Vozgirdaite Daiva, Allard-Vannier Emilie, Velge-Roussel Florence, Douez Emmanuel, Jolivet Louis, Boursin Fanny, Chourpa Igor, Aubrey Nicolas, Hervé-Aubert Katel
UPR 4301 CBM, CNRS, NMNS Department, University of Tours, 37200 Tours, France.
Pharmacy Department, University Hospital Center of Tours, 37200 Tours, France.
Nanoscale. 2025 Feb 13;17(7):4058-4072. doi: 10.1039/d4nr03224a.
Trophoblast cell-surface antigen 2 (TROP 2) has re-emerged as a promising biomarker in triple-negative breast cancer (TNBC), with high overexpression in many TNBC cases. However, despite its potential and approval as an antibody-drug-conjugate for TNBC treatment, TROP 2-targeted delivery systems are currently underexplored. Therefore, this study was aimed at exploiting the potential of TROP 2 targeting by encapsulating metformin (Met), an antidiabetic drug associated with tumor growth inhibitory properties, inside liposomes decorated with TROP 2-targeting single-chain variable fragments (scFvs). The optimization of scFv grafting resulted in Met-immunoliposomes with an average diameter of less than 200 nm, low polydispersity index (∼0.1), negative surface charge (<-10 mV), high Met drug loading (>150 mg g), and high affinity towards TROP 2 binding. Furthermore, Met-immunoliposomes were reproducible, and the scFv conjugation was stable in the presence of serum for five days. Their cellular uptake increased 4 folds in two-dimensional and 9 folds in three-dimensional TNBC models owing to the high affinity towards TROP 2 binding. Finally, it was observed that the therapeutic effect of Met in suppressing cancer cell growth and proliferation was superior when using anti-TROP 2 scFv-grafted Met-immunoliposomes, which completely stopped the spheroid growth and inhibited the expression of adenosine triphosphate. This study is one of the first reports to explore the combination of nanoparticle-based drug delivery systems to target the TROP 2 protein in TNBC, and to the best of our knowledge, this is the first report to specifically combine the use of scFvs with TROP 2 targeting to deliver therapeutics for TNBC treatment.
滋养层细胞表面抗原2（TROP 2）已再度成为三阴性乳腺癌（TNBC）中一种很有前景的生物标志物，在许多TNBC病例中高度过表达。然而，尽管其具有潜力且已获批作为TNBC治疗的抗体药物偶联物，但目前对TROP 2靶向递送系统的研究仍不足。因此，本研究旨在通过将二甲双胍（Met）封装在装饰有TROP 2靶向单链可变片段（scFv）的脂质体内，来挖掘TROP 2靶向的潜力，二甲双胍是一种具有肿瘤生长抑制特性的抗糖尿病药物。scFv嫁接的优化产生了平均直径小于200 nm、低多分散指数（约0.1）、负表面电荷（<-10 mV）、高Met载药量（>150 mg/g）且对TROP 2结合具有高亲和力的Met免疫脂质体。此外，Met免疫脂质体具有可重复性，并且scFv偶联物在血清存在下五天内保持稳定。由于对TROP 2结合具有高亲和力，它们在二维TNBC模型中的细胞摄取增加了4倍，在三维TNBC模型中增加了9倍。最后，观察到当使用抗TROP 2 scFv嫁接的Met免疫脂质体时，Met在抑制癌细胞生长和增殖方面的治疗效果更佳，该脂质体完全阻止了球体生长并抑制了三磷酸腺苷的表达。本研究是最早探索基于纳米颗粒的药物递送系统靶向TNBC中TROP 2蛋白的报告之一，据我们所知，这是首次专门将scFv与TROP 2靶向结合用于递送TNBC治疗药物的报告。
