Exploring Drug Dosing Regimens In Vitro Using Real-Time 3D Spheroid Tumor Growth Assays

McGee, Lauren; Titus, Steven A.; Brimacombe, Kyle R.; Michael, Sam; Sittampalam, G. Sitta; Ferrer, Marc

doi:10.1177/2472555217698818

Cited by 12 publications

(17 citation statements)

References 14 publications

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“…This observation is in line with previous reports showing that spheroids features (size, density, incubation time) may greatly impact subsequent efficacy results, because of changes in cell-cell junctions and cell-matrix junction. 9,21 Here, immunoliposomes proved to perform better than all other treatments, including Her2negative MDA-MB-231 cells. Conversely, T-DM1 failed to exhibit any antiproliferative efficacy in vitro.…”

Section: Discussionmentioning

confidence: 91%

From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer

Rodallec¹,

Sicard²,

Giacometti³

et al. 2018

IJN

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PurposeNanoparticles are of rising interest in cancer research, but in vitro canonical cell monolayer models are not suitable to evaluate their efficacy when prototyping candidates. Here, we developed three-dimensional (3D) spheroid models to test the efficacy of trastuzumab-docetaxel immunoliposomes in breast cancer prior to further testing them in vivo.Materials and methodsImmunoliposomes were synthesized using the standard thin film method and maleimide linker. Two human breast cancer cell lines varying in Her2 expression were tested: Her2+ cells derived from metastatic site: mammary breast MDA-MB-453 and triple-negative MDA-MB-231 cells. 3D spheroids were developed and tested with fluorescence detection to evaluate viability. In vivo efficacy and biodistribution studies were performed on xenograft bearing nude mice using fluorescent and bioluminescent imaging.ResultsIn vitro, antiproliferative efficacy was dependent upon cell type, size of the spheroids, and treatment scheduling, resulting in subsequent changes between tested conditions and in vivo results. Immunoliposomes performed better than free docetaxel + free trastuzumab and ado-trastuzumab emtansine (T-DM1). On MDA-MB-453 and MDA-MB-231 cell growth was reduced by 76% and 25%, when compared to free docetaxel + free trastuzumab and by 85% and 70% when compared to T-DM1, respectively. In vivo studies showed tumor accumulation ranging from 3% up to 15% of the total administered dose in MDA-MB-453 and MDA-MB-231 bearing mice. When compared to free docetaxel + free trastuzumab, tumor growth was reduced by 89% (MDA-MB-453) and 25% (MDA-MB-231) and reduced by 66% (MDA-MB-453) and 29% (MDA-MB-231) when compared to T-DM1, an observation in line with data collected from 3D spheroids experiments.ConclusionWe demonstrated the predictivity of 3D in vitro models when developing and testing nanoparticles in experimental oncology. In vitro and in vivo data showed efficient drug delivery with higher efficacy and prolonged survival with immunoliposomes when compared to current anti-Her2 breast cancer strategies.

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Section: Discussionmentioning

confidence: 91%

From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer

Rodallec¹,

Sicard²,

Giacometti³

et al. 2018

IJN

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“…A collagen solution made up of neutralized collagen type I (2.25 mg/ml, Corning) and is co-polymerized with 2 μm red fluorescent microsphere beads (FluoSpheres™ Carboxylate-Modified Microspheres, 580/605, 2 × 10 6 beads/ml) used to track extracellular matrix deformation. The spheroid generation plate was chilled on ice for 15 min to pre-chill wells 22 . 200 μl of collagen solution was placed into a flat bottom 96-well ultra-microplate (Perkin Elmer, ULA CellCarrier-96 Ultra Microplates) with an optically-clear cyclic olefin bottom for optimal imaging acquisition.…”

Section: Methodsmentioning

confidence: 99%

Characterization of multicellular breast tumor spheroids using image data-driven biophysical mathematical modeling

Bowers

Fannin

Thomas

et al. 2020

Sci Rep

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Multicellular tumor spheroid (MCTS) systems provide an in vitro cell culture model system which mimics many of the complexities of an in vivo solid tumor and tumor microenvironment, and are often used to study cancer cell growth and drug efficacy. Here, we present a coupled experimental-computational framework to estimate phenotypic growth and biophysical tumor microenvironment properties. This novel framework utilizes standard microscopy imaging of MCTS systems to drive a biophysical mathematical model of MCTS growth and mechanical interactions. By extending our previous in vivo mechanically-coupled reaction–diffusion modeling framework we developed a microscopy image processing framework capable of mechanistic characterization of MCTS systems. Using MDA-MB-231 breast cancer MCTS, we estimated biophysical parameters of cellular diffusion, rate of cellular proliferation, and cellular tractions forces. We found significant differences in these model-based biophysical parameters throughout the treatment time course between untreated and treated MCTS systems, whereas traditional size-based morphometric parameters were inconclusive. The proposed experimental-computational framework estimates mechanistic MCTS growth and invasion parameters with significant potential to assist in better and more precise assessment of in vitro drug efficacy through the development of computational analysis methodologies for three-dimensional cell culture systems to improve the development and evaluation of antineoplastic drugs.

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“…Versions of the IncuCyte assay have been used predominantly for measuring drug response in adherent 2D cultures (14) and to a lesser degree in 3D spheroid cultures (15) but without validation in larger scale clinical cohorts.…”

Section: Figure 1 Biophysical Assays For Functional Drug Susceptibilmentioning

confidence: 99%

Functional drug susceptibility testing based on biophysical measurements predicts patient outcome in glioblastoma patient-derived neurosphere models

Stockslager

Malinowski

Touat

et al. 2020

Preprint

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Functional precision medicine aims to match each cancer patient to the most effective treatment by performing ex vivo drug susceptibility testing on the patient’s tumor cells. Despite promising feasibility studies, functional drug susceptibility testing is not yet used in clinical oncology practice to make treatment decisions. Often, functional testing approaches have measured ex vivo drug response using metabolic assays such as CellTiter-Glo, which measures ATP as a proxy for numbers of viable cells. As a complement to these existing metabolic drug response assays, we evaluated whether biophysical assays based on cell mass (the suspended microchannel resonator mass assay) or size as measured by microscopy (the IncuCyte assay) could be used as a readout for ex vivo drug response. Using these biophysical assays, we profiled the ex vivo temozolomide responses of a retrospective cohort of 70 glioblastoma patient-derived neurosphere models with matched clinical outcomes and found that both biophysical assays predicted patients’ overall survival with similar power to MGMT promoter methylation, the clinical gold standard biomarker for predicting temozolomide response in glioblastoma. These findings suggest that biophysical assays could be a useful complement to existing metabolic approaches as “universal biomarkers” to measure sensitivity or resistance to anti-cancer drugs with a wide variety of cytostatic or cytotoxic mechanisms.One-sentence summaryBy using biophysical assays to perform ex vivo drug susceptibility testing on 70 glioblastoma patient-derived neurosphere models, we find that functional testing predicts the duration that patients survive when treated with temozolomide, the standard of care chemotherapy.

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Exploring Drug Dosing Regimens In Vitro Using Real-Time 3D Spheroid Tumor Growth Assays

Cited by 12 publications

References 14 publications

From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer

From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer

Characterization of multicellular breast tumor spheroids using image data-driven biophysical mathematical modeling

Functional drug susceptibility testing based on biophysical measurements predicts patient outcome in glioblastoma patient-derived neurosphere models

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