Metastasis is the leading cause of cancer-related deaths, and metastatic cancers remain largely incurable due to chemoresistance. Biomarkers of metastatic cells are lacking, and probes that could be used to detect and target metastases would be highly valuable. Here we hypothesize that metastatic cancer cells express cell-surface receptors that can be harnessed for identification of molecules homing to metastases. Screening a combinatorial library in a mouse mammary tumor model of spontaneous metastasis identified cyclic peptides with tropism for cancer cells disseminated to the lungs. Two lead peptides, CLRHSSKIC and CRAGVGRGC, bound murine and human cells derived from breast carcinoma and melanoma in culture and were selective for metastatic cells in vivo . In mice, peptide CRAGVGRGC radiolabeled with 67Ga for biodistribution analysis demonstrated selective probe homing to lung metastases. Moreover, systemic administration of 68Ga-labeled CRAGVGRGC enabled noninvasive imaging of lung metastases in mice by PET. A CRAGVGRGC-derived peptide induced apoptosis upon cell internalization in vitro and suppressed metastatic burden in vivo . Colocalization of CLRHSSKIC and CRAGVGRGC with N-cadherin+/E-cadherin− cells indicated that both peptides are selective for cancer cells that have undergone the epithelial-to-mesenchymal transition. We conclude that CRAGVGRGC is useful as a probe to facilitate the development of imaging modalities and therapies targeting metastases. Significance: This study identifies new molecules that bind metastatic cells and demonstrates their application as noninvasive imaging probes and vehicles for cytotoxic therapy delivery in preclinical cancer models.

中文翻译：

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靶向转移性肿瘤细胞的肽作为癌症检测探针和治疗传递载体的表征

转移是癌症相关死亡的主要原因，由于化学抗性，转移性癌症在很大程度上仍然无法治愈。缺乏转移细胞的生物标志物，可用于检测和靶向转移的探针将非常有价值。在这里，我们假设转移性癌细胞表达细胞表面受体，可用于识别归巢到转移灶的分子。在自发转移的小鼠乳腺肿瘤模型中筛选组合文库，鉴定出具有向肺部扩散的癌细胞的环肽。两种先导肽 CLRHSSKIC 和 CRAGVGRGC 在培养物中结合源自乳腺癌和黑色素瘤的鼠和人细胞，并且对体内的转移细胞具有选择性。在老鼠身上，用 67Ga 放射性标记的肽 CRAGVGRGC 用于生物分布分析表明选择性探针归巢至肺转移。此外，全身给药 68Ga 标记的 CRAGVGRGC 能够通过 PET 对小鼠肺转移灶进行无创成像。CRAGVGRGC 衍生肽在体外细胞内化后诱导细胞凋亡，并在体内抑制转移负担。CLRHSSKIC 和 CRAGVGRGC 与 N-钙粘蛋白+/E-钙粘蛋白-细胞的共定位表明这两种肽对已经经历上皮-间质转化的癌细胞具有选择性。我们得出结论，CRAGVGRGC 可用作探针，以促进成像方式和针对转移灶的疗法的发展。意义：