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Synthesis and Biological Evaluation of Rhein-Based MRI Contrast Agents for in Vivo Visualization of Necrosis

Bian, Li, Gao, Meng, Zhang, Dongjian, Ji, Aiyan, Su, Chang, Duan, Xinghua, Luo, Qi, Huang, Dejian, Feng, Yuanbo, Ni, Yicheng, Yin, Zhiqi, Jin, Qiaomei, Zhang, Jian
Analytical chemistry 2018 v.90 no.22 pp. 13249-13256
DNA, acetic acid, animal models, breast neoplasms, gadolinium, image analysis, infarction, liver, magnetic resonance imaging, magnetism, muscles, patients, planning, rats, therapeutics
Early and accurate assessment of therapeutic response to anticancer therapy plays an important role in determining treatment planning and patient management in clinic. Magnetic rseonance imaging (MRI) of necrosis that occurs after cancer therapies provides chances for that. Here, we reported three novel MRI contrast agents, GdL₁, GdL₂, and GdL₃, by conjugating rhein with gadolinium 2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]acetic acid (Gd-DOTA) through different linkers. The T1 relaxivities of three probes (7.28, 7.35, and 8.03 mM–¹ s–¹) were found to be higher than that of Gd-DOTA (4.28 mM–¹ s–¹). Necrosis avidity of GdL₁ was evaluated on the rat models of reperfused liver infarction (RLI) by MRI, which showed an increase of T1-weighted contrast between necrotic and normal liver during 0.5–12 h. Besides, L₁ was also labeled with ⁶⁴Cu to assess its necrosis avidity on rat models of RLI and muscle necrosis (MN) by a γ-counter. The uptakes of ⁶⁴CuL₁ in necrotic liver and muscle were higher than those in normal liver and muscle (P < 0.05). Then, the ability of GdL₁ to assess therapeutic response was tested on rats bearing Walker 256 breast carcinoma injected with a vascular disrupting agent CA4P by MR imaging. The signal intensity of tumoral necrosis was strongly enhanced, and the contrast ratio between necrotic and viable tumor was 1.63 ± 0.11 at 3 h after administration of GdL₁. Besides, exposed DNA in necrosis cells may be an important mechanism of three probes targeting to necrosis cells. In summary, GdL₁ may serve as a promising MRI contrast agent for accurate assessment of treatment response.