title: Evasion from accelerated blood clearance of nanocarrier named as "Lactosome" induced by excessive administration of Lactosome.
abstract: BACKGROUND
  Nanoparticle of Lactosome, which is composed of poly(l-lactic acid)-base depsipeptide with diameter of 35nm, accumulates in solid tumors by the enhanced permeability and retention (EPR) effect. However, a pharmacokinetic alteration of Lactosome was observed when Lactosome was repeatedly administered. This phenomenon is named as the Lactosome accelerated blood clearance (ABC) phenomenon. In this study, the effect of Lactosome dose on the ABC phenomenon was examined and discussed in terms of immune tolerance.
  
  
  METHODS
  To tumor transplanted mice, Lactosome (0-350mg/kg) was administrated. At 7days after the first administration, indocyanine green (ICG)-labeled Lactosome (ICG-Lactosome, 0-350mg/kg) was injected. Near-infrared fluorescence imaging was performed, and biodistribution of ICG-Lactosome was evaluated. Further, the produced amounts of anti-Lactosome IgM were determined by enzyme-linked immunosorbent assay (ELISA).
  
  
  RESULTS
  ICG-Lactosome accumulated in the tumor region when the first Lactosome dose exceeded over 150mg/kg. The amounts of anti-Lactosome IgM were inversely correlated with the first Lactosome doses. Even after establishment of the Lactosome ABC phenomenon with the first Lactosome dose as low as 5.0mg/kg, the Lactosome ABC phenomenon can be evaded apparently by dosing ICG-Lactosome over 50mg/kg regardless of anti-Lactosome IgM production.
  
  
  CONCLUSIONS
  There are two different mechanisms for evasion from the Lactosome ABC phenomenon before and after its establishment. In either mechanism, however, the Lactosome ABC phenomenon can be evaded by excessive administration of Lactosome.
  
  
  CONCLUSIONS
  Lactosome is a potential nanocarrier for drug and/or imaging agent delivery, which can be used for frequent administrations without significant pharmacokinetic alterations.
authors.affiliation: Department of Experimental Therapeutics, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Hara
authors.forename: Akira
authors.initials: A
authors.lastname: Makino
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kurihara
authors.forename: Manabu
authors.initials: M
authors.lastname: Sugai
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.forename: Isao
authors.initials: I
authors.lastname: Hara
authors.forename: Eiichi
authors.initials: E
authors.lastname: Ozeki
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Kimura
mesh_terms: D000818:Animals; D004337:Drug Carriers; D004797:Enzyme-Linked Immunosorbent Assay; D007075:Immunoglobulin M / Q000097:blood; D019344:Lactic Acid / Q000276:immunology / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D053758:Nanoparticles; D010455:Peptides / Q000276:immunology / Q000493:pharmacokinetics*; D011091:Polyesters; D011108:Polymers / Q000493:pharmacokinetics*; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000276:immunology / Q000493:pharmacokinetics
chemical_list: D004337:Drug Carriers; D007075:Immunoglobulin M; D008823:Micelles; D010455:Peptides; D011091:Polyesters; D011108:Polymers; C015475:polysarcosine; D019344:Lactic Acid; C033616:poly(lactide); D012521:Sarcosine