Metformin Reduces Renal Uptake of Radiotracers and Protects Kidneys from Radiation-Induced Damage.,Molecular Pharmaceutics

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Metformin Reduces Renal Uptake of Radiotracers and Protects Kidneys from Radiation-Induced Damage.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2019-01-16 , DOI: 10.1021/acs.molpharmaceut.8b01091
Chiyi Xiong , Dengke Yin , Junjie Li , Qian Huang , Murali K Ravoori , Vikas Kundra , Hua Zhu ₁ , Zhi Yang ₁ , Yang Lu , Chun Li

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Metformin is the most widely prescribed drug for type 2 diabetes. Chemically, metformin is a hydrophilic base that functions as an organic cation, suggesting that it may have the capacity to inhibit the tubular reabsorption of peptide radiotracers. The purpose of this study was to investigate whether metformin could reduce renal uptake of peptidyl radiotracers and serve as a radioprotective agent for peptide receptor radionuclide therapy (PRRT). METHODS We used two radiolabeled peptides: a 68Ga-labeled cyclic (TNYL-RAW) peptide (68Ga-NOTA-c(TNYL-RAW) (NOTA: 1,4,7 triazacyclononane-1,4,7-trisacetic acid) targeting EphB4 receptors and an 111In- or 64Cu-labeled octreotide (111In/64Cu-DOTA-octreotide) (DOTA: 1,4,7,10 triazacyclododecane-1,4,7,10-tetraacetic acid) targeting somatostatin receptors. Each radiotracer was injected intravenously into normal Swiss mice or tumor-bearing nude mice in the presence or absence of metformin administered intravenously or orally. Micropositron emission tomography or microsingle-photon emission computed tomography images were acquired at different times after radiotracer injection, and biodistribution studies were performed at the end of the imaging session. To assess the radioprotective effect of metformin on the kidneys, normal Swiss mice received two doses of 111In-DOTA-octreotidein the presence or absence of metformin, and renal function was analyzed via blood chemistry and histology. RESULTS Intravenous injection of metformin with 68Ga-NOTA-c(TNYL-RAW) or 111In-DOTA-octreotide reduced the renal uptake of the radiotracer by 60% and 35%, respectively, compared to uptake without metformin. These reductions were accompanied by greater uptake in the tumors for both radiolabeled peptides. Moreover, the renal uptake of 111In-DOTA-octreotide was significantly reduced when metformin was administered via oral gavage. Significantly more radioactivity was recovered in the urine collected over a period of 24 h after intravenous injection of 64Cu-DOTA-octreotide in mice that received oral metformin than in mice that received vehicle. Finally, coadministration of 111In-DOTA-octreotide with metformin mitigated radio-nephrotoxicity. CONCLUSION Metformin inhibits kidney uptake of peptidyl radiotracers, protecting the kidney from nephrotoxicity. Further studies are needed to elucidate the mechanisms of these finding and to optimize mitigation of radiation-induced damage to kidney in PRRT.

中文翻译：

二甲双胍可降低肾脏对放射性示踪剂的吸收，并保护肾脏免受辐射引起的损害。

二甲双胍是2型糖尿病最广泛使用的药物。化学上，二甲双胍是充当有机阳离子的亲水性碱，表明其可能具有抑制肽放射性示踪剂的管状重吸收的能力。这项研究的目的是调查二甲双胍是否可以减少肾脏对肽基放射性示踪剂的摄取，并作为肽受体放射性核素治疗（PRRT）的放射防护剂。方法我们使用了两种放射性标记的肽段：靶向EphB4的68Ga标记的环状（TNYL-RAW）肽（68Ga-NOTA-c（TNYL-RAW）（NOTA：1,4,7三氮杂环壬烷-1,4,7-三乙酸））受体和针对生长抑素受体的111In或64Cu标记的奥曲肽（111In / 64Cu-DOTA-奥曲肽）（DOTA：1,4,7,10三氮杂环十二烷-1,4,7,10-四乙酸）。在存在或不存在静脉或口服二甲双胍的情况下，将每种放射性示踪剂静脉内注射到正常的瑞士小鼠或荷瘤裸鼠中。在放射示踪剂注入后的不同时间获取了微正电子发射断层扫描或微单光子发射计算机断层扫描图像，并且在成像过程结束时进行了生物分布研究。为了评估二甲双胍对肾脏的放射防护作用，正常的瑞士小鼠在有或没有二甲双胍的情况下接受了两剂111In-DOTA-奥曲肽的剂量，并通过血液化学和组织学分析了肾功能。结果与不服用二甲双胍的情况相比，静脉注射二甲双胍与68Ga-NOTA-c（TNYL-RAW）或111In-DOTA-奥曲肽可分别使放射性示踪剂的肾脏摄取减少60％和35％。这些减少伴随着两种放射性标记肽在肿瘤中的更大摄取。此外，当通过口服管饲二甲双胍给药时，111In-DOTA-奥曲肽的肾脏摄取显着降低。与口服赋形剂相比，口服二甲双胍的小鼠静脉注射64Cu-DOTA-奥曲肽后24小时内收集到的尿液中回收的放射性明显增加。最后，将111In-DOTA-奥曲肽与二甲双胍共同给药可减轻放射性肾毒性。结论二甲双胍可抑制肾脏摄取肽放射性示踪剂，从而保护肾脏免受肾毒性。需要进一步的研究来阐明这些发现的机制，并优化缓解PRRT对肾脏引起的辐射引起的损害的缓解。

更新日期：2019-01-04

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