Multicellular tumor spheroids as an in vivo-like tumor model for three-dimensional imaging of chemotherapeutic and nano material cellular penetration
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We present a flexible and highly reproducible method using three-dimensional (3D) multicellular tumor spheroids to quantify chemotherapeutic and nanoparticle penetration properties in vitro. We generated HeLa cell-derived spheroids using the liquid overlay method. To properly characterize HeLa spheroids, scanning electron microscopy, transmission electron microscopy, and multiphoton microscopy were used to obtain high-resolution 3D images of HeLa spheroids. Next, pairing high-resolution optical characterization techniques with flow cytometry, we quantitatively compared the penetration of doxorubicin, quantum dots, and synthetic micelles into 3D HeLa spheroid versus HeLa cells grown in a traditional two-dimensional culturing system. Our data revealed that 3D cultured HeLa cells acquired several clinically relevant morphologic and cellular characteristics (such as resistance to chemotherapeutics) often found in human solid tumors. These characteristic, however, could not be captured using conventional two-dimensional cell culture techniques. This study demonstrated the remarkable versatility of HeLa spheroid 3D imaging. In addition, our results revealed the capability of HeLa spheroids to function as a screening tool for nanoparticles or synthetic micelles that, due to their inherent size, charge, and hydrophobicity, can penetrate into solid tumors and act as delivery vehicles for chemotherapeutics. The development of this image-based, reproducible, and quantifiable in vitro HeLa spheroid screening tool will greatly aid future exploration of chemotherapeutics and nanoparticle delivery into solid tumors.
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A range of microscopic techniques has been employed to evaluate spheroid growth, morphology, and internal cellular organization.
“A range of microscopic techniques has been employed to evaluate spheroid growth, morphology, and internal cellular organization [14,182,232].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [232]
The absence of necrosis in the smaller spheroid size (2,500 cells/spheroid) was confirmed via histological staining.
“Although the results are not presented, the absence of necrosis in the smaller spheroid size (2,500 cells/spheroid) was also confirmed via histological staining, as previously reported for tumour based spheroids [48].”
From Direct Measurements of Oxygen Gradients in Spheroid Culture System Using Electron Parametric Resonance Oximetry (2016) · cites this paper as [48]
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- Authors
- Ma, H.-L., Jiang, Q., Han, S., Wu, Y., Tomshine, J. C., Wang, D., Gan, Y., Zou, G., & Liang, X.-J.
- Affiliations
- From the CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing, China, and the Department of Psychiatry, University of California, San Francisco, San Francisco, CA
- University of California, San Francisco (US)
- Corresponding author
- Zou, Guozhang
- Liang, Xing-Jie
- Venue
- Molecular Imaging
- Publisher
- SAGE Publications
- Published
- 2012-11-01
- Volume
- 11
- Issue
- 6
- Pages
- 487-98
- ISSN
- 1535-3508 (ISSN-L)
- 1536-0121
- OpenAlex
- W2121982033
- Cited by
- 182
- References
- 38
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 6 · 2023: 16 · 2022: 12 · 2021: 25 · 2020: 16 · 2019: 15 · 2018: 7 · 2017: 14 · 2016: 19 · 2015: 11 · 2014: 17 · 2013: 6
- FWCI
- 4.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Imaging (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Keywords
- tumor spheroids, HeLa cells, 3D cell culture, quantum dots, nanoparticle delivery, chemoresistance, multiphoton microscopy, in vitro tumor model
- MeSH terms
- Antineoplastic Agents, Doxorubicin, Flow Cytometry, HeLa Cells, Humans, Micelles, Microscopy, Electron, Scanning, Microscopy, Fluorescence, Models, Biological, Neoplasms, Spheroids, Cellular, Imaging, Three-Dimensional, Quantum Dots, Cell Proliferation, Nanostructures
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