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Cited by 79Nanoparticle-Based Drug DeliveryImmune cells in cancerImmunotherapy and Immune Responses

Colorectal cancer triple co-culture spheroid model to assess the biocompatibility and anticancer properties of polymeric nanoparticles

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Bauleth-Ramos, Tomás, Feijão, Tália, Gonçalves, André, Shahbazi, Mohammad-Ali, Liu, Zehua, Barrias, Cristina, Oliveira, Maria José, Granja, Pedro +2 more·2020·Journal of Controlled Release
DOI 10.1016/j.jconrel.2020.04.025
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Abstract

Colorectal cancer (CRC) is the third most common and the second deadliest type of cancer worldwide, urging the development of more comprehensive models and of more efficient treatments. Although the combination of nanotechnology with chemo- and immuno-therapy has represented a promising treatment approach, its translation to the clinic has been hampered by the absence of cellular models that can provide reliable and predictive knowledge about the in vivo efficiency of the formulation. Herein, a 3D model based on CRC multicellular tumor spheroids (MCTS) model was developed by combining epithelial colon cancer cells (HCT116), human intestinal fibroblasts and monocytes. The developed MCTS 3D model mimicked several tumor features with cells undergoing spatial organization and producing extracellular matrix, forming a mass of tissue with a necrotic core. Furthermore, monocytes were differentiated into macrophages with an anti-inflammatory, pro-tumor M2-like phenotype. For a combined chemoimmunotherapy effect, spermine-modified acetalated dextran nanoparticles (NPs) loaded with the chemotherapeutic Nutlin-3a (Nut3a) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were produced and tested in 2D cultures and in the MCTS 3D model. NPs were successfully taken-up by the cells in 2D, but in a significant less extent in the 3D model. However, these NPs were able to induce an anti-proliferative effect both in the 2D and in the 3D models. Moreover, Nut3a was able to partially shift the polarization of the macrophages present in the MCTS 3D model towards an anti-tumor M1-like phenotype. Overall, the developed MCTS 3D model showed to recapitulate key features of tumors, while representing a valuable model to assess the effect of combinatorial nano-therapeutic strategies in CRC. In addition, the developed NPs could represent a promising approach for CRC treatment.

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Crossref · 10.1016/j.jconrel.2020.04.025

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95 of 95 references verified0 citation errors · 0 not checkable

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  • CAFs are key contributors to ECM remodeling, angiogenesis, and metastasis.

    “These CAFs are characterized by the expression of specific markers, such as desmin and fibroblast activation protein, and are now recognized as key contributors to ECM remodeling, angiogenesis, and metastasis [36,37,38,39,40].”

    From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [40]

    Section 3.1.2 (page unavailable) says fibroblasts contribute to ECM production and remodeling and promote cancer progression and metastasis. The cited paper does not establish that CAFs contribute to angiogenesis, so it supports only part of the attributed claim. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Even small amounts of ECM components can promote spheroid compactness by strengthening intercellular adhesion and tightening the interstitial space.

    “Even small amounts of these ECM components can promote spheroid compactness by strengthening intercellular adhesion and tightening the interstitial space [40].”

    From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [40]

    Section 3.1.2 (page unavailable) reports that spheroids with more fibroblasts formed compact structures and had greater fibronectin deposition. The triple-culture discussion (page unavailable) also associates ECM loss with an apparently looser structure. The paper does not establish that small amounts of ECM cause compaction by strengthening intercellular adhesion or narrowing interstitial spaces. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • In colorectal tumor spheroids co-cultured with fibroblasts, expression of mesenchymal markers such as vimentin was markedly increased relative to tumor-only spheroids.

    “In colorectal tumor spheroids co-cultured with fibroblasts, expression of mesenchymal markers such as vimentin was markedly increased relative to tumor-only spheroids [40].”

    From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [40]

    Section 3.1.2 (page unavailable) reports vimentin-positive fibroblasts in colorectal tumor–fibroblast spheroids. It does not report a marked increase in vimentin or other mesenchymal markers relative to tumor-only spheroids; the reported increase relative to monoculture concerns fibronectin deposition. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The extent of ECM deposition scaled with fibroblast density, indicating that stromal cells actively contribute to matrix remodeling within the spheroid microenvironment.

    “Moreover, the extent of ECM deposition scaled with fibroblast density, indicating that stromal cells actively contribute to matrix remodeling within the spheroid microenvironment [40].”

    From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [40]

    Section 3.1.2 reports greater fibronectin deposition in spheroids containing fibroblasts than in monocultures and describes fibroblasts as contributors to ECM production and remodeling. It does not report that ECM deposition increased with fibroblast density across the tested cell ratios; the reported ratio-dependent correlation concerns spheroid diameter. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cites

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1 of the 96 references couldn’t be matched to a known paper.

Research works printed but not linked: 4

  1. X. Zhong, B. Chen, Z. Yang, The Role of Tumor-Associated Macrophages in Colorectal Carcinoma Progression, Cell. Physiol. Biochem., 45 (2018) 356-365.10.1159/000486816 · DOI
  2. J o u r n a l P r e -p r o o f Journal Pre-proof
  3. M.L. Pinto, E. Rios, C. Durães, R. Ribeiro, J.C. Machado, A. Mantovani, M.A. Barbosa, F. Carneiro, M.J. Oliveira, The two faces of tumor-associated macrophages and their clinical significance in colorectal cancer, Front. Immunol., 10 (2019).10.3389/fimmu.2019.01875 · DOI
  4. 1038/nri3088 J o u r n a l P r e -p r o o f Journal Pre-proof Author's statement Tomás Bauleth-Ramos: Conceptualization, Methodology, Writing Tália Feijão: Conceptualization, Methodology André Gonçalves: Conceptualization, Methodology, Writing Mohammad-Ali Shahbazi: Conceptualization, Methodology, Writing Zehua Liu: Methodology Cristina Barrias: Writing, Reviewing and Editing Maria José Oliveira: Writing, Reviewing and Editing Pedro Granja.: Conceptualization Hélder Santos: Conceptualization, Writing, Editing Bruno Sarmento: Conceptualization, Writing, Editing J o u r n a l P r e -p r o o f

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Authors
Bauleth-Ramos, T., Feijão, T., Gonçalves, A., Shahbazi, M.-A., Liu, Z., Barrias, C., Oliveira, M. J., Granja, P., Santos, H. A., & Sarmento, B.
Affiliations
  • Universidade do Porto (PT)
  • Zanjan University of Medical Sciences (IR)
  • University of Helsinki (FI)
Corresponding author
  • Santos, Hélder A.
  • Sarmento, Bruno
ORCID
Venue
Journal of Controlled Release
Publisher
Elsevier BV
Published
2020-07
Volume
323
Pages
398-411
ISSN
0168-3659 (ISSN-L)
DOI
10.1016/j.jconrel.2020.04.025
OpenAlex
W3016902746
Cited by
79
References
96
Citations by year
2026: 10 · 2025: 14 · 2024: 15 · 2023: 16 · 2022: 12 · 2021: 7 · 2020: 5
FWCI
2.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Controlled Release (publishedVersion)
  • PubMed (publishedVersion)
  • Työväentutkimus Vuosikirja (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Funders
  • Fundação para a Ciência e a Tecnologia (SFRH/BD/110859/2015)
  • Institute for Research and Innovation in Health Sciences (UID/BIM/04293/2019)
  • Academy of Finland (317316)
  • Sigrid Jusélius Foundation (4704580)
  • European Research Council Prof-of-Concept Research (4100164)
  • National Infrastructure PPBI - Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
colorectal cancer, tumor spheroids, 3D tumor models, polymeric nanoparticles, acetalated dextran, Nutlin-3a, GM-CSF, chemoimmunotherapy, M2 macrophages, macrophage polarization, HCT116 cells, intestinal fibroblasts, nanoparticle uptake, cancer nanomedicine
MeSH terms
Humans, Colorectal Neoplasms, Spheroids, Cellular, Coculture Techniques, Cell Line, Tumor, Nanoparticles

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