PDF(Pubmed)
Abstract：
Malignant melanoma is one of the most aggressive and resistant tumor types, with high metastatic properties. Because of the lack of suitable chemotherapeutic agents for treatment, the 5-year survival rate of melanoma patients with regional and distant metastases is lower than 10%. Targeted tumor therapy that provides several promising results might be a good option for the treatment of malignant melanomas. Our goal was to develop novel melanoma-specific peptide-drug conjugates for targeted tumor therapy. Melanocortin-1-receptor (MC1R) is a cell surface receptor responsible for melanogenesis and it is overexpressed on the surface of melanoma cells, providing a good target. Its native ligand, α-MSH (α-melanocyte-stimulating hormone) peptide, or its derivatives, might be potential homing devices for this purpose. Therefore, we prepared three α-MSH derivative-daunomycin (Dau) conjugates and their in vitro and in vivo antitumor activities were compared. Dau has an autofluorescence property; therefore, it is suitable for preparing conjugates for in vitro (e.g., cellular uptake) and in vivo experiments. Dau was attached to the peptides via a non-cleavable oxime linkage that was applied efficiently in our previous experiments, resulting in conjugates with high tumor growth inhibition activity. The results indicated that the most promising conjugate was the compound in which Dau was connected to the side chain of Lys (Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2). The highest cellular uptake by melanoma cells was demonstrated using the compound, with the highest tumor growth inhibition detected both on mouse (38.6% on B16) and human uveal melanoma (55% on OMC-1) cells. The effect of the compound was more pronounced than that of the free drug.
摘要：
恶性黑色素瘤是最具侵袭性和耐药性的肿瘤类型之一，具有高转移特性。由于缺乏合适的化疗药物，有区域和远处转移的黑色素瘤患者的5年生存率低于10%.提供几个有希望的结果的靶向肿瘤治疗可能是治疗恶性黑色素瘤的好选择。我们的目标是开发用于靶向肿瘤治疗的新型黑色素瘤特异性肽-药物缀合物。黑皮质素-1受体（MC1R）是负责黑素生成的细胞表面受体，在黑色素瘤细胞表面过度表达，提供一个好的目标。它的天然配体，α-MSH(α-黑素细胞刺激素)肽,或其衍生物，可能是为此目的的潜在归位设备。因此,我们制备了三种α-MSH衍生物-道诺霉素（Dau）缀合物，并比较了它们的体外和体内抗肿瘤活性。Dau具有自发荧光性质；因此，它适用于制备用于体外的缀合物(例如，细胞摄取)和体内实验。Dau通过不可切割的肟键连接到肽上，该键在我们先前的实验中有效应用。导致具有高肿瘤生长抑制活性的缀合物。结果表明，最有希望的缀合物是其中Dau连接到Lys（Ac-SYSNleEHFRWGK（Dau=Aoa）PV-NH2）侧链的化合物。使用该化合物证明了黑素瘤细胞的最高细胞摄取，在小鼠（B16为38.6％）和人葡萄膜黑色素瘤（OMC-1为55％）细胞中均检测到最高的肿瘤生长抑制作用。该化合物的作用比游离药物的作用更明显。
