Storm G, Steerenberg P A, Emmen F, van Borssum Waalkes M, Crommelin D J
Department of Pharmaceutics, Faculty of Pharmacy, University of Utrecht, The Netherlands.
Biochim Biophys Acta. 1988 May 12;965(2-3):136-45. doi: 10.1016/0304-4165(88)90049-9.
Intracellular depot formation may be an important component of the mode of action of doxorubicin (DXR)-containing liposomes. In this paper it was investigated whether it is possible that DXR is released from macrophages which have taken up DXR-containing liposomes in vivo. Macrophages were harvested from the peritoneal cavity of LOU/M rats after i.p. administration of DXR-liposomes. Two different liposome types were used for this investigation. The amount of DXR associated with macrophages was determined by high performance liquid chromatography. In order to monitor DXR release from the macrophages, an in vitro tumor cell growth inhibition assay was applied. Peritoneal macrophages collected 24 h after an i.p. injection of DXR-liposomes (10 mg/kg body weight) caused considerable growth inhibition of tumor cells in culture. The cytostatic potential of macrophage monolayers in vitro depended on the type of injected DXR-liposomes and was directly related to the amount of macrophage-associated DXR. The DXR content of the macrophage monolayers was completely released from the cells into the culture medium during the cocultivation with tumor cells. Supernatants obtained from monolayers, which were cultivated in the absence of tumor cells, showed a high growth-inhibitory activity. DXR either free or in liposomal form was chemically stable for up to 26 h during incubation with lysosomal fractions isolated from rat liver homogenates. The results indicate that release of DXR from macrophages which have phagocytosed DXR-liposomes in vivo is a real possibility.
细胞内储库形成可能是含阿霉素（DXR）脂质体作用方式的一个重要组成部分。本文研究了在体内摄取含DXR脂质体的巨噬细胞是否有可能释放DXR。经腹腔注射DXR脂质体后，从LOU/M大鼠的腹腔中收获巨噬细胞。本研究使用了两种不同类型的脂质体。通过高效液相色谱法测定与巨噬细胞相关的DXR量。为了监测DXR从巨噬细胞中的释放，应用了体外肿瘤细胞生长抑制试验。腹腔注射DXR脂质体（10mg/kg体重）24小时后收集的腹腔巨噬细胞对培养中的肿瘤细胞生长有显著抑制作用。体外巨噬细胞单层的细胞抑制潜力取决于注射的DXR脂质体类型，并且与巨噬细胞相关的DXR量直接相关。在与肿瘤细胞共培养期间，巨噬细胞单层中的DXR含量从细胞中完全释放到培养基中。在没有肿瘤细胞的情况下培养的单层细胞获得的上清液显示出高生长抑制活性。游离或脂质体形式的DXR在与从大鼠肝脏匀浆中分离的溶酶体组分孵育期间，在长达26小时内化学稳定。结果表明，在体内吞噬含DXR脂质体的巨噬细胞释放DXR确实是可能的。
