title: A cell-based pharmacokinetics assay for evaluating tubulin-binding drugs.
abstract: Increasing evidence reveals that traditional pharmacokinetics parameters based on plasma drug concentrations are insufficient to reliably demonstrate accurate pharmacological effects of drugs in target organs or cells in vivo. This underscores the increasing need to improve the types and qualities of cellular pharmacokinetic information for drug preclinical screening and clinical efficacy assessments. Here we report a whole cell-based method to assess drugs that disturb microtubule dynamics to better understand different formulation-mediated intracellular drug release profiles. As proof of concept for this approach, we compared the well-known taxane class of anti-microtubule drugs based on paclitaxel (PTX), including clinically familiar albumin nanoparticle-based Abraxane™, and a polymer nanoparticle-based degradable paclitaxel carrier, poly(L-glutamic acid)-paclitaxel conjugate (PGA-PTX, also known as CT-2103) versus control PTX. This in vitro cell-based evaluation of PTX efficacy includes determining the cellular kinetics of tubulin polymerization, relative populations of cells under G2 mitotic arrest, cell proliferation and total cell viability. For these taxane tubulin-binding compounds, the kinetics of cell microtubule stabilization directly correlate with G2 arrest and cell proliferation, reflecting the kinetics and amounts of intracellular PTX release. Each individual cell-based dose-response experiment correlates with published, key therapeutic parameters and taken together, provide a comprehensive understanding of drug intracellular pharmacokinetics at both cellular and molecular levels. This whole cell-based evaluating method is convenient, quantitative and cost-effective for evaluating new formulations designed to optimize cellular pharmacokinetics for drugs perturbing tubulin polymerization as well as assisting in explaining drug mechanisms of action at cellular levels.
authors.affiliation: 1. Molecular Therapeutics Department, Nitto Denko Technical Corporation, 501 Via Del Monte, Oceanside, CA 92054, USA;
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1. Molecular Therapeutics Department, Nitto Denko Technical Corporation, 501 Via Del Monte, Oceanside, CA 92054, USA;
authors.forename: Jihua
authors.initials: J
authors.lastname: Liu
authors.affiliation: 1. Molecular Therapeutics Department, Nitto Denko Technical Corporation, 501 Via Del Monte, Oceanside, CA 92054, USA;
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 1. Molecular Therapeutics Department, Nitto Denko Technical Corporation, 501 Via Del Monte, Oceanside, CA 92054, USA;
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.affiliation: 1. Molecular Therapeutics Department, Nitto Denko Technical Corporation, 501 Via Del Monte, Oceanside, CA 92054, USA;
authors.forename: Jonathon
authors.initials: J
authors.lastname: Chan
authors.affiliation: 1. Molecular Therapeutics Department, Nitto Denko Technical Corporation, 501 Via Del Monte, Oceanside, CA 92054, USA;
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.affiliation: 1. Molecular Therapeutics Department, Nitto Denko Technical Corporation, 501 Via Del Monte, Oceanside, CA 92054, USA;
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.affiliation: 1. Molecular Therapeutics Department, Nitto Denko Technical Corporation, 501 Via Del Monte, Oceanside, CA 92054, USA;
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: 2. Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, UT 84112, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Grainger
authors.affiliation: 1. Molecular Therapeutics Department, Nitto Denko Technical Corporation, 501 Via Del Monte, Oceanside, CA 92054, USA;
authors.forename: Wenbin
authors.initials: W
authors.lastname: Ying
mesh_terms: D000068196:Albumin-Bound Paclitaxel; D000418:Albumins / Q000008:administration & dosage / Q000493:pharmacokinetics; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004341:Drug Evaluation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D011099:Polyglutamic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D014404:Tubulin; D011099:Polyglutamic Acid; D017239:Paclitaxel; C509139:paclitaxel poliglumex
keywords: antimitotics; in vitro drug testing; microtubule.; paclitaxel; whole cell analysis