Coupled cellular trafficking and diffusional limitations in delivery of immunotoxins to multicell tumor spheroids.
Immunotoxins have the potential to be powerful tools for selective cell killing, but their lack of clinical success against solid tumors indicates a need to better understand factors which limit immunotoxin transport in three-dimensional systems. In this work, a previously developed model which related immunotoxin toxicity to cellular trafficking in a single cell was coupled with a term accounting for diffusive transport of immunotoxin in a solid tumor sphere. This created a mathematical model which is capable of simulating the biological response of multicell tumor spheroids (MTS) to immunotoxin treatment. The model was used to predict the kinetics of protein synthesis inhibition in MTS treated with transferrin receptor-targeted immunotoxins as a function of immunotoxin concentration and toxin choice. HeLa cells were grown as MTS and treated with immunotoxins constructed from the anti-transferrin receptor antibody OKT9 and the toxins gelonin or CRM107, and the average protein synthesis inhibition and growth rates were measured. With no fitted parameters, the mathematical model quantitatively predicted the experimental observations. Immunotoxins were generally less effective against MTS than monolayer cells at equivalent conditions; for OKT9-gelonin at high concentrations this decrease in efficacy was attributed primarily to heterogeneous receptor distribution in MTS whereas for OKT9-CRM107 the decrease was caused primarily by a large barrier to penetration of the immunotoxin into the spheroid. The experimentally verified model was used to define the conditions which lead to large penetration barriers. In general, transport barriers in MTS become more important as immunotoxins become more effective against cells grown as monolayers. The proposed model is unique in its ability to predict toxicity in MTS directly, and is an important step toward understanding immunotoxin effect on tumors in vivo.
Wenning
L A
LA
Department of Chemical Engineering, University of Wisconsin, Madison, Wisconsin 53706, USA.
Murphy
R M
RM
D000818:Animals; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000493:pharmacokinetics; D001665:Binding Sites; D004167:Diphtheria Toxin; D006367:HeLa Cells; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018613:Microscopy, Confocal; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009369:Neoplasms / Q000188:drug therapy; D010940:Plant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D011990:Receptors, Transferrin / Q000378:metabolism; D054789:Ribosome Inactivating Proteins, Type 1; D018874:Spheroids, Cellular
D001427:Bacterial Toxins; C058384:CRM 107; D004167:Diphtheria Toxin; D000922:Immunotoxins; D009363:Neoplasm Proteins; D010940:Plant Proteins; D011500:Protein Synthesis Inhibitors; D011990:Receptors, Transferrin; D054789:Ribosome Inactivating Proteins, Type 1; C025674:GEL protein, Gelonium multiflorum