title: Evaluation of the efficiency of tumor and tissue delivery of carrier-mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric: relative distribution index over time (RDI-OT).
abstract: The pharmacokinetics (PK) of carrier-mediated agents (CMA) is dependent upon the carrier system. As a result, CMA PK differs greatly from the PK of small molecule (SM) drugs. Advantages of CMAs over SMs include prolonged circulation time in plasma, increased delivery to tumors, increased antitumor response, and decreased toxicity. In theory, CMAs provide greater tumor drug delivery than SMs due to their prolonged plasma circulation time. We sought to create a novel PK metric to evaluate the efficiency of tumor and tissue delivery of CMAs and SMs. We conducted a study evaluating the plasma, tumor, liver, and spleen PK of CMAs and SMs in mice bearing subcutaneous flank tumors using standard PK parameters and a novel PK metric entitled relative distribution over time (RDI-OT), which measures efficiency of delivery. RDI-OT is defined as the ratio of tissue drug concentration to plasma drug concentration at each time point. The standard concentration versus time area under the curve values (AUC) of CMAs were higher in all tissues and plasma compared with SMs. However, 8 of 17 SMs had greater tumor RDI-OT AUC0-lastvalues than their CMA comparators and all SMs had greater tumor RDI-OT AUC0-6 hvalues than their CMA comparators. Our results indicate that in mice bearing flank tumor xenografts, SMs distribute into tumor more efficiently than CMAs. Further research in additional tumor models that may more closely resemble tumors seen in patients is needed to determine if our results are consistent in different model systems.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill (UNC) Eshelman School of Pharmacy, 120 Mason Farm Road, Suite 1013, CB 7361, Chapel Hill, NC 27599-7361, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Madden
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill (UNC) Eshelman School of Pharmacy, 120 Mason Farm Road, Suite 1013, CB 7361, Chapel Hill, NC 27599-7361, USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Rawal
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill (UNC) Eshelman School of Pharmacy, 120 Mason Farm Road, Suite 1013, CB 7361, Chapel Hill, NC 27599-7361, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Sandison
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill (UNC) Eshelman School of Pharmacy, 120 Mason Farm Road, Suite 1013, CB 7361, Chapel Hill, NC 27599-7361, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Schell
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill (UNC) Eshelman School of Pharmacy, 120 Mason Farm Road, Suite 1013, CB 7361, Chapel Hill, NC 27599-7361, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Schorzman
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Deal
authors.affiliation: Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Feng
authors.affiliation: Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Ma
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Mumper
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: DeSimone
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill (UNC) Eshelman School of Pharmacy, 120 Mason Farm Road, Suite 1013, CB 7361, Chapel Hill, NC 27599-7361, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
keywords: Chemotherapy; Drug delivery; Nanomedicine; Nanoparticles; Pharmacokinetics