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High-throughput non-homogenous 3D polycaprolactone scaffold for cancer cell and cancer-associated fibroblast mini-tumors to evaluate drug treatment response

Malakpour-Permlid, Atena LU ; Rodriguez, Manuel Marcos ; Untracht, Gavrielle R. ; Andersen, Peter E. ; Oredsson, Stina LU ; Boisen, Anja and Zór, Kinga (2025) In Toxicology Reports 14.
Abstract

High-throughput screening (HTS) three-dimensional (3D) tumor models are a promising approach for cancer drug discovery, as they more accurately replicate in vivo cell behavior than two-dimensional (2D) models. However, assessing and comparing current 3D models for drug efficacy remains essential, given the significant influence of cellular conditions on treatment response. To develop in vivo mimicking 3D models, we evaluated two HTS 3D models established in 96-well plates with 3D polycaprolactone (PCL) scaffolds fabricated using two distinct methods, resulting in scaffolds with either homogenous or non-homogenous fiber networks. These models, based on human HeLa cervical cancer cells and cancer-associated fibroblasts (CAFs) cultured as... (More)

High-throughput screening (HTS) three-dimensional (3D) tumor models are a promising approach for cancer drug discovery, as they more accurately replicate in vivo cell behavior than two-dimensional (2D) models. However, assessing and comparing current 3D models for drug efficacy remains essential, given the significant influence of cellular conditions on treatment response. To develop in vivo mimicking 3D models, we evaluated two HTS 3D models established in 96-well plates with 3D polycaprolactone (PCL) scaffolds fabricated using two distinct methods, resulting in scaffolds with either homogenous or non-homogenous fiber networks. These models, based on human HeLa cervical cancer cells and cancer-associated fibroblasts (CAFs) cultured as mono- or co-cultures within the 3D scaffolds, revealed that anticancer drug paclitaxel (PTX) exhibited consistently higher inhibitory concentration 50 (IC50) in 3D (≥ 1000 nM) compared to 2D (≥ 100 nM), indicating reduced toxicity on cells cultured in 3D. Interestingly, the toxicity of PTX was significantly lower on mini-tumors in non-homogenous 3D (IC50: 600 or 1000 nM) than in homogenous 3D cultures (IC50 exceeding 1000 nM). Microscopic studies revealed that the non-homogenous scaffolds closely resemble the tumor collagen network than their homogeneous counterpart. Both 3D scaffolds offer optimal pore size, facilitating efficient cell infiltration into the depth of 58.1 ± 1.2 µm (homogenous) and 86.4 ± 9.8 µm (non-homogenous) within 3D cultures. Cells cultured in the 3D non-homogenous systems exhibited drug treatment responses closer to in vivo conditions, highlighting the role of scaffold structure and design on cellular response to drug treatment. The PCL-based 3D models provide a robust, tunable, and efficient approach for the HTS of anti-cancer drugs compared to conventional 2D systems.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
3D High throughput screening, Cancer-associated fibroblasts, Cervical cancer cells, Mini-tumor, Paclitaxel, PCL fiber network, Scaffold architecture
in
Toxicology Reports
volume
14
article number
101863
publisher
Elsevier
external identifiers
  • pmid:39758801
  • scopus:85211752630
ISSN
2214-7500
DOI
10.1016/j.toxrep.2024.101863
language
English
LU publication?
yes
id
a60577de-1ae9-4984-81cb-774859a5f717
date added to LUP
2025-02-26 11:54:07
date last changed
2025-07-16 23:46:00
@article{a60577de-1ae9-4984-81cb-774859a5f717,
  abstract     = {{<p>High-throughput screening (HTS) three-dimensional (3D) tumor models are a promising approach for cancer drug discovery, as they more accurately replicate in vivo cell behavior than two-dimensional (2D) models. However, assessing and comparing current 3D models for drug efficacy remains essential, given the significant influence of cellular conditions on treatment response. To develop in vivo mimicking 3D models, we evaluated two HTS 3D models established in 96-well plates with 3D polycaprolactone (PCL) scaffolds fabricated using two distinct methods, resulting in scaffolds with either homogenous or non-homogenous fiber networks. These models, based on human HeLa cervical cancer cells and cancer-associated fibroblasts (CAFs) cultured as mono- or co-cultures within the 3D scaffolds, revealed that anticancer drug paclitaxel (PTX) exhibited consistently higher inhibitory concentration 50 (IC<sub>50</sub>) in 3D (≥ 1000 nM) compared to 2D (≥ 100 nM), indicating reduced toxicity on cells cultured in 3D. Interestingly, the toxicity of PTX was significantly lower on mini-tumors in non-homogenous 3D (IC<sub>50</sub>: 600 or 1000 nM) than in homogenous 3D cultures (IC<sub>50</sub> exceeding 1000 nM). Microscopic studies revealed that the non-homogenous scaffolds closely resemble the tumor collagen network than their homogeneous counterpart. Both 3D scaffolds offer optimal pore size, facilitating efficient cell infiltration into the depth of 58.1 ± 1.2 µm (homogenous) and 86.4 ± 9.8 µm (non-homogenous) within 3D cultures. Cells cultured in the 3D non-homogenous systems exhibited drug treatment responses closer to in vivo conditions, highlighting the role of scaffold structure and design on cellular response to drug treatment. The PCL-based 3D models provide a robust, tunable, and efficient approach for the HTS of anti-cancer drugs compared to conventional 2D systems.</p>}},
  author       = {{Malakpour-Permlid, Atena and Rodriguez, Manuel Marcos and Untracht, Gavrielle R. and Andersen, Peter E. and Oredsson, Stina and Boisen, Anja and Zór, Kinga}},
  issn         = {{2214-7500}},
  keywords     = {{3D High throughput screening; Cancer-associated fibroblasts; Cervical cancer cells; Mini-tumor; Paclitaxel; PCL fiber network; Scaffold architecture}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Toxicology Reports}},
  title        = {{High-throughput non-homogenous 3D polycaprolactone scaffold for cancer cell and cancer-associated fibroblast mini-tumors to evaluate drug treatment response}},
  url          = {{http://dx.doi.org/10.1016/j.toxrep.2024.101863}},
  doi          = {{10.1016/j.toxrep.2024.101863}},
  volume       = {{14}},
  year         = {{2025}},
}