Effect of Repeated Injections of Adenosine Diphosphate-Encapsulated Liposomes Coated with a Fibrinogen γ-Chain Dodecapeptide Developed as a Synthetic Platelet Substitute on Accelerated Blood Clearance in a Healthy and an Anticancer Drug-Induced Thrombocytopenia Rat Model

Abstract

Adenosine diphosphate (ADP)-encapsulated liposomes coated with a fibrinogen γ-chain dodecapeptide [H12 (dodecapeptide ((400) HHLGGAKQAGDV(411) ))-(ADP)-liposome] is a synthetic platelet substitute, in which the surface is covered with polyethylene glycol (PEG). It has been reported that repeated injections of PEGylated liposomes induce an accelerated blood clearance (ABC) phenomenon, which involves a loss in the long-circulation half-life of the material when administered repeatedly to the same animals. The objective of this study was to determine whether the ABC phenomenon was induced by repeated injections of H12-(ADP)-liposome in healthy and anticancer drug-induced thrombocytopenia model rats. The findings show that the ABC phenomenon was induced by healthy rats that were repeatedly injected with H12-(ADP)-liposomes at the interval of 5 days at a dose of 10 mg lipids/kg. The ABC phenomenon involves the production of anti-H12-(ADP)-liposome immunoglobulin M (IgM) and complement activation. On the other hand, when thrombocytopenia model rats were repeatedly injected with H12-(ADP)-liposomes under the same conditions, no ABC phenomenon, nor was any suppression of anti-H12-(ADP)-liposome IgM-mediated complement activation observed. We thus conclude that the repeated injection of H12-(ADP)-liposome treatment in rat model with anticancer drug-induced thrombocytopenia did not induce the ABC phenomenon.

Pharmacokinetic Properties of Single and Repeated Injection of Liposomal Platelet Substitute in a Rat Model of Red Blood Cell Transfusion-Induced Dilutional Thrombocytopenia

“…In fact, the induction of the ABC phenomenon in healthy rats was observed with the production of IgM against H12‐(ADP)‐liposomes, whereas no ABC phenomenon was observed in anticancer drug‐induced thrombocytopenic rats because of the suppression of IgM against H12‐(ADP)‐liposomes production . Moreover, previous study using healthy rats clearly showed that anti‐H12‐(ADP)‐liposomes IgM specifically reacted with both DSPE‐PEG and H12‐PEG‐Glu2C18, whereas other lipid components (DPPC, cholesterol, and DHSG) were negligible . Therefore, the production of IgM against H12‐(ADP)‐liposomes, especially IgM against both DSPE‐PEG and H12‐PEG‐Glu2C18, would cause the induction of the ABC phenomenon of H12‐(ADP)‐liposomes in the RBC transfusion‐induced dilutional thrombocytopenic rats.…”

“…Figure shows the time course for the plasma concentration curve for the 14 C‐, 3 H‐labeled H12‐(ADP)‐liposomes administrated once or twice to RBC transfusion‐induced dilutional thrombocytopenic rats at a dose of 10 mg lipids/kg. The time interval for the injection was 5 days, based on our previous study . As a result, the plasma concentration curves for both 14 C radioactivity and 3 H radioactivity indicate that, in the case of a second injection, the radioactivity was cleared more rapidly compared with the first injection.…”

“…It is widely known that the intravenous injection of PEGylated liposomes causes a second dose of PEGylated liposomes to lose their long circulating characteristics when administrated twice in the same animal (referred to as the “accelerated blood clearance (ABC) phenomenon”) . In a previous study, we showed that the ABC phenomenon was induced in healthy rats that were repeatedly injected with H12‐(ADP)‐liposomes at intervals of 5 days at a dose of 10 mg lipids/kg, but was not induced in the anticancer‐induced thrombocytopenic rats . Therefore, we finally investigated the issue of whether the first injection of H12‐(ADP)‐liposomes affects the pharmacokinetic behavior of a subsequent second injection of H12‐(ADP)‐liposomes in RBC transfusion‐induced thrombocytopenic rats.…”

“…Furthermore, it was reported that the intensity of the ABC phenomenon of second injected PEGylated liposome is correlated with the concentration of IgM (anti‐PEG IgM) in serum . In fact, the induction of the ABC phenomenon in healthy rats was observed with the production of IgM against H12‐(ADP)‐liposomes, whereas no ABC phenomenon was observed in anticancer drug‐induced thrombocytopenic rats because of the suppression of IgM against H12‐(ADP)‐liposomes production . Moreover, previous study using healthy rats clearly showed that anti‐H12‐(ADP)‐liposomes IgM specifically reacted with both DSPE‐PEG and H12‐PEG‐Glu2C18, whereas other lipid components (DPPC, cholesterol, and DHSG) were negligible .…”

“…One‐hundred microliter of 475 ng lipids/mL H12‐(ADP)‐liposomes (comprising DPPC, cholesterol, DHSG, DSPE‐PEG, and H12‐PEG‐Glu2C18) was added to 96 well plates. ELISA was employed to detect IgG and IgM against H12‐(ADP)‐liposomes using previously described method …”