Abstract 2901: Development of mannose-polyethyleneglycol-modified liposomes for idiopathic thrombocytopenic purpura

Abstract

Abstract [Objective]Idiopathic thrombocytopenic purpura(ITP) among thrombocytopenia is an acquired autoimmune disease and is not clear on the cause of disease. ITP is produced antibodies to the platelet by immunological action and is thrombocytopenia with platelet phagocytosis by macrophages in the spleen. There is a few deaths by the thrombocytopenia, whereas its effective treatment has not been developed. Polyethyleneglycol(PEG) modification of liposome as drug carrier is known to provide blood circulation. The surface of macrophages is overexpressed mannose receptor. Namely, mannose-PEG-modified liposome contained cytotoxic agent is expected to accumulate in macrophage and show cytotoxic effect. The effect of novel therapy for ITP was examined on platelet count and tissue distribution of cytotoxic agent. [Methods]Doxorubicin(DOX) as cytotoxic agent, containing liposome(LDOX), PEG-modified LDOX(PEG-LDOX) and mannose-modified PEG-LDOX(Man-PEG-LDOX) were prepared by remote loading method. ITP model mouse was created by administration of anti-platelet antibodies. Each liposome was administered from the tail vein in the ITP model mouse. On 24hr after each liposome administration, the platelet count was measured and DOX concentration was determined in each tissue. [Results]ITP model mouse was reduced to 7.1% of normal platelet count by anti-platelet antibodies treatment. In LDOX and PEG-LDOX groups, the platelet count does not recover to normal level and DOX concentration in the spleen was low. In contrast, the platelet count in Man-PEG-LDOX group recovered to normal level. Furthermore, DOX concentration in the spleen after Man-PEG-LDOX treatment showed a 2.7-fold of that in LDOX group. [Discussion]To be effective splenectomy for ITP treatment, it is prospected that the accumulation of cytotoxic agent in the spleen is useful. As liposome with PEG-modification has been developed for avoiding the reticuloendotherial system cells such as liver and spleen, this liposome can not show accumulation in the spleen and cytotoxic effect on the macrophages. Thus, PEG-modified liposome is unable to suppress platelets reduction by macrophage phagocytosis. In contrast, after Man-PEG-LDOX administration, DOX concentration in the spleen significantly increased, and thus the platelet count was recovered by cytotoxic effect on the macrophages. Furthermore, DOX accumulations in the heart and other normal tissue in the Man-PEG-LDOX group were lower levels, and DOX induced adverse reaction was expected to be not observed. In conclusion, Man-PEG-LDOX is hoped to be effective as novel treatment for ITP. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2901. doi:1538-7445.AM2012-2901