Abstract:
Dynamin II (dynII) plays a significant role in the internalization pathways of endocytic cells, by allowing membrane invaginations to \"bud off\". An important class of dynII inhibitors that are used clinically are phenothiazines, such as prochlorperazine (PCZ). PCZ is an antipsychotic drug but is also currently in clinical trials at higher concentrations as an adjuvant in cancer patients that increases the efficacy of monoclonal antibodies at high intravenous doses. It is unknown, however, whether high-dose dynII inhibitors have the potential to alter the pharmacokinetics of co-administered chemotherapeutic nanomedicines that are largely cleared via the mononuclear phagocyte system. This work therefore sought to investigate the impact of clinically relevant concentrations of phenothiazines, PCZ and thioridazine, on in vitro liposome endocytosis and in vivo liposome pharmacokinetics after PCZ infusion in rats. The uptake of fluorescently labeled PEGylated liposomes into differentiated and undifferentiated THP-1 and RAW246.7 cells, and primary human peripheral white blood cells, was investigated via flow cytometry after co-incubation with dynII inhibitors. The IV pharmacokinetics of PEGylated liposomes were also investigated in rats after a 20 min infusion with PCZ. Phenothiazines and dyngo4a reduced the uptake of PEGylated liposomes by THP-1 and RAW264.7 cells in a concentration-dependent manner in vitro. However, dynII inhibitors did not alter the mean uptake of liposomes by human peripheral white blood cells, but endocytic white cells from some donors exhibited sensitivity to phenothiazine exposure. When a clinically relevant dose of PCZ was co-administered with PEGylated liposomal doxorubicin (Caelyx/Doxil) in rats, the pharmacokinetics and biodistribution of liposomes were unaltered. These data suggest that while clinically relevant doses of dynII inhibitors can inhibit the uptake of liposomes by endocytic cells in vitro, they are unlikely to significantly affect the pharmacokinetics of long-circulating, co-administered liposomes.
摘要:
DynaminII(dynII)在内吞细胞的内化途径中起着重要作用,通过允许膜内陷“芽脱落”。临床上使用的一类重要的dynII抑制剂是酚噻嗪,例如丙氯拉嗪(PCZ)。PCZ是一种抗精神病药物,但目前也在临床试验中,作为癌症患者的佐剂浓度较高,可提高高静脉内剂量单克隆抗体的疗效。它是未知的,然而,高剂量dynII抑制剂是否有可能改变共同给药的化疗纳米药物的药代动力学,这些药物通过单核吞噬细胞系统被清除。因此,这项工作试图调查临床相关浓度的酚噻嗪的影响,PCZ和硫利达嗪,PCZ输注后大鼠体内脂质体内吞作用和体内脂质体药代动力学。荧光标记的聚乙二醇化脂质体摄取分化和未分化的THP-1和RAW246.7细胞,和原发性人类外周血白细胞,在与dynII抑制剂共孵育后,通过流式细胞术进行了研究。用PCZ输注20分钟后,还在大鼠中研究了PEG化脂质体的IV药代动力学。菲噻嗪和dyngo4a在体外以浓度依赖性方式降低了THP-1和RAW264.7细胞对PEG化脂质体的摄取。然而,dynII抑制剂不会改变人外周血白细胞对脂质体的平均摄取,但是来自一些供者的内吞白细胞表现出对酚噻嗪暴露的敏感性。当临床相关剂量的PCZ与聚乙二醇化脂质体多柔比星(Caelyx/Doxil)在大鼠中共同给药时,脂质体的药代动力学和生物分布没有改变。这些数据表明,虽然临床相关剂量的dynII抑制剂可以在体外抑制内吞细胞对脂质体的摄取,它们不太可能显著影响长循环的药代动力学,共同施用的脂质体。