Quantitative Molecular Imaging with a Single Gd-Based Contrast Agent Reveals Specific Tumor Binding and Retention in Vivo

Abstract

Magnetic Resonance Imaging (MRI) has become an indispensable tool in the diagnosis and treatment of many diseases, especially cancer. However, the poor sensitivity of MRI relative to other imaging modalities, such as PET, has hindered the development and clinical use of molecular MRI contrast agents that could provide vital diagnostic information by specifically locating a molecular target altered in the disease process. This work describes the specific and sustained in vivo binding and retention of a protein tyrosine phosphatase mu (PTPμ)-targeted, molecular MR contrast agent with a single gadolinium (Gd) chelate using a quantitative MRI T1 mapping technique in glioma xenografts. Quantitative T1 mapping is an imaging method used to measure the longitudinal relaxation time, the T1 relaxation time, of protons in a magnetic field after excitation by a radiofrequency pulse. T1 relaxation times can in turn be used to calculate the concentration of a gadolinium-containing contrast agent in a region of interest, thereby allowing the retention or clearance of an agent to be quantified. In this context, retention is a measure of molecular contrast agent binding. Using conventional peptide chemistry, a PTPmu-targeted peptide was linked to a chelator that had been conjugated to a lysine residue. Following complexation with Gd, this PTPmu-targeted molecular contrast agent containing a single Gd ion showed significant tumor enhancement and a sustained increase in Gd concentration in both heterotopic and orthotopic tumors using dynamic quantitative MRI. This single Gd-containing PTPmu agent was more effective than our previous version with three Gd ions. Differences between non-specific and specific agents, due to specific tumor binding, can be determined within the first 30 minutes after agent administration by examining clearance rates. This more facile chemistry, when combined with quantitative MR techniques, allows for widespread adoption by academic and commercial entities in the field of molecular MRI ultimately leading to improved detection of disease.

Insulin Hexamer‐Caged Gadolinium Ion as MRI Contrast‐o‐phore

“…Changes in relaxation time (T i )w ere even detected at sub-mm concentrations (Figure 3u pper inset, LoD [29] for T 1 and T 2 of 500 and 200 nm respectively), indicatingt he potential for minimization of quantities of Gd III administered, and potential, as well as limitations, as at argeted-MRI contrast agent. [13,14,30,31] The r 1 and r 2 relaxivities are amongst the highest reported per Gd III ion (cf.,T able 1).I nt he case of the hexamer,t he tumbling time is calculated at % 20 ns (50 MHz), ac lose match to the Larmor precession time for the water proton at 1.4 T (60 MHz), which is ar equirement to maximize relaxivity through an increase in molecular size (i.e. tumbling time).…”

“…Changes in relaxation time ( T i ) were even detected at sub-μM concentrations (Figure 3 upper inset, LoD [29] for T 1 and T 2 of 500 and 200 nM respectively), indicating the potential for minimization of quantities of Gd(III) administered, and potential, as well as limitations, as a targeted-MRI contrast agent. [13,14,30,31]…”

Monoclonal antibody-based molecular imaging strategies and theranostic opportunities

“…Classical MRI imaging uses non-targeted contrast agents such as superparamagnetic iron oxide (SPIO) or paramagnetic gadolinium (Gd) to complement natural tissue contrasts. These contrast agents can be targeted using nanoparticles or monocloncal antibodies and can thereby extend MRI to a functional imaging modality whereas traditionally it is a rather anatomical modality 14.…”

Targeted Contrast Agents for Molecular MRI

“…This probe has a relaxivity of 8.3 mM −1 •s −1 per Gd 3+ at 1.41 T and is able to target heterotopic xenograft model of brain tumour, showing prolonged tumour retention when compared with a non-specific CA and a SBK2-scrambled-(Gd-DOTA) 3 version. More recently, a single Gd 3+ unit version of this CA, using a lysine residue as spacer, SBK2-Lys-(Gd-DOTA), showed a relaxivity of 8.4 ± 0.1 mM −1 •s −1 at 1.41 T (6.0 ± 0.1 mM −1 •s −1 at 9.4 T) allowing a good tumour enhancement, in both heterotopic and orthotopic glioma murine models [49]. Importantly, this recent "mono-Gd 3+ " version could be injected in the typical dose (0.1 mmol Gd 3+ /kg), while the tris-DOTA version could only be detected using 0.2 mmol Gd 3+ /kg.…”