Opportunities and challenges for use of tumor spheroids as models to test drug delivery and efficacy
Open accessAbstract
Multicellular spheroids are three dimensional in vitro microscale tissue analogs. The current article examines the suitability of spheroids as an in vitro platform for testing drug delivery systems. Spheroids model critical physiologic parameters present in vivo, including complex multicellular architecture, barriers to mass transport, and extracellular matrix deposition. Relative to two-dimensional cultures, spheroids also provide better target cells for drug testing and are appropriate in vitro models for studies of drug penetration. Key challenges associated with creation of uniformly sized spheroids, spheroids with small number of cells and co-culture spheroids are emphasized in the article. Moreover, the assay techniques required for the characterization of drug delivery and efficacy in spheroids and the challenges associated with such studies are discussed. Examples for the use of spheroids in drug delivery and testing are also emphasized. By addressing these challenges with possible solutions, multicellular spheroids are becoming an increasingly useful in vitro tool for drug screening and delivery to pathological tissues and organs.
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Cells in the intermediate zone of a spheroid are often senescent.
“cells located in the intermediate zone are often senescent”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [184]
In the Introduction section “Spheroids as appropriate models for drug delivery” (page not available), the paper describes the layer between the necrotic core and proliferating outer rim as quiescent, not senescent. Quiescence and senescence are distinct cellular states; the cited passage does not support substituting one for the other. (LLM, conf=0.83)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredInclusion of spheroids within ECM contributes to better reproducing tumor-specific hallmarks.
“Emerging evidence has demonstrated that the inclusion of spheroids within ECM contributes to better reproducing of tumor‐specific hallmarks.[ 62 ]”
From 3D Biomimetic Models to Reconstitute Tumor Microenvironment In Vitro: Spheroids, Organoids, and Tumor‐on‐a‐Chip (2023) · cites this paper as [62]
In the Introduction’s “Challenge 3” section (page not provided), the paper says spheroids can integrate ECM and that capturing microenvironmental interactions helps make 3-D models more faithful to tissue. It does not specifically show that embedding spheroids within ECM improves reproduction of tumor-specific hallmarks; the reported improvement in modeling tumor progression concerns co-culture with endothelial cells. (LLM, conf=0.82)
Experimental — accuracy not yet measuredHanging drop methods have high reliability and reproducibility but fluid volume is limited and the method is not good for long-term culture due to difficulty in refreshing the culture medium.
“It has high reliability and reproducibility but fluid volume is limited and the method is not good for long-term culture due to difficulty in refreshing the culture medium [58,75].”
From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [58]
In ‘Challenge 1: Forming and maintaining spheroids of uniform size’ (page not provided), the paper says conventional hanging drops allow defined spheroid size but that changing medium is time-consuming, supporting the culture-maintenance concern. It describes 15–20 μl drops in a particular plate, not a general fluid-volume limit, and does not establish high reliability for hanging-drop methods generally. It also reports that an improved hanging-drop plate enables long-term culture, so the limitation needs to be qualified as applying to conventional methods. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSpheroids exhibit spatially organized regions of proliferation, quiescence, and hypoxia.
“Spheroids exhibit spatially organized regions of proliferation, quiescence, and hypoxia, and can incorporate non-tumor cells to mimic tumor–stroma crosstalk.”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [184]
Cells in the outermost layer of a spheroid are typically highly proliferative due to proximity to nutrients and oxygen.
“Cells in the outermost layer of the spheroid are typically highly proliferative due to their proximity to nutrients and oxygen.”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [184]
Cells in the central core of a spheroid exist in a hypoxic state.
“those in the central core exist in a hypoxic state [101,184,186,187]”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [184]
These gradients typically emerge when spheroids exceed ~500 μm in diameter, with proliferative cells localized to the outer rim, quiescent cells residing in intermediate zones, and hypoxic or necrotic cores forming at the center due to limited diffusion.
“These gradients typically emerge when spheroids exceed ~500 μm in diameter, with proliferative cells localized to the outer rim, quiescent cells residing in intermediate zones, and hypoxic or necrotic cores forming at the center due to limited diffusion [17,184,185].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [184]
Spheroids have a distinct spatial organization that reflects intratumoral gradients observed in solid tumors.
“Spheroids are characterized by a distinct spatial organization that reflects intratumoral gradients observed in solid tumors [101,184].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [184]
Using the hanging drop technique for spheroid creation has logistical issues with media replacements, drug addition, evaporation and downstream analysis of individual spheroids per hanging drop.
“While simple in design, using the hanging drop technique for spheroid creation has logistical issues with media replacements, drug addition, evaporation and downstream analysis of individual spheroids per hanging drop (Kunz-Schughart et al., 2004; Mehta et al., 2012).”
From Three-dimensional modelling of ovarian cancer: from cell lines to organoids for discovery and personalized medicine (2022) · cites this paper as Mehta et al., 2012
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- Authors
- Mehta, G., Hsiao, A. Y., Ingram, M., Luker, G. D., & Takayama, S.
- Affiliations
- University of Michigan (US)
- Huntington Medical Research Institutes (US)
- Corresponding author
- Mehta, Geeta
- Takayama, Shuichi
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 164
- Issue
- 2
- Pages
- 192-204
- ISSN
- 0168-3659 (ISSN-L)
- PMC
- PMC3436947
- OpenAlex
- W2105017561
- Cited by
- 1,172
- References
- 158
- Citations by year
- 2026: 56 · 2025: 76 · 2024: 84 · 2023: 87 · 2022: 93 · 2021: 108 · 2020: 125 · 2019: 99 · 2018: 102 · 2017: 113 · 2016: 86 · 2015: 61 · 2014: 52 · 2013: 27 · 2012: 3
- FWCI
- 26.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- National Cancer Institute (R01CA136829, R01CA136553, P50CA093990, P30CA046592)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- tumor spheroids, 3D cell culture, drug delivery systems, drug penetration, drug efficacy testing, in vitro drug testing, extracellular matrix deposition, co-culture spheroids, drug screening assay
- MeSH terms
- Animals, Antineoplastic Agents, Disease Models, Animal, Humans, Neoplasms, Tumor Cells, Cultured, Drug Delivery Systems, Treatment Outcome, Spheroids, Cellular
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