Design and Evaluation of Rhein-Based MRI Contrast Agents for Visualization of Tumor Necrosis Induced by Combretastatin A-4 Disodium Phosphate.

PURPOSE: Visualization of tumor necrosis can determine tumor response to therapy. Our previous study showed that the rhein-based magnetic resonance imaging (MRI) contrast agent with alkane linker (GdL2) could clearly image tumor necrosis. However, its water solubility and cell safety needed to be improved. Herein, three rhein-based MRI agents with ether or lysine linkers were designed. PROCEDURES: Three rhein-based MRI agents were synthesized with a tetracarbon ether (GdP1), a hexacarbon ether (GdP2), and a lysine (GdP3) linker, respectively. Their octanol-water partition coefficients (log P) and cytotoxicity were determined. Necrosis avidity of the leading agent was explored on HepG2 cells and ischemia reperfusion-induced liver necrosis (IRLN) rats by MRI. The effect of visualization of tumor necrosis was tested on nude mice with W256 tumor treated by combretastatin-A4 phosphate (CA4P). DNA binding assays were applied to evaluate the possible necrosis-avidity mechanism of the leading agent. RESULTS: The log P of three agents (- 1.66 ± 0.09, - 1.74 ± 0.01, - 1.95 ± 0.01) decreased when compared with GdL2, indicating higher water solubility. GdP1 not only presented lower cytotoxicity and good necrotic affinity in vitro and in vivo, but also can be fast excreted by renal. According to MRI results of tumor, distinct visualization of tumor necrosis can be discernible from 3 to 4.5 h post-injection of GdP1. In DNA-binding assays, the fluorescence quenching constant KSV (1.00 × 104 M-1) and the ultraviolet binding constant Kb (1.11 × 104 M-1) suggested that GdP1 may bind to DNA through intercalation. CONCLUSION: GdP1 may serve as a potential candidate for early evaluation of tumor response to CA4P treatment.