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 (R2 = 0.43, P = 0.04) and ROS production (R2 = 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.
Footnotes
- Received August 14, 2013.
- Accepted September 9, 2013.
This work was supported by the National Institutes of Health National Cancer Institute [Grants 1U54-CA151652-01 and P01-CA142538] (to Carolina Center for Cancer Nanotechnology Excellence); the Nationals Institutes of Health National Institute of Environmental Health Sciences [Grant R01-ES0201900]; the University Cancer Research Fund Grant from UNC Lineberger Comprehensive Cancer Center; and the North Carolina Translational and Clinical Sciences Institute, NC TraC$ Award [Grant 10KR61005].This work was previously presented as follows: Caron WP, Lay JC, Fong AM, La-Beck NM, Newman SE, Clarke-Pearson DL, Brewster WR, Van Le L, Bae-Jump VL, Gehrig PA, et al. (2012) Cellular function of the mononuclear phagocyte system (MPS) as a phenotypic probe for pharmacokinetics (PK) and pharmacodynamics (PD) of PEGylated liposomal doxorubicin (PLD) in patients with recurrent ovarian cancer, in Proceedings of the 2012 Annual Meeting of the American Society of Clinical Oncology; 2012 June 1–5; Chicago, IL.
Caron WP, Lay JC, Fong AM, La-Beck NM, Newman SE, Clarke-Pearson DL, Brewster WR, Van Le L, Bae-Jump VL, Gehrig PA, et al. (2011) Cellular function of the mononuclear phagocyte system (MPS) as a phenotypic probe for pegylated liposomal doxorubicin (PLD) pharmacokinetics (PK) in patients with recurrent ovarian cancer. Proceedings of the 2011 Annual Meeting of the American Society of Clinical Oncology; 2011 June 4–8; Chicago, IL.
Conflicts of Interest/Patents Filed: Caron WP and Zamboni WC (2010), inventor; University of North Carolina at Chapel Hill, assignee. Predictors of the pharmacokinetic and pharmacodynamic disposition of carrier-mediated agents. U.S. Patent Application 61/325,698. 2010 April 19.
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- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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