Microfluidic 3D intestine tumor spheroid model for efficient in vitro investigation of nanoparticular formulations

Elberskirch, Linda; Knoll, Thorsten; Königsmark, Rebecca; Renner, Janis; Wilhelm, Nadine; Briesen, Hagen von; Wagner, Sylvia

doi:10.1016/j.jddst.2021.102496

Cited by 10 publications

(9 citation statements)

References 45 publications

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“…Ideally, in vivo effects should be predicted by in vitro experiments: thus, we aimed to establish a system which enabled the investigation of the anti-tumor efficacy of magnetically accumulated particles or immune cells against spheroids. Hitherto, others had performed investigations on tumor spheroids with nanoparticles under flow conditions, but without magnetic fields [ 49 , 50 ]. We had already performed a pilot study employing colon carcinoma spheroids placed in hand-made agarose beds in Ibidi µ-slides [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

In Vitro Setup for Determination of Nanoparticle-Mediated Magnetic Cell and Drug Accumulation in Tumor Spheroids under Flow Conditions

Behr

Carnell

Stein

et al. 2022

Cancers

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Superparamagnetic iron oxide nanoparticles (SPIONs) are used in nanomedicine as transporter systems for therapeutic cargos, or to magnetize cells to make them magnetically guidable. In cancer treatment, the site-directed delivery of chemotherapeutics or immune effector cells to the tumor can increase the therapeutic efficacy in the target region, and simultaneously reduce toxic side-effects in the rest of the body. To enable the transfer of new methods, such as the nanoparticle-mediated transport from bench to bedside, suitable experimental setups must be developed. In vivo, the SPIONs or SPION-loaded cells must be applied into the blood stream, to finally reach the tumor: consequently, targeting and treatment efficacy should be analyzed under conditions which are as close to in vivo as possible. Here, we established an in vitro method, including tumor spheroids placed in a chamber system under the influence of a magnetic field, and adapted to a peristaltic pump, to mimic the blood flow. This enabled us to analyze the magnetic capture and antitumor effects of magnetically targeted mitoxantrone and immune cells under dynamic conditions. We showed that the magnetic nanoparticle-mediated accumulation increased the anti-tumor effects, and reduced the unspecific distribution of both mitoxantrone and cells. Especially for nanomedical research, investigation of the site-specific targeting of particles, cells or drugs under circulation is important. We conclude that our in vitro setup improves the screening process of nanomedical candidates for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

In Vitro Setup for Determination of Nanoparticle-Mediated Magnetic Cell and Drug Accumulation in Tumor Spheroids under Flow Conditions

Behr

Carnell

Stein

et al. 2022

Cancers

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“…While two-dimensional (2D) cell cultures are useful for mimicking certain aspects of mucosae, they are limited in their ability to reproduce the dynamic conditions found in vivo. To tackle this shortcoming, three-dimensional (3D) tumor spheroids made from HT29-MTX-E12 cells were flowed through a microfluidic device to test adsorption and permeation of model nanoparticles under flow, showing significant differences between static and dynamic conditions (Figure a) . Similarly, 3D cell-based cocultures and organoids have also been used to more reliably model drug transport through representative tissues than their 2D counterparts. − …”

Section: Strategies To Study Mucus-nanoparticle Interactionsmentioning

confidence: 99%

Section: Strategies To Study Mucus-nanoparticle Interactionsmentioning

confidence: 99%

“…To tackle this shortcoming, three-dimensional (3D) tumor spheroids made from HT29-MTX-E12 cells were flowed through a microfluidic device to test adsorption and permeation of model nanoparticles under flow, showing significant differences between static and dynamic conditions (Figure 9a). 297 Similarly, 3D cell-based cocultures and organoids have also been used to more reliably model drug transport through representative tissues than their 2D counterparts. 313−315 For cell types that naturally secrete mucus, monocultures can be used to produce representative mucus models.…”

Section: Strategies To Study Mucus-nanoparticlementioning

confidence: 99%

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Untangling Mucosal Drug Delivery: Engineering, Designing, and Testing Nanoparticles to Overcome the Mucus Barrier

Watchorn

Clasky

Prakash

et al. 2022

ACS Biomater. Sci. Eng.

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Mucus is a complex viscoelastic gel and acts as a barrier covering much of the soft tissue in the human body. High vascularization and accessibility have motivated drug delivery to various mucosal surfaces; however, these benefits are hindered by the mucus layer. To overcome the mucus barrier, many nanomedicines have been developed, with the goal of improving the efficacy and bioavailability of drug payloads. Two major nanoparticle-based strategies have emerged to facilitate mucosal drug delivery, namely, mucoadhesion and mucopenetration. Generally, mucoadhesive nanoparticles promote interactions with mucus for immobilization and sustained drug release, whereas mucopenetrating nanoparticles diffuse through the mucus and enhance drug uptake. The choice of strategy depends on many factors pertaining to the structural and compositional characteristics of the target mucus and mucosa. While there have been promising results in preclinical studies, mucus−nanoparticle interactions remain poorly understood, thus limiting effective clinical translation. This article reviews nanomedicines designed with mucoadhesive or mucopenetrating properties for mucosal delivery, explores the influence of site-dependent physiological variation among mucosal surfaces on efficacy, transport, and bioavailability, and discusses the techniques and models used to investigate mucus−nanoparticle interactions. The effects of non-homeostatic perturbations on protein corona formation, mucus composition, and nanoparticle performance are discussed in the context of mucosal delivery. The complexity of the mucosal barrier necessitates consideration of the interplay between nanoparticle design, tissue-specific differences in mucus structure and composition, and homeostatic or disease-related changes to the mucus barrier to develop effective nanomedicines for mucosal delivery.

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“…Despite the fact that spheroids lack vascularization and cellular heterogeneity, it has been shown that gene expression profiles, pathway regulations and phenotype of 3D cultures resemble the ones observed in the tissue of origin [ 17 , 18 , 19 ]. Currently, spheroids have been successfully established from many tissues, including the ovary [ 20 , 21 ], liver [ 22 ], intestine [ 23 ], brain [ 24 , 25 ] and bone [ 26 , 27 ] and have been providing useful information regarding cellular differentiation, disease modeling and response to novel drug candidates. Although several studies report the usage of trophoblast spheroids [ 28 , 29 , 30 , 31 ], they are still largely under-represented in obstetrics preclinical studies as it is challenging for researchers to decide which model is the most appropriate to study particular placenta-related functions.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Three-Dimensional Trophoblast Spheroids: An Alternative Model to Study the Physiological Properties of the Placental Unit

Stojanovska

Arnold

Bauer

et al. 2022

Cells

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It was postulated that 3D cell culture models more accurately reflect the complex tissue physiology and morphology in comparison to 2D cell monolayers. Currently, there is a shortage of well-characterized and easily maintainable high-throughput experimental models of the human placenta. Here, we characterized three different 3D cultures (e.g., spheroids) derived from trophoblast cell lines and studied their functionality in comparison to primary fetal trophoblasts and placental tissue. The spheroid growth rates of JEG3, BeWo and HTR8/SVneo cell lines were similar among each other and were significantly larger in comparison to primary trophoblast spheroids. All spheroids exhibited migratory properties and shortest distances were registered for JEG3 spheroids. Even though all spheroids displayed invasive capabilities, only the invasive features of HTR8/SVneo spheroids resulted in specific branching. This was in agreement with the invasive properties of the spheroids obtained from primary trophoblasts. Human chorionic gonadotropin production was highest in JEG3 spheroids and only increased when stimulated with cAMP and forskolin in BeWo, but not HTR8/SVneo spheroids. The gene expression analysis confirmed that 3D trophoblast cell cultures and especially HTR8/SVneo spheroids showed considerable similarities with the gene expression profile of primary placental tissue. This study offers a broad characterization of 3D trophoblast spheroids that, in turn, can help in selecting the best model depending on the scientific question that needs to be answered.

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Microfluidic 3D intestine tumor spheroid model for efficient in vitro investigation of nanoparticular formulations

Cited by 10 publications

References 45 publications

In Vitro Setup for Determination of Nanoparticle-Mediated Magnetic Cell and Drug Accumulation in Tumor Spheroids under Flow Conditions

In Vitro Setup for Determination of Nanoparticle-Mediated Magnetic Cell and Drug Accumulation in Tumor Spheroids under Flow Conditions

Untangling Mucosal Drug Delivery: Engineering, Designing, and Testing Nanoparticles to Overcome the Mucus Barrier

Characterization of Three-Dimensional Trophoblast Spheroids: An Alternative Model to Study the Physiological Properties of the Placental Unit

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