Jordà-Redondo Mireia, Piqueras Ana, Castillo Ana, Fernández Pedro Luis, Bresolí-Obach Roger, Blay Lidia, Julián Ibáñez Joan Francesc, Nonell Santi
Institut Químic de Sarrià, Universitat Ramon Llull, 08017, Barcelona, Spain.
Departments of General and Gastrointestinal Surgery, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Department of Surgery, 08916, Badalona, Spain.
Eur J Med Chem. 2025 Jun 5;290:117511. doi: 10.1016/j.ejmech.2025.117511. Epub 2025 Mar 14.
HER2-positive breast cancer, characterized by the overexpression of HER2 receptors, often develops resistance to trastuzumab, limiting its therapeutic efficacy. In this study, we explore the use of photodynamic therapy (PDT) with a trastuzumab-IRDye700DX photoimmunoconjugate (Tz-IR700) as a strategy to overcome trastuzumab resistance. Tz-IR700 combines the antibody's selectivity for the tumoral cells with the cytotoxic effect of IR700, induced by red light. Our results demonstrate that Tz-IR700 selectively accumulates in trastuzumab-resistant HER2-positive tumours (HCC1954) thereby enabling precise tumour localization by fluorescence imaging. Upon irradiation with red light, Tz-IR700 induces significant HCC1954 cell viability reduction both in vitro and in vivo, notably overcoming trastuzumab resistance in this HER2-positive breast cancer cell line. Mechanistic studies unequivocally demonstrate that the primary cytotoxic species is singlet oxygen. These findings suggest that Tz-IR700 could serve as a valuable treatment option for trastuzumab-resistant HER2-positive breast cancer and may also be used as an adjuvant to fluorescence-guided surgery, improving surgical outcomes and reducing the likelihood of tumour recurrence and metastasis.
人表皮生长因子受体2（HER2）阳性乳腺癌以HER2受体过表达为特征，常对曲妥珠单抗产生耐药性，限制了其治疗效果。在本研究中，我们探索使用光动力疗法（PDT），将曲妥珠单抗-IRDye700DX光免疫偶联物（Tz-IR700）作为克服曲妥珠单抗耐药性的策略。Tz-IR700将抗体对肿瘤细胞的选择性与红外700（IR700）的细胞毒性作用相结合，IR700的细胞毒性作用由红光诱导产生。我们的结果表明，Tz-IR700选择性地在对曲妥珠单抗耐药的HER2阳性肿瘤（HCC1954）中蓄积，从而能够通过荧光成像对肿瘤进行精确定位。在用红光照射后，Tz-IR700在体外和体内均能显著降低HCC1954细胞的活力，尤其克服了这种HER2阳性乳腺癌细胞系中的曲妥珠单抗耐药性。机制研究明确表明，主要的细胞毒性物质是单线态氧。这些发现表明，Tz-IR700可作为对曲妥珠单抗耐药的HER2阳性乳腺癌的一种有价值的治疗选择，也可作为荧光引导手术的辅助手段，改善手术效果，降低肿瘤复发和转移的可能性。
