Author: Catherine Coolens, Janny Yeyoung Kim, Michael Milosevic, Noha Sinno 👨🔬
Affiliation: Princess Margaret Hospital, University of Toronto 🌍
Purpose: In solid tumors, Interstitial fluid pressure (IFP) acts as a barrier to molecular transport to the tumor center and serves as a predictor of cancer patients’ treatment responsiveness. The novel Cross-Voxel Exchange Model (CVXM) with DCE-MRI allows for the quantification of tracer transport, such as extravasation, velocity, and the hydraulic conductivity coefficient (K), providing valuable insights into biophysical properties of tumors related to IFP.
Methods: The ME180 cervical carcinoma xenograft model was chosen as its IFP and transport dynamics are well-characterized. Mice (n=15) with orthotopic tumors (~800 mm³) underwent 7T DCE-MRI (Bruker) using Gd-DTPA (1mmol/mL; Gadovist, Bayer) as a contrast agent. CVXM was applied on DCE-MR images using MATLAB to generate various transport maps. Direct IFP measurements were taken with a 0.33 mm microtip pressure transducer (SPR-1000, Millar) under ultrasound guidance. The experimental K was measured via ex vivo intratumoral infusion and application of Darcy’s law for unidirectional flow. CVXM velocity maps and direct IFP data were used to calculate CVXM-predicted K using Darcy’s law: v = -K • ∇Pressure.
Results: CVXM generated various cross-voxel transport parameters, overcoming the limitations of other conventional pharmacokinetic models. The average tracer velocity in ME180 orthotopic tumors was 2.98±0.853µm/s, peripheral velocity ranging from 1.31-6.84µm/s. The mean and the standard deviation of the IFP values were 17.1±4.7mmHg. From the velocity and IFP measurements, the CVXM-predicted K was determined to be 4.11×10-7±1.31×10-7cm2/(mmHg • s). The experimentally measured K was 1.30×10-7±1.66×10-7cm2/(mmHg • s).
Conclusion: CVXM with DCE-MRI quantified convectional cross-voxel exchange in ME180 murine tumors. Validation was achieved through experimental K and IFP measurements, with CVXM-predicted K aligning with the previously reported range in the literature. By visualizing and quantifying transport mechanisms, CVXM offers clinical potential to optimize drug delivery, guide treatment planning, and enhance targeting efficacy, addressing major barriers to solid tumor therapy.