“…While the roles of E-selectin haven’t been deeply explored in complex 3D tumor spheroids comprising heterotypic cultures, other works have demonstrated the importance of this cell-adhesion molecule. Triculture tumor spheroids comprised of E-selectin expressing endothelial cells, normal human lung fibroblasts and human breast cancer cell line have been used to study an E-selectin drug delivery system for targeting tumor vasculature [ 123 ]. Tumor spheroids of Lewis lung carcinoma had been previously implanted in dorsal skinfold chambers of nude mice to study leukocyte adhesion in blood vessels induced by tumor spheroids.…”
Section: Modeling the Tumor Microenvironment In Vitromentioning
Cancer remains a serious burden in society and while the pace in the development of novel and more effective therapeutics is increasing, testing platforms that faithfully mimic the tumor microenvironment are lacking. With a clear shift from animal models to more complex in vitro 3D systems, spheroids emerge as strong options in this regard. Years of development have allowed spheroid-based models to better reproduce the biomechanical cues that are observed in the tumor-associated extracellular matrix (ECM) and cellular interactions that occur in both a cell–cell and cell-ECM manner. Here, we summarize some of the key cellular interactions that drive tumor development, progression and invasion, and how successfully are these interactions recapitulated in 3D spheroid models currently in use in the field. We finish by speculating on future advancements in the field and on how these can shape the relevance of spherical 3D models for tumor modelling.
“…While the roles of E-selectin haven’t been deeply explored in complex 3D tumor spheroids comprising heterotypic cultures, other works have demonstrated the importance of this cell-adhesion molecule. Triculture tumor spheroids comprised of E-selectin expressing endothelial cells, normal human lung fibroblasts and human breast cancer cell line have been used to study an E-selectin drug delivery system for targeting tumor vasculature [ 123 ]. Tumor spheroids of Lewis lung carcinoma had been previously implanted in dorsal skinfold chambers of nude mice to study leukocyte adhesion in blood vessels induced by tumor spheroids.…”
Section: Modeling the Tumor Microenvironment In Vitromentioning
Cancer remains a serious burden in society and while the pace in the development of novel and more effective therapeutics is increasing, testing platforms that faithfully mimic the tumor microenvironment are lacking. With a clear shift from animal models to more complex in vitro 3D systems, spheroids emerge as strong options in this regard. Years of development have allowed spheroid-based models to better reproduce the biomechanical cues that are observed in the tumor-associated extracellular matrix (ECM) and cellular interactions that occur in both a cell–cell and cell-ECM manner. Here, we summarize some of the key cellular interactions that drive tumor development, progression and invasion, and how successfully are these interactions recapitulated in 3D spheroid models currently in use in the field. We finish by speculating on future advancements in the field and on how these can shape the relevance of spherical 3D models for tumor modelling.
“…11 B). The heterotypic HUVECs/lung fibroblast spheroids can develop angiogenic sprouts and produce a continues vascular network of HUVECs, which are seeded in microfluidic channels of the device [ 93 ]. Fig.…”
Section: Application Of Tumor Co-culture Spheroid Models In Nanomedicinementioning
confidence: 99%
“…Finally, as can be seen, a vascular network has been formed on the seventh day, Reproduced with permission from Ref. [ 93 ], Copyright 2022 Elsevier …”
Section: Application Of Tumor Co-culture Spheroid Models In Nanomedicinementioning
Nanomedicine has emerged as a promising therapeutic approach, but its translation to the clinic has been hindered by the lack of cellular models to anticipate how tumor cells will respond to therapy. Three-dimensional (3D) cell culture models are thought to more accurately recapitulate key features of primary tumors than two-dimensional (2D) cultures. Heterotypic 3D tumor spheroids, composed of multiple cell types, have become more popular than homotypic spheroids, which consist of a single cell type, as a superior model for mimicking in vivo tumor heterogeneity and physiology. The stromal interactions demonstrated in heterotypic 3D tumor spheroids can affect various aspects, including response to therapy, cancer progression, nanomedicine penetration, and drug resistance. Accordingly, to design more effective anticancer nanomedicinal therapeutics, not only tumor cells but also stromal cells (e.g., fibroblasts and immune cells) should be considered to create a more physiologically relevant in vivo microenvironment. This review aims to demonstrate current knowledge of heterotypic 3D tumor spheroids in cancer research, to illustrate current advances in utilizing these tumor models as a novel and versatile platform for in vitro evaluation of nanomedicine-based therapeutics in cancer research, and to discuss challenges, guidelines, and future directions in this field.
Graphical Abstract
“…For instance, these systems enable the simulation of tissue structures and fluid dynamics, which closely resemble physiological conditions. We are actively developing and characterizing an organ-on-a-chip that mimics various organs (e.g., the liver, 22−24 kidney, 25,26 intestine, 27 and tumors 28 to assess ADME/Tox and drug delivery systems. Current research has not only pivoted to replicate the physiological functions of individual organs but also to explore interorgan interactions facilitated by microfluidic channels.…”
Section: Introductionmentioning
confidence: 99%
“…For instance, these systems enable the simulation of tissue structures and fluid dynamics, which closely resemble physiological conditions. We are actively developing and characterizing an organ-on-a-chip that mimics various organs (e.g., the liver, − kidney, , intestine, and tumors to assess ADME/Tox and drug delivery systems. Current research has not only pivoted to replicate the physiological functions of individual organs but also to explore interorgan interactions facilitated by microfluidic channels. ,,− The gut-liver-on-a-chip has been used to examine drug metabolism − and the intricate network of inflammatory intertissue crosstalk. − The use of small-volume microfluidic channels to connect cells provides the distinct advantage of reducing the dilution of secreted humoral factors in the culture medium, which influences cellular function.…”
In
the evolving field of drug discovery and development, multiorgans-on-a-chip
and microphysiological systems are gaining popularity owing to their
ability to emulate in vivo biological environments. Among the various
gut-liver-on-a-chip systems for studying oral drug absorption, the
chip developed in this study stands out with two distinct features:
incorporation of perfluoropolyether (PFPE) to effectively mitigate
drug sorption and a unique enterohepatic single-passage system, which
simplifies the analysis of first-pass metabolism and oral bioavailability.
By introducing a bolus drug injection into the liver compartment,
hepatic extraction alone could be evaluated, further enhancing our
estimation of intestinal availability. In a study on midazolam (MDZ),
PFPE-based chips showed more than 20-times the appearance of intact
MDZ in the liver compartment effluent compared to PDMS-based counterparts.
Notably, saturation of hepatic metabolism at higher concentrations
was confirmed by observations when the dose was reduced from 200 μM
to 10 μM. This result was further emphasized when the metabolism
was significantly inhibited by the coadministration of ketoconazole.
Our chip, which is designed to minimize the dead volume between the
gut and liver compartments, is adept at sensitively observing the
saturation of metabolism and the effect of inhibitors. Using genome-edited
CYP3A4/UGT1A1-expressing Caco-2 cells, the estimates for intestinal
and hepatic availabilities were 0.96 and 0.82, respectively; these
values are higher than the known human in vivo values. Although the
metabolic activity in each compartment can be further improved, this
gut-liver-on-a-chip can not only be used to evaluate oral bioavailability
but also to carry out individual assessment of both intestinal and
hepatic availability.
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