Histological study on side effects and tumor targeting of a block copolymer micelle on rats.
Histological examinations were performed with polymeric micelle-injected rats for evaluations of possible toxicities of polymeric micelle carriers. Weight of major organs as well as body weight of rats was measured after multiple intravenous injections of polymeric micelles forming from poly(ethylene glycol)-b-poly(aspartate) block copolymer. No pathological toxic side effects were observed at two different doses, followed only by activation of the mononuclear phagocyte system (MPS) in the spleen, liver, lung, bone marrow, and lymph node. This finding confirms the absence of--or the very low level of--in vivo toxicity of the polymeric micelle carriers that were reported in previous animal experiments and clinical results. Then, immunohistochemical analyses with a biotinylated polymeric micelle confirmed specific accumulation of the micelle in the MPS. The immunohistochemical analyses also revealed, first, very rapid and specific accumulation of the micelle in the vasculatures of tumor capsule of rat ascites hepatoma AH109A, and second, the micelle's scanty infiltration into tumor parenchyma. This finding suggests a unique tumor-accumulation mechanism that is very different from simple EPR effect-based tumor targeting.
Kawaguchi
Takanori
T
Department of Pathology, Aizu Central Hospital, Aizu Wakamatsu 965-8611, Japan.
Honda
Takashi
T
Nishihara
Masamichi
M
Yamamoto
Tatsuhiro
T
Yokoyama
Masayuki
M
D000818:Animals; D001201:Ascites / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001224:Aspartic Acid / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics* / Q000633:toxicity*; D001704:Biopolymers / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics* / Q000633:toxicity*; D019921:Biotinylation; D001835:Body Weight; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005260:Female; D007267:Injections; D008823:Micelles; D012157:Mononuclear Phagocyte System / Q000187:drug effects / Q000276:immunology; D009368:Neoplasm Transplantation; D009929:Organ Size; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats
D001704:Biopolymers; D008823:Micelles; C416210:poly(ethylene oxide)-block-poly(beta-benzyl aspartate); D001224:Aspartic Acid; D011092:Polyethylene Glycols