Development of a Suite of Gadolinium-Free OATP1-Targeted Paramagnetic Probes for Liver MRI.

Five amphiphilic, anionic Mn(II) complexes were synthesized as contrast agents targeted to organic anion transporting polypeptide transporters (OATP) for liver magnetic resonance imaging (MRI). The Mn(II) complexes are synthesized in three steps, each from the commercially available trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (CDTA) chelator, with T1-relaxivity of complexes ranging between 2.3 and 3.0 mM-1 s-1 in phosphate buffered saline at an applied field strength of 3.0 T. Pharmacokinetics were assessed in female BALB/c mice by acquiring T1-weighted images dynamically for 70 min after agent administration and determining contrast enhancement and washout in various organs. Uptake of Mn(II) complexes in human OATPs was investigated through in vitro assays using MDA-MB-231 cells engineered to express either OATP1B1 or OATP1B3 isoforms. Our study introduces a new class of Mn-based OATP-targeted contrast that can be broadly tuned via simple synthetic protocols.

A Genetically Encoded Magnetic Resonance Imaging Reporter Enables Sensitive Detection and Tracking of Spontaneous Metastases in Deep Tissues.

Metastasis is the leading cause of cancer-related death. However, it remains a poorly understood aspect of cancer biology, and most preclinical cancer studies do not examine metastasis, focusing solely on the primary tumor. One major factor contributing to this paradox is a gap in available tools for accurate spatiotemporal measurements of metastatic spread in vivo. Here, our objective was to develop an imaging reporter system that offers sensitive three-dimensional (3D) detection of cancer cells at high resolutions in live mice. An organic anion-transporting polypeptide 1b3 (oatp1b3) was used as an MRI reporter gene, and its sensitivity was systematically optimized for in vivo tracking of viable cancer cells in a spontaneous metastasis model. Metastases with oatp1b3-MRI could be observed at the single lymph node level and tracked over time as cancer cells spread to multiple lymph nodes and different organ systems in individual animals. While initial single lesions were successfully imaged in parallel via bioluminescence, later metastases were largely obscured by light scatter from the initial node. Importantly, MRI could detect micrometastases in lung tissue comprised on the order of 1,000 cancer cells. In summary, oatp1b3-MRI enables longitudinal tracking of cancer cells with combined high resolution and high sensitivity that provides 3D spatial information and the surrounding anatomical context. SIGNIFICANCE: An MRI reporter gene system optimized for tracking metastasis in deep tissues at high resolutions and able to detect spontaneous micrometastases in lungs of mice provides a useful tool for metastasis research.