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Purpose <p>Sunitinib is an anti-angiogenic drug that can induce drug resistance characterized by hypoxia. We aimed to synthesize two novel radiolabeled LyP-1 peptides, <sup>99m</sup>Tc-HYNIC-LyP-1 and <sup>131</sup>I-LyP-1, to detect sunitinib-induced changes in the tumor microenvironment and improve the therapeutic effects in triple-negative breast cancer (TNBC) mice models.</p> Methods <p>We synthesized <sup>99m</sup>Tc-HYNIC-LyP-1 using hydrazinonicotinamide (HYNIC) as the chelating agent and labeled the LyP-1 peptide with <sup>131</sup>I using the chloramine-T method to synthesize <sup>131</sup>I-LyP-1. Radiochemical purity and stability of the peptides were assessed in vitro using thin-layer chromatography. Tumor accumulation and biodistribution of <sup>99m</sup>Tc-HYNIC-LyP-1 were measured in 4T1 xenografts with or without sunitinib treatment. Immunohistochemical analysis was performed to detect sunitinib-induced changes. The therapeutic potential of <sup>131</sup>I-LyP-1 alone and in combination with sunitinib was evaluated in a TNBC mouse model.</p> Results <p><sup>99m</sup>Tc-HYNIC-LyP-1 and <sup>131</sup>I-LyP-1 could be readily prepared with satisfactory labeling efficiency (95.4% ± 0.6% and 72.5% ± 4.5%, respectively) and stability (both more than 90%) in vitro. Micro-single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging of mice transplanted with 4T1 tumors using <sup>99m</sup>Tc-HYNIC-LyP-1 demonstrated that the uptake of this probe was high in 4T1 xenografts treated with sunitinib at 90&#xa0;min, whereas it was mild in the control group. Semiquantitative analysis of the ratio of radioactivity intensity at tumor site to that of adjacent muscles (T/M value) showed that the average T/M value of the sunitinib treatment group at 90&#xa0;min was 3.27, while it was 0.91 in the control group (<i>p</i> = 0.0022). <sup>131</sup>I-LyP-1 could significantly inhibited tumor growth with good organ compatibility and had a synergistic therapeutic effect when combined with sunitinib, with an approximately threefold reduction in the tumor volume in comparison with the control group</p> Conclusion <p>Micro-SPECT/CT imaging using <sup>99m</sup>Tc-HYNIC-LyP-1 can be used to monitor sunitinib-induced changes in the TNBC tumor microenvironment. The combination of <sup>131</sup>I-LyP-1 and sunitinib may serve as a novel treatment for TNBC.</p>

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Preclinical Study of Radiolabeled LyP-1 for Detecting Sunitinib-induced Changes in the Tumor Microenvironment and Synergistic Antitumor Effects in Triple-negative Breast Cancer

  • 期刊论文

  • 发表日期：

    2026年4月1日

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  • Sisi Liao,
  • Qinli Qi,
  • Lifang Jin,
  • Jiali Gong,
  • Lingzhou Zhao,
  • Jinhua Zhao,
  • Meilin Zhu,
  • Ningning Song

摘要

Purpose

Sunitinib is an anti-angiogenic drug that can induce drug resistance characterized by hypoxia. We aimed to synthesize two novel radiolabeled LyP-1 peptides, 99mTc-HYNIC-LyP-1 and 131I-LyP-1, to detect sunitinib-induced changes in the tumor microenvironment and improve the therapeutic effects in triple-negative breast cancer (TNBC) mice models.

Methods

We synthesized 99mTc-HYNIC-LyP-1 using hydrazinonicotinamide (HYNIC) as the chelating agent and labeled the LyP-1 peptide with 131I using the chloramine-T method to synthesize 131I-LyP-1. Radiochemical purity and stability of the peptides were assessed in vitro using thin-layer chromatography. Tumor accumulation and biodistribution of 99mTc-HYNIC-LyP-1 were measured in 4T1 xenografts with or without sunitinib treatment. Immunohistochemical analysis was performed to detect sunitinib-induced changes. The therapeutic potential of 131I-LyP-1 alone and in combination with sunitinib was evaluated in a TNBC mouse model.

Results

99mTc-HYNIC-LyP-1 and 131I-LyP-1 could be readily prepared with satisfactory labeling efficiency (95.4% ± 0.6% and 72.5% ± 4.5%, respectively) and stability (both more than 90%) in vitro. Micro-single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging of mice transplanted with 4T1 tumors using 99mTc-HYNIC-LyP-1 demonstrated that the uptake of this probe was high in 4T1 xenografts treated with sunitinib at 90 min, whereas it was mild in the control group. Semiquantitative analysis of the ratio of radioactivity intensity at tumor site to that of adjacent muscles (T/M value) showed that the average T/M value of the sunitinib treatment group at 90 min was 3.27, while it was 0.91 in the control group (p = 0.0022). 131I-LyP-1 could significantly inhibited tumor growth with good organ compatibility and had a synergistic therapeutic effect when combined with sunitinib, with an approximately threefold reduction in the tumor volume in comparison with the control group

Conclusion

Micro-SPECT/CT imaging using 99mTc-HYNIC-LyP-1 can be used to monitor sunitinib-induced changes in the TNBC tumor microenvironment. The combination of 131I-LyP-1 and sunitinib may serve as a novel treatment for TNBC.