| 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].Chinese Journal of Radiological Medicine and Protection,2026,46(8):749-754 |
| Renoprotective effect of canagliflozin by inhibiting the uptake of radionuclide drug conjugates in the renal proximal tubule |
| Received:September 16, 2025 |
| DOI：10.3760/cma.j.cn112271-20250916-00333 |
| KeyWords:Radiation-induced nephropathy|Renoprotective agent|Radionuclide drug conjugates (RDCs)|Canagliflozin (CANA)|177Lu-TFR1 |
| FundProject:国家自然科学基金(U24A20765);苏州市基础研究试点项目(SSD2024097) |
| Author Name | Affiliation | E-mail | | Zheng Junyao | Department of Emergency Medicine, The First Affiliated Hospital of Soochow University, Suzhou 215006, China | | | Zheng Meng | National Institution of Drug Clinical Trial, The First Affiliated Hospital of Soochow University, Suzhou 215006, China | | | Wang Yan | Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China | | | Xiao Mengya | Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China | | | Qin Songbing | Department of Radiation Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China | | | Li Ming | Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China | szdrli@163.com | | Miao Liyan | National Institution of Drug Clinical Trial, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China | |
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| Abstract:: |
| 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 (T1/2) 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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