单核吞噬细胞系统表型探针和脂质体药理学的转化研究。
Translational studies of phenotypic probes for the mononuclear phagocyte system and liposomal pharmacology.
机构信息
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy (W.P.C., P.K., S.E.N., W.C.Z.), School of Medicine (J.C.L., A.M.F., D.L.C.-P., W.R.B., L.V.L., V.L.B.-J., P.A.G.), Department of Biostatistics (H.Z., J.H.M.), Lineberger Comprehensive Cancer Center (D.L.C.-P., W.R.B., L.V.L., V.L.B.-J., P.A.G., W.C.Z.), Institute for Pharmacogenomics and Individualized Therapy (W.C.Z.), Carolina Center of Cancer Nanotechnology Excellence (W.C.Z.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; School of Pharmacy, Texas Tech University Health Sciences Center, St. Amarillo, Texas (N.M.L.-B.); and North Carolina Biomedical Innovation Network, Research Triangle Park, North Carolina (W.C.Z.).
出版信息
J Pharmacol Exp Ther. 2013 Dec;347(3):599-606. doi: 10.1124/jpet.113.208801. Epub 2013 Sep 16.
As nanoparticles (NPs) are cleared via phagocytes of the mononuclear phagocyte system (MPS), we hypothesized that the function of circulating monocytes and dendritic cells (MO/DC) in blood can predict NP clearance (CL). We measured MO/DC phagocytosis and reactive oxygen species (ROS) production in mice, rats, dogs, and patients with refractory solid tumors. Pharmacokinetic studies of polyethylene glycol (PEG)-encapsulated liposomal doxorubicin (PEGylated liposomal doxirubicin [PLD]), CKD-602 (S-CKD602), and cisplatin (SPI-077) were performed at the maximum tolerated dose. MO/DC function was also evaluated in patients with recurrent epithelial ovarian cancer (EOC) administered PLD. Across species, a positive association was observed between cell function and CL of PEGylated liposomes. In patients with EOC, associations were observed between PLD CL and phagocytosis (R(2) = 0.43, P = 0.04) and ROS production (R(2) = 0.61, P = 0.008) in blood MO/DC. These findings suggest that probes of MPS function may help predict PEGylated liposome CL across species and PLD CL in patients with EOC.
由于纳米颗粒（NPs）通过单核吞噬细胞系统（MPS）中的吞噬细胞清除，我们假设循环单核细胞和树突状细胞（MO/DC）在血液中的功能可以预测 NP 清除（CL）。我们测量了小鼠、大鼠、狗和患有难治性实体瘤的患者的 MO/DC 吞噬作用和活性氧（ROS）产生。在最大耐受剂量下进行了聚乙二醇（PEG）包封的脂质体多柔比星（PEGylated liposomal doxirubicin [PLD]）、CKD-602（S-CKD602）和顺铂（SPI-077）的药代动力学研究。还在接受 PLD 治疗的复发性上皮性卵巢癌（EOC）患者中评估了 MO/DC 功能。在所有物种中，细胞功能与 PEG 化脂质体的 CL 之间存在正相关。在 EOC 患者中，PLD CL 与血液 MO/DC 中的吞噬作用（R(2) = 0.43，P = 0.04）和 ROS 产生（R(2) = 0.61，P = 0.008）之间存在关联。这些发现表明，MPS 功能的探针可能有助于预测不同物种的 PEG 化脂质体 CL 和 EOC 患者的 PLD CL。
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