Mathematical modeling and sensitivity analysis of hypoxia-activated drugs

Alessandro Coclite; Riccardo Montanelli Eccher; Luca Possenti; Piermario Vitullo; Paolo Zunino; Alessandro Coclite; Riccardo Montanelli Eccher; Luca Possenti; Piermario Vitullo; Paolo Zunino

doi:10.3934/math.20251130

AIMS Mathematics

2025, Volume 10, Issue 11: 25504-25544. doi: 10.3934/math.20251130

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Mathematical modeling and sensitivity analysis of hypoxia-activated drugs

1.
Dipartimento di Ingegneria Elettrica e dell'Informazione (DEI), Politecnico di Bari, Bari, Italy
2.
MOX, Dipartimento di Matematica, Politecnico di Milano, Milano, Italy
3.
Data Science Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

Received: 09 June 2025 Revised: 03 October 2025 Accepted: 09 October 2025 Published: 06 November 2025
MSC : 35Q92, 35R20, 65M60, 92C45, 92C50

Hypoxia-activated prodrugs offer a promising strategy for targeting oxygen-deficient regions in solid tumors, which are often resistant to conventional therapies. However, modeling their behavior is challenging because of the complex interplay between oxygen availability, drug activation, and cell survival. In this work, we developed a multi-scale and mixed-dimensional model that coupled spatially resolved drug and oxygen transport with pharmacokinetics and pharmacodynamics to simulate the cellular response. The model integrated blood flow, oxygen diffusion, and consumption, drug delivery, and metabolism. To reduce computational cost, we mitigated the global nonlinearity by coupling the multi-scale and mixed-dimensional models one-way with a reduced 0D model for drug metabolization. The global sensitivity analysis was then used to identify key parameters influencing drug activation and therapeutic outcome. This approach enabled efficient simulation and supports the design of optimized therapies targeting hypoxia.
- mathematical oncology,
- drug transport and metabolism,
- hypoxia-activated prodrugs,
- multi-scale modeling,
- numerical simulation,
- global sensitivity analysis
Citation: Alessandro Coclite, Riccardo Montanelli Eccher, Luca Possenti, Piermario Vitullo, Paolo Zunino. Mathematical modeling and sensitivity analysis of hypoxia-activated drugs[J]. AIMS Mathematics, 2025, 10(11): 25504-25544. doi: 10.3934/math.20251130

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Abstract

Hypoxia-activated prodrugs offer a promising strategy for targeting oxygen-deficient regions in solid tumors, which are often resistant to conventional therapies. However, modeling their behavior is challenging because of the complex interplay between oxygen availability, drug activation, and cell survival. In this work, we developed a multi-scale and mixed-dimensional model that coupled spatially resolved drug and oxygen transport with pharmacokinetics and pharmacodynamics to simulate the cellular response. The model integrated blood flow, oxygen diffusion, and consumption, drug delivery, and metabolism. To reduce computational cost, we mitigated the global nonlinearity by coupling the multi-scale and mixed-dimensional models one-way with a reduced 0D model for drug metabolization. The global sensitivity analysis was then used to identify key parameters influencing drug activation and therapeutic outcome. This approach enabled efficient simulation and supports the design of optimized therapies targeting hypoxia.

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