title: Intracellular PK/PD Relationships of Free and Liposomal Doxorubicin: Quantitative Analyses and PK/PD Modeling.
abstract: Nanomedicines are widely studied for intracellular delivery of cancer drugs. However, the relationship between intracellular drug concentrations and drug responses are poorly understood. In this study, cellular and nuclear concentrations of doxorubicin were quantified with LC/MS after cell exposure with free and liposomal doxorubicin (pH-sensitive and pegylated liposomes). Cellular uptake of pegylated liposomes was low (∼3-fold extracellular concentrations) compared with doxorubicin in free form and pH-sensitive liposomes (up to 280-fold extracellular concentrations) in rat glioma (BT4C) and renal clear cell carcinoma (Caki-2) cells. However, after the cell exposure with pegylated liposomes, intracellular doxorubicin was distributed into the nuclear compartment in both cell types. Despite high drug concentrations in the nuclei, Caki-2 cells showed strong resistance toward doxorubicin. A model was successfully built to describe PK/PD relationship between drug concentrations in nucleus and cytotoxic responses in BT4C cells. This model is the first step to link target site concentration of doxorubicin into its effect and can be a useful part of more comprehensive future in vivo PK/PD models.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , Kuopio campus, P.O. Box 1627, FI-70211, Kuopio, Finland.
authors.forename: Suvi K
authors.initials: SK
authors.lastname: Soininen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , Kuopio campus, P.O. Box 1627, FI-70211, Kuopio, Finland.
authors.forename: Kati-Sisko
authors.initials: KS
authors.lastname: Vellonen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , Kuopio campus, P.O. Box 1627, FI-70211, Kuopio, Finland.
authors.forename: Aki T
authors.initials: AT
authors.lastname: Heikkinen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , Kuopio campus, P.O. Box 1627, FI-70211, Kuopio, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Auriola
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , Kuopio campus, P.O. Box 1627, FI-70211, Kuopio, Finland.
authors.forename: Veli-Pekka
authors.initials: VP
authors.lastname: Ranta
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , Kuopio campus, P.O. Box 1627, FI-70211, Kuopio, Finland.|Centre for Drug Research, Faculty of Pharmacy, University of Helsinki , P.O. Box 56, FI-00014, Helsinki, Finland.
authors.forename: Arto
authors.initials: A
authors.lastname: Urtti
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , Kuopio campus, P.O. Box 1627, FI-70211, Kuopio, Finland.
authors.forename: Marika
authors.initials: M
authors.lastname: Ruponen
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats
chemical_list: D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: cell fractionation; doxil; doxorubicin; intracellular concentration; intracellular distribution; liposome