Size-tuneable Nanometric MRI Contrast Agents for the Imaging of Molecular Weight Dependent Transport Processes

The purpose of the current study was to evaluate size-tuneable polymeric glycol-chitosan (GC)-DTPAGadolinium (Gd) conjugates as MRI contrast agents that can be used as a platform for imaging of molecular weight (MW) dependent transport processes. GC-DTPA-Gd conjugates of precisely controlled MWs were synthesised and evaluated in mice against Gd-DTPA using time series of high-resolution MRI images of trunk, head, and xenograft flank tumours. GC-DTPA modification ratio was one DTPA per 3.9-5.13 of GC monomers. GC-DTAP-Gd provided overall superior contrast compared to Gd-DTPA with the duration of the enhancement depending on MW (≥1hr for 40kD). The kidneys showed early enhancement also, particularly in the renal pelvis, suggesting renal elimination. Imaging of the head with GC-DTPA-Gd allowed detailed anatomical identification of specific blood vessels in particular with the high MW CA agent. Sequential, high-resolution, isotropic imaging of established A431 xenograft flank tumours with DTPA-Gd and GC-DTPA-Gd demonstrated that the initial distribution of the contrast agents was well correlated with blood vessels and supply. In contrast, subsequent tissue transport was primarily by diffusion and limited by CA molecular weight. The data also highlight the role of heterogeneity in CA distribution which was more prominent for the high MW agent. Precise control of glycol chitosan (GC) polymer chemistry facilitates synthesis of a family of Gd-based MRI contrast agents of tuneable MW but otherwise identical physicochemical properties. Such agents allow isotropic high-resolution threedimensional imaging of MW dependent transport processes relevant to the clinical and pre-clinical prediction of drug transport processes.