title: Multichannel imaging to quantify four classes of pharmacokinetic distribution in tumors.
abstract: Low and heterogeneous delivery of drugs and imaging agents to tumors results in decreased efficacy and poor imaging results. Systemic delivery involves a complex interplay of drug properties and physiological factors, and heterogeneity in the tumor microenvironment makes predicting and overcoming these limitations exceptionally difficult. Theoretical models have indicated that there are four different classes of pharmacokinetic behavior in tissue, depending on the fundamental steps in distribution. In order to study these limiting behaviors, we used multichannel fluorescence microscopy and stitching of high-resolution images to examine the distribution of four agents in the same tumor microenvironment. A validated generic partial differential equation model with a graphical user interface was used to select fluorescent agents exhibiting these four classes of behavior, and the imaging results agreed with predictions. BODIPY-FL exhibited higher concentrations in tissue with high blood flow, cetuximab gave perivascular distribution limited by permeability, high plasma protein and target binding resulted in diffusion-limited distribution for Hoechst 33342, and Integrisense 680 was limited by the number of binding sites in the tissue. Together, the probes and simulations can be used to investigate distribution in other tumor models, predict tumor drug distribution profiles, and design and interpret in vivo experiments.
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, 48109.
authors.forename: Sumit
authors.initials: S
authors.lastname: Bhatnagar
authors.forename: Emily
authors.initials: E
authors.lastname: Deschenes
authors.forename: Jianshan
authors.initials: J
authors.lastname: Liao
authors.forename: Cornelius
authors.initials: C
authors.lastname: Cilliers
authors.forename: Greg M
authors.initials: GM
authors.lastname: Thurber
mesh_terms: D006801:Humans; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000378:metabolism*; D010599:Pharmacokinetics
keywords: Krogh cylinder; drug transport; fluorescence microscopy; imaging methods; in vivo/in vitro correlations (IVIVC); mathematical model; predictive partial differential equation simulations