Evasion from accelerated blood clearance of nanocarrier named as “Lactosome” induced by excessive administration of Lactosome |
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Authors: | Eri Hara Akira Makino Kensuke Kurihara Manabu Sugai Akira Shimizu Isao Hara Eiichi Ozeki Shunsaku Kimura |
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Institution: | 1. Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto, 606-8507, Japan;2. Division of Molecular Imaging, Biomedical Imaging Research Center, University of Fukui, Fukui, 910-1193, Japan;3. Clinical Division of Diagnostic Radiology, Kyoto University Hospital, Kyoto, 606-8507, Japan;4. Technology Research Laboratory, Shimadzu Corporation, Kyoto, 619-0237, Japan;5. Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, 615-8510, Japan |
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Abstract: | BackgroundNanoparticle of Lactosome, which is composed of poly(l-lactic acid)-base depsipeptide with diameter of 35 nm, 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.MethodsTo tumor transplanted mice, Lactosome (0–350 mg/kg) was administrated. At 7 days after the first administration, indocyanine green (ICG)-labeled Lactosome (ICG-Lactosome, 0–350 mg/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).ResultsICG-Lactosome accumulated in the tumor region when the first Lactosome dose exceeded over 150 mg/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 5.0 mg/kg, the Lactosome ABC phenomenon can be evaded apparently by dosing ICG-Lactosome over 50 mg/kg regardless of anti-Lactosome IgM production.ConclusionsThere 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.General significanceLactosome is a potential nanocarrier for drug and/or imaging agent delivery, which can be used for frequent administrations without significant pharmacokinetic alterations. |
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Keywords: | Molecular imaging Nanoparticle ABC phenomenon Immune tolerance |
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