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Examining the efficacy of localised gemcitabine therapy for the treatment of pancreatic cancer using a hybrid agent-based model

View ORCID ProfileAdrianne L. Jenner, View ORCID ProfileWayne Kelly, Michael Dallaston, Robyn Araujo, View ORCID ProfileIsobelle Parfitt, Dominic Steinitz, Pantea Pooladvand, Peter S. Kim, Samantha J. Wade, Kara L. Vine
doi: https://doi.org/10.1101/2022.04.18.488716
Adrianne L. Jenner
1School of Mathematical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
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  • For correspondence: adrianne.jenner@qut.edu.au
Wayne Kelly
2School of Computer Science, Queensland University of Technology, Brisbane, QLD, Australia
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Michael Dallaston
1School of Mathematical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
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Robyn Araujo
1School of Mathematical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
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Isobelle Parfitt
1School of Mathematical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
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Dominic Steinitz
3Tweag Software Innovation Lab, London, United Kingdom
4Kingston University, Kingston, United Kingdom
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Pantea Pooladvand
5School of Mathematics and Statistics, University of Sydney, NSW, Australia
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Peter S. Kim
5School of Mathematics and Statistics, University of Sydney, NSW, Australia
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Samantha J. Wade
6Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia
7School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia
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Kara L. Vine
6Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia
7School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia
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Abstract

The prognosis for pancreatic ductal adenocarcinoma (PDAC) patients has not significantly improved in the past 3 decades, highlighting the need for more effective treatment approaches. Poor patient outcomes and lack of response to therapy can be attributed, in part, to the dense, fibrotic nature of PDAC tumours, which impedes the uptake of systemically administered drugs. Wet-spun alginate fibres loaded with the chemotherapeutic agent gemcitabine have been developed as a potential tool for overcoming the physical and biological barriers presented by the PDAC tumour microenvironment and deliver high concentrations of drug to the tumour directly over an extended period of time. While exciting, the practicality, safety, and effectiveness of these devices in a clinical setting requires further investigation. Furthermore, an in-depth assessment of the drug-release rate from these devices needs to be undertaken to determine whether an optimal release profile exists. Using a hybrid computational model (agent-based model and partial differential equation system), we developed a simulation of pancreatic tumour growth and response to treatment with gemcitabine loaded alginate fibres. The model was calibrated using in vitro and in vivo data and simulated using a finite volume method discretization. We then used the model to compare different intratumoural implantation protocols and gemcitabine-release rates. In our model, the primary driver of pancreatic tumour growth was the rate of tumour cell division and degree of extracellular matrix deposition. We were able to demonstrate that intratumoural placement of gemcitabine loaded fibres was more effective than peritumoural placement. Additionally, we found that an exponential gemcitabine release rate would improve the tumour response to fibres placed peritumourally. Altogether, the model developed here is a tool that can be used to investigate other drug delivery devices to improve the arsenal of treatments available for PDAC and other difficult-to-treat cancers in the future.

Author Summary Pancreatic cancer has a dismal prognosis with a median survival of 3-5 months for untreated disease. The treatment of pancreatic cancer is challenging due to the dense nature of pancreatic tumours which impedes retention of drug at the tumour site. As such, systemic administration of chemotherapies, such as gemcitabine, has a limited efficacy. To overcome this, sustained-release devices have been proposed. These devices are injected locally and release drug slowly over time, providing a concentrated local, sustained drug concentration. To investigate the possible efficacy of these devices, we developed a mathematical model that would allow us to probe treatment perturbations in silico. We modelled the individual cancer cells and their growth and death from gemcitabine loaded into the sustained delivery devices. Our platform allows future investigations for these devices to be run in silico so that we may better understand the forms of the drug release-profile that are necessary for optimal treatment.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted April 19, 2022.
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Examining the efficacy of localised gemcitabine therapy for the treatment of pancreatic cancer using a hybrid agent-based model
Adrianne L. Jenner, Wayne Kelly, Michael Dallaston, Robyn Araujo, Isobelle Parfitt, Dominic Steinitz, Pantea Pooladvand, Peter S. Kim, Samantha J. Wade, Kara L. Vine
bioRxiv 2022.04.18.488716; doi: https://doi.org/10.1101/2022.04.18.488716
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Examining the efficacy of localised gemcitabine therapy for the treatment of pancreatic cancer using a hybrid agent-based model
Adrianne L. Jenner, Wayne Kelly, Michael Dallaston, Robyn Araujo, Isobelle Parfitt, Dominic Steinitz, Pantea Pooladvand, Peter S. Kim, Samantha J. Wade, Kara L. Vine
bioRxiv 2022.04.18.488716; doi: https://doi.org/10.1101/2022.04.18.488716

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