Size-tuneable nanometric MRI contrast agents for the imaging of molecular weight dependent transport processes

Abstract

Purpose: To evaluate size-tuneable nanomeric glycol-chitosan-DTPA-Gd conjugates as MRI contrast agents for the imaging of molecular weight (MW) dependent transport processes. Material & Methods: Glycol chitosans (GC) – DTPA conjugates of precisely controlled MWs were synthesised and evaluated in mice against Gd-DTPA using times series of high-resolution MRI images of trunk, head, and xenograft flank tumours. All animal studies were approved by the local ethics committee and the UK authorities. Results: GC-DTPA modification ratio was one DTPA per 3.9 – 5.13 of GC monomers. GC-DTAPGd provided overall superior contrast compared to Gd-DTPA with the duration of the enhancement depending on MW (≥ 1h for 40kD). Kidneys showed early enhancement also 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 agent. Sequential high-resolution isotropic imaging of established A431 xenograft flank tumours with DTPA-Gd and GC-DTPA-Gd demonstrated that the initial delivery of the contrast agents was well correlated with blood supply. Subsequent tissue transport was primarily by diffusion and was limited by molecular weight. The data also highlight the role of heterogeneity in CA distribution that was again more prominent for the high MW agent. Conclusion: GC-DTPA-Gd with identical physical chemical properties but precisely controlled MW allow isotropic high-resolution three-dimensional imaging of molecular weight dependent transport processes which could potentially lead to clinical biomarkers for molecular weight dependent drug transport and support selection of suitable tumour models for pre-clinical development