title: Translational studies of phenotypic probes for the mononuclear phagocyte system and liposomal pharmacology.
abstract: 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.
authors.affiliation: 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.).
authors.forename: Whitney P
authors.initials: WP
authors.lastname: Caron
authors.forename: John C
authors.initials: JC
authors.lastname: Lay
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fong
authors.forename: Ninh M
authors.initials: NM
authors.lastname: La-Beck
authors.forename: Parag
authors.initials: P
authors.lastname: Kumar
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Newman
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhou
authors.forename: Jane H
authors.initials: JH
authors.lastname: Monaco
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Clarke-Pearson
authors.forename: Wendy R
authors.initials: WR
authors.lastname: Brewster
authors.forename: Linda
authors.initials: L
authors.lastname: Van Le
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bae-Jump
authors.forename: Paola A
authors.initials: PA
authors.lastname: Gehrig
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D003713:Dendritic Cells / Q000187:drug effects; D004285:Dogs; D004339:Drug Compounding; D005260:Female; D006207:Half-Life; D006801:Humans; D008081:Liposomes / Q000494:pharmacology*; D051379:Mice; D008875:Middle Aged; D012157:Mononuclear Phagocyte System / Q000187:drug effects*; D053758:Nanoparticles; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010587:Phagocytosis / Q000187:drug effects; D010599:Pharmacokinetics; D010641:Phenotype; D011092:Polyethylene Glycols; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D057170:Translational Research, Biomedical
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols
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