A computational diffusion model to study antibody transport within reconstructed tumor microenvironments

Abstract

Background Antibodies revolutionized cancer treatment over the past decades. Despite their successfully application, there are still challenges to overcome to improve efficacy, such as the heterogeneous distribution of antibodies within tumors. Tumor microenvironment features, such as the distribution of tumor and other cell types and the composition of the extracellular matrix may work together to hinder antibodies from reaching the target tumor cells. To understand these interactions, we propose a framework combining in vitro and in silico models. We took advantage of in vitro cancer models previously developed by our group, consisting of tumor cells and fibroblasts co-cultured in 3D within alginate capsules, for reconstruction of tumor microenvironment features. Results In this work, an experimental-computational framework of antibody transport within alginate capsules was established, assuming a purely diffusive transport, combined with an exponential saturation effect that mimics the saturation of binding sites on the cell surface. Our tumor microenvironment in vitro models were challenged with a fluorescent antibody and its transport recorded using light sheet fluorescence microscopy. Diffusion and saturation parameters of the computational model were adjusted to reproduce the experimental antibody distribution, with root mean square error under 5%. This computational framework is flexible and can simulate different random distributions of tumor microenvironment elements (fibroblasts, cancer cells and collagen fibers) within the capsule. The random distribution algorithm can be tuned to follow the general patterns observed in the experimental models. Conclusions We present a computational and microscopy framework to track and simulate antibody transport within the tumor microenvironment that complements the previously established in vitro models platform. This framework paves the way to the development of a valuable tool to study the influence of different components of the tumor microenvironment on antibody transport.

Modular multimodal platform for classical and high throughput light sheet microscopy

“…Additionally, more complex experiments in which the imaging of various samples can be repeated before and after a defined interaction (e.g. to obtain a control image 32 , or the addition of a drug) are now possible, thanks to the easiness of sample’s loading and unloading procedures that maintain sample’s viability. Note that in the Hybrid LSFM , as in the Flow LSFM , the medium that fills the FEP tube can be the medium that best fit the experimental need (e.g.…”

Modeling Biochemical Gradients In Vitro to Control Cell Compartmentalization in a Microengineered 3D Model of the Intestinal Epithelium

“…Fluorescently labeled gradients were visualized in-chip by LSFM. [30] LSFM technique was selected as it permits fast imaging (minimal photobleaching) at large working distances with fine axial resolution, a trade-off difficult to achieve by traditional confocal microscopy. [45,46] By decoupling the illumination and detection light paths, LSFM allows a flexible sample access and mounting, which was needed for the microfluidic device (Figure 2A For the characterization of the biomolecular diffusion dynamics, Texas Red-labeled BSA was selected as the model protein.…”

Therapeutic antibodies – natural and pathological barriers and strategies to overcome them

“…An inverse correlation between sulphated glycosaminoglycans and IgG penetration was later reported ( Davies Cde, Berk, Pluen, & Jain, 2002 ). 3D in vitro co-culture cancer models were recently developed to assess IgG distribution within the ECM ( Estrada et al, 2016 ; Rebelo et al, 2018 ) and a computational ( in silico ) model was calibrated based on these data ( Cartaxo et al, 2020 ). Such models offer a valuable and modular tool to study the influence of different components of the ECM on antibody transport without the need for in vivo models.…”