Coupled cellular trafficking and diffusional limitations in delivery of immunotoxins to multicell tumor spheroids

Abstract

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. © 1999 John Wiley & Sons, Inc. Biotechnol Bioeng 62: 562–575, 1999.

Convergent Potency of Internalized Gelonin Immunotoxins across Varied Cell Lines, Antigens, and Targeting Moieties

“…These K d values were also slightly higher than those found for the parent Fn3 fragments, 2 nM for C743 and 3 nM for E246. 3 Differences in overall signal were attributed to differences in the degree of biotinylation of immunotoxins. Biotinylated rGel showed no significant signal when titrated over the same range of concentrations.…”

“…Clinical success for immunotoxins has been mostly limited to hematological malignancies due to transport limitations in solid tumors (1). Such limitations have been extensively studied experimentally (2) and with several computational models (3,4).…”

Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

“…107,108 All these models focused mainly on the penetration of macromolecules (ie, dextrans and antibodies) in MCTS and showed strong evidence of transport barriers that impair macromolecule diffusion in MCTS. Currently, there is an increasing interest in the use of large NPs such as liposomes and polymeric NPs for drug delivery.…”

Mathematical Modeling of Vesicle Drug Delivery Systems 2: Targeted Vesicle Interactions with Cells, Tumors, and the Body

“…The drugs of interest used in previous models range from several nanometers (such as an antibody) up to 200 nm (such as a viral vector), but they share a similar mathematical model. [20][21][22] Most models consider tumor spheroids as strictly spherical and assume no convection inside the spheroid. A general mathematical model for diffusion of vesicles can be written based on the conservation of species equation.…”