Mathematical modeling and sensitivity analysis of hypoxia-activated drugs

TL;DR

This paper presents a comprehensive multiscale model combining oxygen and drug transport with pharmacokinetics to better understand and optimize hypoxia-activated cancer therapies, supported by sensitivity analysis.

Contribution

It introduces a novel integrated multiscale and mixed-dimensional modeling framework with reduced computational complexity for hypoxia-activated drugs.

Findings

Key parameters influencing drug activation identified

Model enables efficient simulation of tumor hypoxia response

Supports design of optimized hypoxia-targeted therapies

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 develop a multiscale and mixed-dimensional model that couples spatially resolved drug and oxygen transport with pharmacokinetics and pharmacodynamics to simulate the cellular response. The model integrates blood flow, oxygen diffusion and consumption, drug delivery, and metabolism. To reduce computational cost, we mitigate the global nonlinearity through a one-way coupling of the multiscale and mixed/dimensional models with a reduced 0D model for the drug metabolism. The global sensitivity analysis is then used to identify key parameters influencing drug activation and therapeutic outcome. This approach enables efficient simulation and supports the design of optimized hypoxia-targeted therapies.