中华放射医学与防护杂志

郑君瑶,郑梦,王燕,等.卡格列净通过抑制近端肾小管摄取核素偶联药物发挥肾保护作用的研究[J].中华放射医学与防护杂志,2026,46(8):749-754.Zheng Junyao,Zheng Meng,Wang Yan,et al.Renoprotective effect of canagliflozin by inhibiting the uptake of radionuclide drug conjugates in the renal proximal tubule[J].Chin J Radiol Med Prot,2026,46(8):749-754

卡格列净通过抑制近端肾小管摄取核素偶联药物发挥肾保护作用的研究

Renoprotective effect of canagliflozin by inhibiting the uptake of radionuclide drug conjugates in the renal proximal tubule

投稿时间：2025-09-16

DOI：10.3760/cma.j.cn112271-20250916-00333

中文关键词: 放射性肾损伤|肾保护剂|核素偶联药物|卡格列净|¹⁷⁷Lu-TFR1

英文关键词:Radiation-induced nephropathy|Renoprotective agent|Radionuclide drug conjugates (RDCs)|Canagliflozin (CANA)|¹⁷⁷Lu-TFR1

基金项目:国家自然科学基金(U24A20765);苏州市基础研究试点项目(SSD2024097)

作者	单位	E-mail
郑君瑶	苏州大学附属第一医院急诊医学科, 苏州 215006
郑梦	苏州大学附属第一医院药物临床试验机构, 苏州 215006
王燕	苏州大学附属第一医院临床药理实验室, 苏州 215006
肖梦雅	苏州大学附属第一医院肾内科, 苏州 215006
秦颂兵	苏州大学附属第一医院放疗科, 苏州 215006
李明	苏州大学附属第一医院肾内科, 苏州 215006	szdrli@163.com
缪丽燕	苏州大学附属第一医院药物临床试验机构, 苏州 215006 苏州大学附属第一医院临床药理实验室, 苏州 215006

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中文摘要:

目的评估卡格列净(CANA)对核素偶联药物(RDCs)所致肾损伤的保护作用及其潜在机制。方法以本课题组自主研制的¹⁷⁷Lu-转铁蛋白受体1(TFR1)为工具药,CCK-8实验检测CANA联合¹⁷⁷Lu-TFR1对肾小管上皮细胞系HK-2和人结直肠癌细胞HT-29细胞活力的影响,细胞摄取实验检测CANA对HT-29细胞和HK-2细胞摄取¹⁷⁷Lu-TFR1的影响;动物实验将小鼠按体重排序,分层随机法分为对照组、CANA组、¹⁷⁷Lu-TFR1组和¹⁷⁷Lu-TFR1+CANA组,每组3只。CANA以20 mg·kg^-1·d^-1的剂量给小鼠灌胃,在灌胃第7天从小鼠尾静脉注射3.7×10⁷ Bq/只剂量的¹⁷⁷Lu-TFR1,Phoenix WinNonLin 6.4计算¹⁷⁷Lu-TFR1的药物代谢动力学参数(半衰期T_1/2,曲线下面积),γ计数检测并计算小鼠给药后4和72 h各组织放射性摄取值(%ID/g),收集各组给药后1、3、7、28 d血清和尿液,检测血肌酐和尿蛋白,同时将各组给药后第28天的肾脏进行HE染色,并进行组织病理学评分。结果 ¹⁷⁷Lu-TFR1组HK-2细胞抑制率显著高于¹⁷⁷Lu-TFR1+CANA组(t = 5.66、7.18、11.57,P <0.001),联合应用CANA并未对¹⁷⁷Lu-TFR1抑制肿瘤细胞增殖的效果产生负面影响;给药后24、48和72 h,与¹⁷⁷Lu-TFR1组相比,¹⁷⁷Lu-TFR1+CANA组HK-2细胞对¹⁷⁷Lu-TFR1的放射性摄取减少(t = 5.92、4.30、2.69,P <0.05),而两组HT-29细胞对¹⁷⁷Lu-TFR1的放射性摄取差异均无统计学意义(P > 0.05)。给药后4和72 h,¹⁷⁷Lu-TFR1+CANA组小鼠肾脏的放射性摄取值均低于¹⁷⁷Lu-TFR1组(t = 11.09、3.28,P <0.05);给药后第28天,¹⁷⁷Lu-TFR1+CANA组小鼠尿蛋白和肾脏组织病理学评分均低于¹⁷⁷Lu-TFR1组(t = 7.72、18.00,P <0.001)。结论 CANA通过减少近端肾小管上皮细胞对¹⁷⁷Lu-TFR1的摄取,在¹⁷⁷Lu-TFR1治疗肿瘤过程中发挥了肾保护作用。

英文摘要:

Objective To evaluate the renoprotective effect of canagliflozin (CANA) against kidney injury caused by radionuclide drug conjugates (RDCs), in order to explore potential mechanisms. Methods ¹⁷⁷Lu-TFR1, an investigational drug independently developed by the authors'team, was used as a tool drug in this study. Cell counting kit-8 (CCK-8) assay was conducted to detect the effects of CANA combined with ¹⁷⁷Lu-TFR1 on the viability of renal tubular epithelial cell line HK-2 and human colorectal carcinoma cell line HT-29. Meanwhile, cell uptake experiments were carried out to explore the effects of CANA on the uptake of ¹⁷⁷Lu-TFR1 in HT-29 and HK-2 cell lines. Mice were divided into four different groups (n = 3) according to body weight using stratified randomization: the control, CANA, ¹⁷⁷Lu-TFR1, and ¹⁷⁷Lu-TFR1 + CANA groups. CANA was administered to mice via gavage at a dosage of 20 mg·kg^-1·d^-1. At 7 d post-gavage, ¹⁷⁷Lu-TFR1 was injected into the tail vein of the mice at a dose of 3.7×10⁷ Bq per mouse. The pharmacokinetic parameters of ¹⁷⁷Lu-TFR1, including half-life (T_1/2) and area under the curve (AUC), were calculated using the Phoenix WinNonLin software (version 6.4). The radioactive uptake (%ID/g) in various tissues at 4 and 72 h post-administration was detected and calculated using γ counting. The serum and urine of mice in various groups were collected at 1, 3, 7, and 28 d post-administration to detect serum creatinine and urine protein. At 28 d post-administration, the kidneys of mice in various groups were subjected to hematoxylin and eosin (H&E) staining, followed by histopathological scoring. Results The ¹⁷⁷Lu-TFR1 group exhibited significantly higher inhibitory rates of the HK-2 cell line than the ¹⁷⁷Lu-TFR1 + CANA group (t = 5.66, 7.18, 11.57, P < 0.001), which indicated that the combined application of CANA exerted a nominal negative impact on the role of ¹⁷⁷Lu-TFR1 in inhibiting tumor cell proliferation. At 24, 48, and 72 h post-administration, the ¹⁷⁷Lu-TFR1 + CANA group exhibited reduced radioactive uptake of ¹⁷⁷Lu-TFR1 in the HK-2 cell line compared to the ¹⁷⁷Lu-TFR1 group (t = 5.92, 4.30, 2.69, P < 0.05), but no statistically significant difference in the radioactive uptake of ¹⁷⁷Lu-TFR1 in the HT-29 cell line was observed between both groups(P>0.05). At 4 and 72 h post-administration, the ¹⁷⁷Lu-TFR1 + CANA group showed lower radioactive uptake in the kidney than the ¹⁷⁷Lu-TFR1 group (t = 11.09, 3.28, P < 0.05). At 28 d post-administration, the urine protein levels and renal histopathological scores of the ¹⁷⁷Lu-TFR1 + CANA group were both lower than those of the ¹⁷⁷Lu-TFR1 group (t = 7.72, 18.00, P < 0.001). Conclusions In the treatment of tumors using ¹⁷⁷Lu-TFR1, CANA plays a renoprotective role by reducing the uptake of ¹⁷⁷Lu-TFR1 in renal proximal tubular epithelial cells.

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