Rhein‐based necrosis‐avid MRI contrast agents for early evaluation of tumor response to microwave ablation therapy

Abstract

Purpose Early evaluation of tumor response to thermal ablation therapy can help identify untreated tumor cells and then perform repeated treatment as soon as possible. The purpose of this work was to explore the potential of rhein‐based necrosis‐avid contrast agents (NACAs) for early evaluation of tumor response to microwave ablation (MWA). Methods 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyl tetrazolium bromide (MTT) assay was performed to test the cytotoxicity of rhein‐based NACAs against HepG2 cells. Rat models of liver MWA were used for investigating the effectiveness of rhein‐based NACAs in imaging the MWA lesion, the optimal time period for post‐MWA MRI examination, and the metabolic behaviors of 68Ga‐labeled rhein‐based NACAs. Rat models of orthotopic liver W256 tumor MWA were used for investigating the time window of rhein‐based NACAs for imaging the MWA lesion, the effectiveness of these NACAs in distinguishing the residual tumor and the MWA lesion, and their feasibility in early evaluating the tumor response to MWA. Results Gadolinium 2,2',2''‐(10‐(2‐((4‐(4,5‐Dihydroxy‐9,10‐dioxo‐9,10‐dihydroanthracene‐2‐carboxamido)butyl)amino)‐2‐oxoethyl)‐1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyl)triacetic acid (GdL2) showed low cytotoxicity and high quality in imaging the MWA region. The optimal time period for post‐MWA MRI examination using GdL2 was 2 to 24 h after the treatment. During 2.5 to 3.5 h postinjection, GdL2 can better visualize the MWA lesion in comparison with gadolinium 2‐[4,7,10‐tris(carboxymethyl)‐1,4,7,10‐tetraazacyclododec‐1‐yl]acetic acid (Gd‐DOTA), and the residual tumor would not be enhanced. The tumor response to MWA as evaluated by using GdL2‐enhanced MRI was consistent with histological examination. Conclusion GdL2 appears to be a promising NACA for the tumor response assessment after thermal ablation therapies.

Discovery of necrosis avidity of rhein and its applications in necrosis imaging

“…It was demonstrated that GdL 2 could enhance the ablated lesion in rats with liver MWA as early as 2 h post ablation and could maintain a stable contrast ratio of ablated lesion to normal liver until 24 h post ablation, which supported its potential use for early assessment of thermal ablation therapy response [48]. Then the capability of GdL 2 to distinguish residual tumor from MWA lesion was evaluated in a rat model of liver tumor hyperintensity relative to normal liver at 3 h post injection (Figure 4B), thus allowing noninvasive identification of unaffected residual tumor [48]. Moreover, it was found that the optimal time window for visualizing the MWA lesion appeared at 2.5 to 3.5 h post injection of GdL 2 in rat models of liver tumor MWA [48].…”

“…Therefore, GdL 1 may serve as a potential MRI contrast agent for early evaluation of tumor response to necrosis-inducing therapies. [48]. The results demonstrated that GdL 3 was not as safe as GdL 1 and GdL 2 in the concentration range from 25 to 1000 μM [48].…”

“…The results demonstrated that GdL 3 was not as safe as GdL 1 and GdL 2 in the concentration range from 25 to 1000 μM [48]. Further comparison of GdL 1 and GdL 2 for imaging MWA-induced necrotic lesion in a rat model of liver MWA showed that much clearer visualization of the MWA lesion was observed both at 3 and 6 h post injection of GdL 2 in contrast to GdL 1 [48]. Thus, GdL 2 was selected for further evaluation.…”

“…Then the capability of GdL 2 to distinguish residual tumor from MWA lesion was evaluated in a rat model of liver tumor hyperintensity relative to normal liver at 3 h post injection (Figure 4B), thus allowing noninvasive identification of unaffected residual tumor [48]. Moreover, it was found that the optimal time window for visualizing the MWA lesion appeared at 2.5 to 3.5 h post injection of GdL 2 in rat models of liver tumor MWA [48]. In the subsequent comparative study of GdL 2 and Gd-DOTA for the therapeutic evaluation of MWA, GdL 2 showed significantly better contrast-enhanced imaging performance than Gd-DOTA [48].…”

“…[18][19][20]. More recently, based on our previous studies on necrosis avidity of bisanthracene nuclear anthraquinone compounds and in pursuit for NAAs with improved physicochemical properties, pharmacokinetics and biodistribution, monomeric anthraquinone compound rhein was demonstrated to have a newly discovered necrosis-avid trait and to show promising applications in noninvasive visualization of myocardial necrosis and early monitoring of tumor response to therapy [44][45][46][47][48][49].…”