High-throughput screening with nanoimprinting 3D culture for efficient drug development by mimicking the tumor environment

Yoshii, Yukie; Furukawa, Takako; Waki, Atsuo; Okuyama, Hiroaki; Inoue, Masahiro; Itoh, Masatoshi; Zhang, Ming Rong; Wakizaka, Hidekatsu; Sogawa, Chizuru; Kiyono, Yasushi; Yoshii, Hiroshi; Fujibayashi, Yasuhisa; Saga, Tsuneo

doi:10.1016/j.biomaterials.2015.02.008

Cited by 65 publications

(56 citation statements)

References 61 publications

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“…In particular, the lack of a high-throughput endpoint test that has hypoxic specificity is hindering the effectiveness of spheroids in hypoxia screening applications and will most likely be expedited by the utilisation of bioreporter assays to enable imaging of localised responses as an endpoint. Increased use of protocols developed for the successful growth of spheroids from primary patient tumour material may in future enable drug screening in a pretreatment patient spheroid model as a concept of personalised medicine [31]. …”

Section: Discussionmentioning

confidence: 99%

“…Resazurin reduction assay, acid phosphatase assay and cell counts can be carried out on the same spheroids sequentially as described in [40]. Similar assays have also been performed including the cell titre glo assay to measure ATP levels [31].…”

Section: Cell Viabilitymentioning

confidence: 99%

“…However, only a few of these were designed to identify genes required for, or drugs targeting, the hypoxic microenvironment in particular [31,53,59]. Although other studies have investigated hypoxia related phenotypes such as stem cells [60] and invasion [51] both of which are increased in response to hypoxia [7], these studies did not investigate the hypoxic role specifically.…”

Section: Spheroid Based Screeningmentioning

confidence: 99%

“…Similarly oxygen levels can be measured by a number of probe systems including the NanO 2 probe (Luxcel Biosciences) which enabled direct, real-time analysis of spheroid O 2 distribution using one-photon confocal PLIM imaging [55]. Alternatively, as a simple binary solution, the presence or absence of low oxygen levels in spheroids can be identified with the fluorescent hypoxia probe, LOX-1 (SCIVAX Life Sciences) [31]. However, this begins to fluoresce between 10 and 5 % O 2 concentration [56] well within the O 2 range of normal tissue.…”

Section: Quantifying Oxygen Levels and Phmentioning

confidence: 99%

“…This is thought to increase cell viability by reducing cell-death induced when cells are separated from a substrate such as extra-cellular matrix. NCP have been used in high-throughput drug screening and are now commercially available [31].…”

Section: The Future Of Spheroid Culture: Micro-fluidic Self-assembly mentioning

confidence: 99%

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Methods: Using Three-Dimensional Culture (Spheroids) as an In Vitro Model of Tumour Hypoxia

Leek

Grimes

Harris

et al. 2016

Advances in Experimental Medicine and Biology

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Regions of hypoxia in tumours can be modelled in vitro in 2D cell cultures with a hypoxic chamber or incubator in which oxygen levels can be regulated. Although this system is useful in many respects, it disregards the additional physiological gradients of the hypoxic microenvironment, which result in reduced nutrients and more acidic pH. Another approach to hypoxia modelling is to use three-dimensional spheroid cultures. In spheroids, the physiological gradients of the hypoxic tumour microenvironment can be inexpensively modelled and explored. In addition, spheroids offer the advantage of more representative modelling of tumour therapy responses compared with 2D culture. Here, we review the use of spheroids in hypoxia tumour biology research and highlight the different methodologies for spheroid formation and how to obtain uniformity. We explore the challenge of spheroid analyses and how to determine the effect on the hypoxic versus normoxic components of spheroids. We discuss the use of high-throughput analyses in hypoxia screening of spheroids. Furthermore, we examine the use of mathematical modelling of spheroids to understand more fully the hypoxic tumour microenvironment.

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Section: Discussionmentioning

confidence: 99%

Section: Cell Viabilitymentioning

confidence: 99%

Section: Spheroid Based Screeningmentioning

confidence: 99%

Section: Quantifying Oxygen Levels and Phmentioning

confidence: 99%

Section: The Future Of Spheroid Culture: Micro-fluidic Self-assembly mentioning

confidence: 99%

See 3 more Smart Citations

Methods: Using Three-Dimensional Culture (Spheroids) as an In Vitro Model of Tumour Hypoxia

Leek

Grimes

Harris

et al. 2016

Advances in Experimental Medicine and Biology

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The Current Landscape of 3D In Vitro Tumor Models: What Cancer Hallmarks Are Accessible for Drug Discovery?

Rodenhizer

Dean

D’Arcangelo

et al. 2018

Adv Healthcare Materials

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Cancer prognosis remains a lottery dependent on cancer type, disease stage at diagnosis, and personal genetics. While investment in research is at an all-time high, new drugs are more likely to fail in clinical trials today than in the 1970s. In this review, a summary of current survival statistics in North America is provided, followed by an overview of the modern drug discovery process, classes of models used throughout different stages, and challenges associated with drug development efficiency are highlighted. Then, an overview of the cancer hallmarks that drive clinical progression is provided, and the range of available clinical therapies within the context of these hallmarks is categorized. Specifically, it is found that historically, the development of therapies is limited to a subset of possible targets. This provides evidence for the opportunities offered by novel disease-relevant in vitro models that enable identification of novel targets that facilitate interactions between the tumor cells and their surrounding microenvironment. Next, an overview of the models currently reported in literature is provided, and the cancer biology they have been used to explore is highlighted. Finally, four priority areas are suggested for the field to accelerate adoption of in vitro tumour models for cancer drug discovery.

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3D Biomimetic Models to Reconstitute Tumor Microenvironment In Vitro: Spheroids, Organoids, and Tumor‐on‐a‐Chip

Zhou

et al. 2023

Adv Healthcare Materials

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Decades of efforts in engineering in vitro cancer models have advanced drug discovery and the insight into cancer biology. However, the establishment of preclinical models that enable fully recapitulating the tumor microenvironment remains challenging owing to its intrinsic complexity. Recent progress in engineering techniques has allowed the development of a new generation of in vitro preclinical models that can recreate complex in vivo tumor microenvironments and accurately predict drug responses, including spheroids, organoids, and tumor‐on‐a‐chip. These biomimetic 3D tumor models are of particular interest as they pave the way for better understanding of cancer biology and accelerating the development of new anticancer therapeutics with reducing animal use. Here, the recent advances in developing these in vitro platforms for cancer modeling and preclinical drug screening, focusing on incorporating hydrogels are reviewed to reconstitute physiologically relevant microenvironments. The combination of spheroids/organoids with microfluidic technologies is also highlighted to better mimic in vivo tumors and discuss the challenges and future directions in the clinical translation of such models for drug screening and personalized medicine.

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High-throughput screening with nanoimprinting 3D culture for efficient drug development by mimicking the tumor environment

Cited by 65 publications

References 61 publications

Methods: Using Three-Dimensional Culture (Spheroids) as an In Vitro Model of Tumour Hypoxia

Methods: Using Three-Dimensional Culture (Spheroids) as an In Vitro Model of Tumour Hypoxia

The Current Landscape of 3D In Vitro Tumor Models: What Cancer Hallmarks Are Accessible for Drug Discovery?

3D Biomimetic Models to Reconstitute Tumor Microenvironment In Vitro: Spheroids, Organoids, and Tumor‐on‐a‐Chip

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