Evaluation of Physicochemical Properties, Pharmacokinetics, Biodistribution, Toxicity, and Contrast-Enhanced Cancer MRI of a Cancer-Targeting Contrast Agent, MT218.
Evaluation of Physicochemical Properties, Pharmacokinetics, Biodistribution, Toxicity, and Contrast-Enhanced Cancer MRI of a Cancer-Targeting Contrast Agent, MT218.
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DOI：
10.1097/rli.0000000000000881
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发表时间：
2022-10-01
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
根据美国食品药品监督管理局指南进行临床前评估，以确定MT 218的理化性质、药代动力学、清除率、安全性和肿瘤特异性磁共振（MR）成像，MT 218是一种基于钆的肽类MR成像剂，靶向域外B纤连蛋白，用于侵袭性肿瘤的MR分子成像。在体外评价了弛豫率、螯合稳定性、结合亲和力、安全性相关靶点分析以及对CYP 450酶和转运蛋白的影响。用携带前列腺癌异种移植物的大鼠、携带鼠胰腺癌同种异体移植物的免疫活性小鼠和携带不同剂量的MT 218的肺癌异种移植物的小鼠进行磁共振成像。在大鼠和清醒比格犬中测定了对心血管、呼吸和中枢神经系统的药理作用。在大鼠和犬中检测药代动力学。在大鼠中研究了生物分布和排泄。在大鼠和犬中评价了单次和重复给药毒性。还进行了体外和体内遗传毒性、体外溶血和过敏反应性试验。在1.4 T下，MT 218的弛豫率在纯水中分别为5.43和7.40 mM−1 s−1，在磷酸盐缓冲盐水中分别为6.58和8.87 mM−1 s−1，在人血清白蛋白水溶液中分别为6.54和8.70 mM−1 s−1。MT 218与结构域外B片段的结合亲和力为3.45 μM。MT 218在生理条件下没有表现出Gd（III）螯合物的解离。在大鼠、犬和人血浆中，MT 218的肽降解半衰期（t1/2）分别为1.63、5.85和2.63小时。对CYP 450酶和转运蛋白影响不大。MT 218以0.04 mmol/kg的剂量至少30分钟在域外B纤连蛋白富集肿瘤中产生高达7倍的对比噪声比增加。MT 218对中枢神经、心血管或呼吸系统几乎没有药理作用。在0.1 mmol/kg剂量下，大鼠和犬中MT 218的平均血浆消除半衰期（t1/2）分别为0.31和0.89小时。大鼠注射0.1 mmol/kg MT 218后6小时，脑中未观察到可检测到的Gd沉积。MT 218无致突变性，在大鼠或犬中分别高达1.39和0.70 mmol/kg/d时无死亡或发病。在Sprague-Dawley大鼠中，MT 218单次给药的无明显不良作用水平为1.39 mmol/kg，重复给药的无明显不良作用水平为0.46 mmol/kg/d。犬中未观察到不良作用的水平为0.07 mmol/kg/d。MT 218没有表现出遗传毒性、溶血和过敏反应性。临床前评估表明，靶向造影剂MT 218具有较高的r1和r2弛豫率、令人满意的理化性质、药代动力学和安全性特征，并在大鼠和小鼠中以较低剂量对多种癌症类型产生有效的肿瘤增强作用。
Preclinical assessments were performed according to the US Food and Drug Administration guidelines to determine the physicochemical properties, pharmacokinetics, clearance, safety, and tumor-specific magnetic resonance (MR) imaging of MT218, a peptidic gadolinium-based MR imaging agent targeting to extradomain B fibronectin for MR molecular imaging of aggressive tumors. Relaxivity, chelation stability, binding affinity, safety-related target profiling, and effects on CYP450 enzymes and transporters were evaluated in vitro. Magnetic resonance imaging was performed with rats bearing prostate cancer xenografts, immunocompetent mice bearing murine pancreatic cancer allografts, and mice bearing lung cancer xenografts at different doses of MT218. Pharmacological effects on cardiovascular, respiratory, and central nervous systems were determined in rats and conscious beagle dogs. Pharmacokinetics were tested in rats and dogs. Biodistribution and excretion were studied in rats. Single and repeated dosing toxicity was evaluated in rats and dogs. In vitro and in vivo genotoxicity, in vitro hemolysis, and anaphylactic reactivity were also performed. At 1.4 T, the r1 and r2 relaxivities of MT218 were 5.43 and 7.40 mM−1 s−1 in pure water, 6.58 and 8.87 mM−1 s−1 in phosphate-buffered saline, and 6.54 and 8.70 mM−1 s−1 in aqueous solution of human serum albumin, respectively. The binding affinity of MT218 to extradomain B fragment is 3.45 μM. MT218 exhibited no dissociation of the Gd(III) chelates under physiological conditions. The peptide degradation half-life (t1/2) of MT218 was 1.63, 5.85, and 2.63 hours in rat, dog, and human plasma, respectively. It had little effect on CYP450 enzymes and transporters. MT218 produced up to 7-fold increase of contrast-to-noise ratios in the extradomain B fibronectin–rich tumors with a dose of 0.04 mmol/kg for at least 30 minutes. MT218 had little pharmacological effect on central nervous, cardiovascular, or respiratory systems. MT218 had a mean plasma elimination half-life (t1/2) of 0.31 and 0.89 hours in rats and dogs at 0.1 mmol/kg, respectively. No detectable Gd deposition was observed in the brain at 6 hours postinjection of MT218 at 0.1 mmol/kg in rats. MT218 was not mutagenic and had no mortality or morbidity in the rats or dogs up to 1.39 and 0.70 mmol/kg/d, respectively. The no observed adverse effect level of MT218 in Sprague-Dawley rats was 1.39 mmol/kg for single dosing and 0.46 mmol/kg/d for repeated dosing. The no observed adverse effect level in dogs was 0.07 mmol/kg/d. MT218 exhibited no genotoxicity, hemolysis, and anaphylactic reactivity. The preclinical assessments showed that the targeted contrast agent MT218 has high r1 and r2 relaxivities, satisfactory physicochemical properties, pharmacokinetic, and safety profiles and produces effective tumor enhancement in multiple cancer types in rats and mice at reduced doses.
影响因子：
12.4
作者：
Sun Y;Kim HS;Park J;Li M;Tian L;Choi Y;Choi BI;Jon S;Moon WK
通讯作者：
Moon WK