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Purpose <p>To develop a novel molecular scaffold designed for dual targeting via site-specific&#xa0;[<sup>99m</sup>Tc] Tc labeling, we report its radiochemical evaluation and preliminary targeting efficacy in acidic tumor models.</p> Procedures <p>The pHLIP-RGD scaffold was synthesized by conjugating pHLIP variant 7 (var7) with cyclo(RGDfK) peptide.&#xa0;Pharmacokinetic assessment of [<sup>99m</sup>Tc] Tc-pHLIP-RGD was performed in MDA-MB-231 xenograft-bearing mice through quantitative biodistribution studies and small-animal single photon emission computed tomography (SPECT) imaging.</p> Results <p>[<sup>99m</sup>Tc] Tc-pHLIP-RGD demonstrated high stability in mouse serum for at least 4&#xa0;h and exhibited strong binding affinity and specificity both <i>in vitro</i> and <i>in vivo</i>. Biodistribution studies revealed rapid tumor accumulation and prolonged retention, with uptake values of 7.01 ± 1.28, 4.23 ± 0.44, 8.04 ± 0.63, and 9.60 ± 1.26%ID/g at 0.5, 1.0, 2.0, and 4.0&#xa0;h post-injection, respectively. Off-target accumulation was primarily observed in the liver. In blocking studies, the administration of non-radioactive pHLIP-RGD partially reduced tumor uptake of [<sup>99m</sup>Tc] Tc-pHLIP-RGD, with tumor distribution values at 0.5, 1.0, 2.0, and 4.0&#xa0;h of 4.66 ± 0.49, 3.25 ± 0.36, 3.04 ± 1.15, and 3.75 ± 0.57%ID/g, respectively. SPECT imaging findings were consistent with biodistribution data, showing clear visualization of tumors at all time points. Tumor visibility was significantly reduced in the blocking study, with a corresponding increase in liver uptake.</p> Conclusions <p>The heterodimeric radiotracer [<sup>99m</sup>Tc] Tc-pHLIP-RGD exhibited high radiochemical yield, good stability, and favorable tumor uptake and retention characteristics. These proof-of-concept results suggest the potential of the dual-targeting design strategy for developing diagnostic imaging agents for triple-negative breast cancer (TNBC).</p>

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Design of a Bifunctional pHLIP-RGD Scaffold for Site-Specific [99mTc] Tc Labeling: Radiochemical Evaluation and Proof-of-Concept Tumor Targeting

  • 期刊论文

  • 发表日期：

    2026年3月4日

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  • Mingming Yu,
  • Yuehua Chen,
  • Bangxu Yu,
  • Xia Li,
  • Yuan Su,
  • Zhenguang Wang

摘要

Purpose

To develop a novel molecular scaffold designed for dual targeting via site-specific [99mTc] Tc labeling, we report its radiochemical evaluation and preliminary targeting efficacy in acidic tumor models.

Procedures

The pHLIP-RGD scaffold was synthesized by conjugating pHLIP variant 7 (var7) with cyclo(RGDfK) peptide. Pharmacokinetic assessment of [99mTc] Tc-pHLIP-RGD was performed in MDA-MB-231 xenograft-bearing mice through quantitative biodistribution studies and small-animal single photon emission computed tomography (SPECT) imaging.

Results

[99mTc] Tc-pHLIP-RGD demonstrated high stability in mouse serum for at least 4 h and exhibited strong binding affinity and specificity both in vitro and in vivo. Biodistribution studies revealed rapid tumor accumulation and prolonged retention, with uptake values of 7.01 ± 1.28, 4.23 ± 0.44, 8.04 ± 0.63, and 9.60 ± 1.26%ID/g at 0.5, 1.0, 2.0, and 4.0 h post-injection, respectively. Off-target accumulation was primarily observed in the liver. In blocking studies, the administration of non-radioactive pHLIP-RGD partially reduced tumor uptake of [99mTc] Tc-pHLIP-RGD, with tumor distribution values at 0.5, 1.0, 2.0, and 4.0 h of 4.66 ± 0.49, 3.25 ± 0.36, 3.04 ± 1.15, and 3.75 ± 0.57%ID/g, respectively. SPECT imaging findings were consistent with biodistribution data, showing clear visualization of tumors at all time points. Tumor visibility was significantly reduced in the blocking study, with a corresponding increase in liver uptake.

Conclusions

The heterodimeric radiotracer [99mTc] Tc-pHLIP-RGD exhibited high radiochemical yield, good stability, and favorable tumor uptake and retention characteristics. These proof-of-concept results suggest the potential of the dual-targeting design strategy for developing diagnostic imaging agents for triple-negative breast cancer (TNBC).