title: Accelerated drug release and clearance of PEGylated epirubicin liposomes following repeated injections: a new challenge for sequential low-dose chemotherapy.
abstract: BACKGROUND
  Sequential low-dose chemotherapy has received great attention for its unique advantages in attenuating multidrug resistance of tumor cells. Nevertheless, it runs the risk of producing new problems associated with the accelerated blood clearance phenomenon, especially with multiple injections of PEGylated liposomes.
  
  
  METHODS
  Liposomes were labeled with fluorescent phospholipids of 1,2-dipalmitoyl-snglycero-3-phosphoethanolamine-N-(7-nitro-2-1,3-benzoxadiazol-4-yl) and epirubicin (EPI). The pharmacokinetics profile and biodistribution of the drug and liposome carrier following multiple injections were determined. Meanwhile, the antitumor effect of sequential low-dose chemotherapy was tested. To clarify this unexpected phenomenon, the production of polyethylene glycol (PEG)-specific immunoglobulin M (IgM), drug release, and residual complement activity experiments were conducted in serum.
  
  
  RESULTS
  The first or sequential injections of PEGylated liposomes within a certain dose range induced the rapid clearance of subsequently injected PEGylated liposomal EPI. Of note, the clearance of EPI was two- to three-fold faster than the liposome itself, and a large amount of EPI was released from liposomes in the first 30 minutes in a complement-activation, direct-dependent manner. The therapeutic efficacy of liposomal EPI following 10 days of sequential injections in S180 tumor-bearing mice of 0.75 mg EPI/kg body weight was almost completely abolished between the sixth and tenth day of the sequential injections, even although the subsequently injected doses were doubled. The level of PEG-specific IgM in the blood increased rapidly, with a larger amount of complement being activated while the concentration of EPI in blood and tumor tissue was significantly reduced.
  
  
  CONCLUSIONS
  Our investigation implied that the accelerated blood clearance phenomenon and its accompanying rapid leakage and clearance of drug following sequential low-dose injections may reverse the unique pharmacokinetic-toxicity profile of liposomes which deserved our attention. Therefore, a more reasonable treatment regime should be selected to lessen or even eliminate this phenomenon.
authors.affiliation: College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yang
authors.forename: Yanling
authors.initials: Y
authors.lastname: Ma
authors.forename: Yongxue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Zhennan
authors.initials: Z
authors.lastname: She
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Chunling
authors.initials: C
authors.lastname: Wang
authors.forename: Yihui
authors.initials: Y
authors.lastname: Deng
mesh_terms: D000818:Animals; D003165:Complement System Proteins / Q000378:metabolism; D015251:Epirubicin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D007075:Immunoglobulin M / Q000097:blood; D007275:Injections, Intravenous; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D053769:Nanocapsules / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D007075:Immunoglobulin M; D008081:Liposomes; D053769:Nanocapsules; D011092:Polyethylene Glycols; D015251:Epirubicin; D003165:Complement System Proteins
keywords: PEGylated liposomes; accelerated blood clearance (ABC) phenomenon; complement; epirubicin; sequential low-dose injections