A tumor cord model for doxorubicin delivery and dose optimization in solid tumors

Area of Science:

• Pharmacology
• Mathematical Modeling
• Oncology

Background:

• Doxorubicin is a widely used chemotherapy drug with dose-limiting cardiotoxicity.
• Tumor vasculature irregularities hinder drug penetration and efficacy.
• Peak plasma concentration correlates with cardiac toxicity.

Purpose of the Study:

• To model doxorubicin delivery into solid tumors using a tumor cord model.
• To investigate the impact of dosage regimens and tumor microenvironments on drug penetration.
• To identify strategies for optimizing anti-tumor activity while minimizing cardiotoxicity.

Main Methods:

• A coupled ordinary differential equation-partial differential equation (ODE-PDE) model was utilized.
• Solute transport principles governed drug movement from vasculature to tumor cords.
• Saturable pharmacokinetics and cell death were modeled based on intracellular drug concentration.

Main Results:

• Diffusive transport of free drug dominates initial delivery.
• Large intercapillary distance significantly impedes drug delivery.
• Optimal infusion strategy (bolus vs. continuous vs. fractionated) depends on drug dose.

Conclusions:

• Infusion time critically influences spatial cell kill patterns.
• Extended infusion times and dose fractionation can enhance efficacy and reduce cardiotoxicity.
• Doxorubicin delivery into advanced solid tumors may remain limited even with optimized strategies.