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 (GdL 2 ) 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 GdL 2 , 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 K SV (1.00 × 10 4 M −1 ) and the ultraviolet binding constant K b (1.11 × 10 4 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.