:Topotecan / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D007075:Immunoglobulin M; D008081:Liposomes; D010743:Phospholipids; D011092:Polyethylene Glycols; D019772:Topotecan; D004317:Doxorubicin; D008942:Mitoxantrone