Reducing renal radioactivity of radiolabeled tetravalent RGD peptides via cleavable linkers for targeted radionuclide therapy.

Authors

Thanakrit Suebboonprathueng, Yuki Mizuno, Tomoya Uehara, Yuji Kuge

Published in

Nuclear medicine and biology. Volume 160-161. Pages 109665. Aug 06, 2026. Epub Aug 06, 2026.

Abstract

In targeted radionuclide therapy, high renal radioactivity raises concerns that nephrotoxicity may limit therapeutic utility. Our recently developed ²¹¹At-labeled tetravalent RGD peptide ([²¹¹At]At-(RGD)₄) also faces this challenge, despite achieving high and persistent tumor accumulation. Here, we evaluated whether introducing renal brush-border enzyme-cleavable linkers (renal brush-border strategy) could reduce renal radioactivity and improve the tumor-to-kidney ratio of radiolabeled tetravalent RGD peptides. ¹²⁵I-labeled analogues were used due to limited availability of ²¹¹At.
Gly-Lys (GK) or Gly-Asp (GD) linkers were inserted between the radiolabeling moiety and the tetravalent RGD peptide. The biodistribution of [¹²⁵I]GK-(RGD)₄ and [¹²⁵I]GD-(RGD)₄ was evaluated in nude mice bearing U87MG human glioblastoma. Metabolite analysis was performed using urine, kidney, and tumor samples. U87MG cells were incubated with [¹²⁵I]I-(RGD)₄ or [¹²⁵I]GD-(RGD)₄ in the presence or absence of lysosomal enzyme inhibitors. Fluorescently labeled tetravalent RGD peptide (FL-(RGD)₄) was used to evaluate cellular internalization.
Both [¹²⁵I]GK-(RGD)₄ and [¹²⁵I]GD-(RGD)₄ showed reduced renal retention compared with [¹²⁵I]I-(RGD)₄ but also exhibited decreased tumor retention, resulting in an unchanged tumor-to-kidney ratio. [¹²⁵I]iodohippuric acid was detected in the tumor, kidney, and urine samples, confirming in vivo linker cleavage. Lysosomal enzyme inhibition restored the cellular accumulation of [¹²⁵I]GD-(RGD)₄ to levels comparable to [¹²⁵I]I-(RGD)₄. Fluorescence microscopy visualized internalization of FL-(RGD)₄ followed by trafficking to lysosomal compartments.
GK and GD linkers reduced renal radioactivity but impaired tumor retention, likely due to internalization and lysosomal linker cleavage. These findings clarify both the utility and limitations of the renal brush-border strategy for improving tumor-to-kidney ratios.

PMID:
42574781
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.

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