Synthesis and Evaluation of Diindole-Based MRI Contrast Agent for In Vivo Visualization of Necrosis.

Abstract

PURPOSE:

Noninvasive imaging of cell necrosis can provide an early evaluation of tumor response to treatments. Here, we aimed to design and synthesize a novel diindole-based magnetic resonance imaging (MRI) contrast agent (Gd-bis-DOTA-diindolylmethane, Gd-DIM) for assessment of tumor response to therapy at an early stage.

PROCEDURES:

The oil-water partition coefficient (Log P) and relaxivity of Gd-DIM were determined in vitro. Then, its necrosis avidity was examined in necrotic cells in vitro and in rat models with microwave ablation-induced muscle necrosis (MAMN) and ischemia reperfusion-induced liver necrosis (IRLN) by MRI. Visualization of tumor necrosis induced by combretastatin A-4 disodium phosphate (CA4P) was evaluated in rats bearing W256 orthotopic liver tumor by MRI. Finally, DNA binding assay was performed to explore the possible necrosis-avidity mechanism of Gd-DIM.

RESULTS:

The Log P value and T1 relaxivity of Gd-DIM is - 2.15 ± 0.01 and 6.61 mM-1 s-1, respectively. Gd-DIM showed predominant necrosis avidity in vitro and in vivo. Clear visualization of the tumor necrosis induced by CA4P was achieved at 60 min after administration of Gd-DIM. DNA binding study indicated that the necrosis-avidity mechanism of Gd-DIM may be due to its binding to exposed DNA in necrotic cells.

CONCLUSION:

Gd-DIM may serve as a promising necrosis-avid MRI contrast agent for early assessment of tumor response to therapy.

• Authors: Libang Zhang, Lichao Liu, Dongjian Zhang, Qiaomei Jin, Meng Gao, Tianze Wu, Yuanbo Feng, Yicheng Ni, Zhiqi Yin, Jian Zhang
• Journal: Molecular imaging and biology (Mol Imaging Biol) Vol. 22 Issue 3 Pg. 593-601 (06 2020) ISSN: 1860-2002 [Electronic] United States
• PMID: 31332630 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Contrast Media
• Stilbenes
• fosbretabulin

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Cell Line, Tumor
• Contrast Media (chemical synthesis, pharmacokinetics)
• Disease Models, Animal
• Liver Neoplasms (diagnostic imaging, drug therapy, metabolism, pathology)
• Lung Neoplasms (diagnostic imaging, drug therapy, metabolism, pathology)
• Magnetic Resonance Imaging (methods)
• Male
• Necrosis
• Rats
• Rats, Sprague-Dawley
• Stilbenes (pharmacology)