Synthesis, Preclinical Toxicity, and Biodistribution of [18F]AVT-011 to Assess the P-Glycoprotein Function.

IF 2.4 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cancer Biotherapy and Radiopharmaceuticals Pub Date : 2024-09-12 DOI:10.1089/cbr.2024.0114
Riptee Thakur,Manoj Kumar,Aishwarya Kumar,Raman Kumar Joshi,Divya Maheshwari,Afsal Mohammed Km,Manjunatha Venkataswamy,Bhabani Mohanty,Pradip Chaudhari,Hosahalli K Mohan,Pardeep Kumar
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Abstract

Introduction: Many studies have reported the role of P-glycoprotein (Pgp) in chemoresistance in various pathological conditions such as cancer and neurodegenerative diseases, such as Alzheimer's. In this study, we are reporting the high-performance liquid chromatography (HPLC)-based purification of fluorine-18 [18F]AVT-011 and its preclinical evaluation. Methods: AVT-011 was labeled with 18F using the nucleophilic substitution method by heating the reaction mixture at 110°C for 10 min, followed by purification using preparative HPLC and C18ec cartridge. The in vitro cell uptake study was carried out in U87 cells with and without an inhibitor. The preclinical toxicity was carried out in CD1 mice in three groups, including control, AVT-011 treated, and [18F]AVT-011 treated. The biodistribution study was done in CD1 mice (n = 12) after intravenous injection of 4-6 MBq [18F]AVT-011, and mice were sacrificed at various time intervals. A dose of 3.7 ± 0.7 MBq of [18F]AVT-011 was injected intravenously in the healthy Swiss albino mice, and the whole-body micro-positron emission tomography was acquired at 0-, 30-, 60-, and 120-min postinjection. Results: The radiochemical purity of [18F]AVT-011 was 97 ± 1.5% as evaluated by radio-HPLC with a yield of 14 ± 2% and was stable up to 95% under in vitro conditions in blood and in vivo conditions up to 4 h. The in vitro cell uptake study showed a significant difference in control (27.4 ± 2.1%) and blocked U987 cells (73.2 ± 3.2%) after incubation of 120 min. The tissue distribution in mice showed the highest uptake in the liver (17.3 ± 2.4%), kidneys (16.6 ± 3.1%), lungs (10.4 ± 2.9%), and spleen (5.6 ± 0.8%) at 15 min, and the activity was washed out with time. The radioactivity cleared through the hepatorenal pathway. The animal imaging study also demonstrates a similar biodistribution pattern. Conclusions: [18F]AVT-011 showed higher specific activity than the cartridge-based method but showed similar biological activity.
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用于评估 P 糖蛋白功能的 [18F]AVT-011 的合成、临床前毒性和生物分布。
导言:许多研究都报道了 P 糖蛋白(Pgp)在癌症和神经退行性疾病(如阿尔茨海默氏症)等各种病理情况下的化疗耐药性中的作用。本研究报告了基于高效液相色谱法(HPLC)的氟-18 [18F]AVT-011 的纯化及其临床前评估。方法:采用亲核取代法在 110°C 下加热反应混合物 10 分钟,用 18F 标记 AVT-011,然后使用制备型 HPLC 和 C18ec 滤芯进行纯化。体外细胞摄取研究是在含有和不含抑制剂的 U87 细胞中进行的。临床前毒性研究在 CD1 小鼠中进行,分为三组,包括对照组、AVT-011 处理组和 [18F]AVT-011 处理组。静脉注射 4-6 MBq [18F]AVT-011 后,对 CD1 小鼠(n = 12)进行生物分布研究,并在不同时间间隔将小鼠处死。健康瑞士白化小鼠静脉注射 3.7 ± 0.7 MBq [18F]AVT-011 剂量,分别在注射后 0、30、60 和 120 分钟进行全身微正电子发射断层扫描。结果显示体外细胞摄取研究显示,培养 120 分钟后,对照组(27.4 ± 2.1%)和阻断的 U987 细胞(73.2 ± 3.2%)的摄取量有显著差异。小鼠的组织分布显示,15 分钟后,肝脏(17.3 ± 2.4%)、肾脏(16.6 ± 3.1%)、肺脏(10.4 ± 2.9%)和脾脏(5.6 ± 0.8%)的摄取量最高,随着时间的推移,活性被冲淡。放射性通过肝肾途径清除。动物成像研究也显示了类似的生物分布模式。结论[18F]AVT-011的特异性活性高于盒式方法,但具有相似的生物活性。
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来源期刊
CiteScore
7.80
自引率
2.90%
发文量
87
审稿时长
3 months
期刊介绍: Cancer Biotherapy and Radiopharmaceuticals is the established peer-reviewed journal, with over 25 years of cutting-edge content on innovative therapeutic investigations to ultimately improve cancer management. It is the only journal with the specific focus of cancer biotherapy and is inclusive of monoclonal antibodies, cytokine therapy, cancer gene therapy, cell-based therapies, and other forms of immunotherapies. The Journal includes extensive reporting on advancements in radioimmunotherapy, and the use of radiopharmaceuticals and radiolabeled peptides for the development of new cancer treatments.
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