Intratumor mapping of intracellular water lifetime: Metabolic images of breast cancer?

Shutter-speed pharmacokinetic analysis of dynamic-contrast-enhanced (DCE)-MRI data allows evaluation of equilibrium inter-compartmental water interchange kinetics. The process measured here - transcytolemmal water exchange - is characterized by the mean intracellular water molecule lifetime (τ_i). The τ_i biomarker is a true intensive property not accessible by any formulation of the tracer pharmacokinetic paradigm, which inherently assumes it is effectively zero when applied to DCE-MRI. We present population-averaged in vivo human breast whole tumor τ_i changes induced by therapy, along with those of other pharmacokinetic parameters. In responding patients, the DCE parameters change significantly after only one neoadjuvant chemotherapy cycle: while K^trans (measuring mostly contrast agent (CA) extravasation) and k_ep (CA intravasation rate constant) decrease, τ_i increases. However, high-resolution, (1mm)², parametric maps exhibit significant intratumor heterogeneity, which is lost by averaging. A typical 400ms τ_i value means a trans-membrane water cycling flux of 10¹³ H₂O molecules s^-1/cell for a 12μm diameter cell. Analyses of intratumor variations (and therapy-induced changes) of τ_i in combination with concomitant changes of v_e (extracellular volume fraction) indicate that the former are dominated by alterations of the equilibrium cell membrane water permeability coefficient, P_W, not of cell size. These can be interpreted in light of literature results showing that τ_i changes are dominated by a P_W(active) component that reciprocally reflects the membrane driving P-type ATPase ion pump turnover. For mammalian cells, this is the Na⁺,K⁺-ATPase pump. These results promise the potential to discriminate metabolic and microenvironmental states of regions within tumors in vivo, and their changes with therapy.