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Updated: Aug 22, 2026
Monitoring Cancer Cell Invasion and T-Cell Cytotoxicity in 3D Culture
Published on: June 23, 2020
Direct assessment of drug penetration into tissue using a novel application of three-dimensional cell culture
Alastair H Kyle1, Lynsey A Huxham, Aaron S J Chiam
1Department of Medical Biophysics, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Abstract:
The failure of many anticancer drugs to control growth of solid cancers may stem in part from inadequate delivery to tumor regions distant from vasculature. Although the identification of new anticancer drug targets has led to the development of many new drug candidates, there is a lack of methodology for identifying drugs that adequately penetrate tumor tissue. We have developed a novel multilayered cell culture-based assay, which detects the penetration of anticancer drugs based on their effect within tissue. Drug exposures are made over 1 hour to one side of a disk of tissue approximately 150-microm thick, with the other side temporarily closed off, and penetration is then assessed 1-3 days later via bromodeoxyuridine-based detection of S-phase cells. Using this assay, the tissue distribution of a selection of anthracycline analogues was assessed. At clinically relevant exposures, none of the agents were able to affect cells on the far side of the culture at levels approaching that seen on the near (exposed) side. Doxorubicin and epirubicin exhibited approximately 10-fold decreases in the drug exposure seen by the cells on the far side relative to those on the near side of the cultures, whereas for daunorubicin and mitoxantrone, approximately 30-fold and >30-fold decreases were observed respectively. Results were consistent with the observed gradients in drug-derived fluorescence of doxorubicin, epirubicin, and daunorubicin. This model could be applied as a simple anticancer drug development screen to discover drugs that exhibit desirable penetration properties.
Insights
Many anticancer drugs fail in solid tumors due to poor tissue penetration. A new assay reveals significant drug loss, highlighting the need for better anticancer drug delivery strategies.
Area of Science:
- Oncology
- Pharmacology
- Biomedical Engineering
Background:
- Solid tumor growth is often limited by insufficient drug delivery to distant regions.
- Developing new anticancer drugs lacks methods to assess tumor tissue penetration.
- Effective drug penetration is crucial for solid cancer treatment efficacy.
Purpose of the Study:
- To develop and validate a novel multilayered cell culture assay for assessing anticancer drug penetration.
- To evaluate the tissue distribution and penetration of anthracycline analogues using the developed assay.
- To identify anticancer drugs with improved tumor penetration properties.
Main Methods:
- A novel multilayered cell culture assay was designed to mimic tumor tissue.
- Drug penetration was assessed by exposing one side of a 150-microm thick tissue disk and measuring cell effects on the opposite side.
- Bromodeoxyuridine (BrdU) detection of S-phase cells was used to quantify drug penetration and efficacy.
Main Results:
- None of the tested anthracycline analogues effectively penetrated the tissue to affect distant cells at clinically relevant exposures.
- Doxorubicin and epirubicin showed approximately 10-fold decreases in efficacy on the far side, while daunorubicin and mitoxantrone showed 30-fold and >30-fold decreases, respectively.
- Drug-derived fluorescence gradients confirmed the observed penetration patterns.
Conclusions:
- The developed multilayered cell culture assay effectively quantifies anticancer drug penetration.
- Current anthracycline analogues exhibit limited penetration in simulated tumor tissue.
- This assay can serve as a screening tool for discovering anticancer drugs with enhanced tissue penetration capabilities.
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