Search

Water cycling across the membrane transporters is considered a hallmark of cellular metabolism and it could be of high diagnostic relevance in the characterization of tumors and other diseases. The method relies on the response of intracellular proton exchanging molecules to the presence of extracellular Gd‐based contrast agents (GBCAs). Paramagnetic GBCAs enhances the relaxation rate of water molecules in the extracellular compartment and, through membrane exchange, the relaxation enhancement is transferred to intracellular molecules. The effect is detected at the MRI‐CEST (Magnetic Resonance Imaging ‐ Chemical Exchange Saturation Transfer) signal of intracellular proton exchanging molecules. The magnitude of the change in the CEST response reports on water cycling across the membrane. The method has been tested on Red Blood Cells and on orthotopic murine models of breast cancer with different degree of malignancy (4T1, TS/A and 168FARN). The distribution of voxels reporting on membrane permeability fits well with the cells' aggressiveness and acts as an early reporter to monitor therapeutic treatments. [ABSTRACT FROM AUTHOR]

Purpose: Malaria is a global health problem with the most malignant form caused by Plasmodium falciparum (P. falciparum). Parasite maturation in red blood cells (RBCs) is accompanied by changes including the formation of paramagnetic hemozoin (HZ) nanocrystals, and increased metabolism and variation in membrane lipid composition. Herein, MR relaxometry (MRR) was applied to investigate water exchange across RBCs' membrane and HZ formation in parasitized RBCs. Methods: Transverse water protons relaxation rate constants (R2 = 1/T2) were measured for assessing HZ formation in P. falciparum‐parasitized human RBCs. Moreover, water exchange lifetimes across the RBC membrane (τi) were assessed by measuring longitudinal relaxation rate constants (R1 = 1/T1) at 21.5 MHz in the presence of a gadolinium complex dissolved in the suspension medium. Results: τi increased after invasion of parasites (ring stage, mean τi/τi0 = 1.234 ± 0.022) and decreased during maturation to late trophozoite (mean τi/τi0 = 0.960 ± 0.075) and schizont stages (mean τi/τi0 = 1.019 ± 0.065). The HZ accumulation in advanced stages was revealed by T2‐shortening. The curves reporting R2 (1/T2) vs. magnetic field showed different slopes for non‐parasitized RBCs (npRBCs) and parasitized RBCs (pRBCs), namely 0.003 ± 0.001 for npRBCs, 0.009 ± 0.002, 0.028 ± 0.004 and 0.055 ± 0.002 for pRBCs at ring‐, early trophozoite‐, and late trophozoite stage, respectively. Antimalarial molecules dihydroartemisinin and chloroquine elicited measurable changes in parasitized RBCs, namely dihydroartemisinin modified τi, whereas the interference of chloroquine with HZ formation was detectable by a significant T2 increase. Conclusions: MRR can be considered a useful tool for reporting on P. falciparum blood stages and for screening potential antimalarial molecules. [ABSTRACT FROM AUTHOR]

The water exchange lifetime (τ i ) through red blood cell (RBC) membranes can be measured by analyzing the water protons bi-exponential T 1 and T 2 curves when RBCs are suspended in a medium supplemented with paramagnetic species. Since the seminal papers published in the early '70s of the previous century, paramagnetic Mn 2 + ions were used for doping the extracellular compartment in the RBCs suspension. The obtained τ i values fall in the range of 9.8–14 ms. Conversely, other physic-chemical measurements afforded longer τ i values. Herein, it is shown that the replacement of Mn 2 + with the highly stable, hydrophilic Gd(III) complexes used as paramagnetic magnetic resonance imaging (MRI) contrast agents led to measure τ i values of 19.1 ± 0.65 ms at 25 °C. The observed difference is ascribed to the occurrence of enhanced permeability of RBC membrane in the presence of Mn 2 + ions. This view finds support from the observation that an analogous behavior was shown in the presence of other divalent cations, such Ca 2 + and Zn 2 + ions. A possible role of scramblase has been hypothesized. Finally, τ i has been measured in presence of alcohols to show that the herein proposed method can detect minor changes in RBC membranes' stiffness upon the incorporation of aliphatic alcohols. [ABSTRACT FROM AUTHOR]