Huang Rong, Sun Yu, Zhang Xiang-yang, Sun Bai-wang, Wang Qiu-cui, Zhu Jin
School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210096, China.
School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210096, China; School of Pharmacy, Wannan Medical College, Wuhu 241002, China.
Biomed Pharmacother. 2015 Jul;73:116-22. doi: 10.1016/j.biopha.2015.05.013. Epub 2015 Jun 4.
Platinum-based drugs have been widely used for the treatment of malignant tumors. However, their applications are limited by severe side effects for their lack of selectivity for cancer cells. The development of antibody drug conjugates (ADCs) have provided a platform to reduce drug toxicity and improve drug efficacy. Here we describe a nover conjugate comprising of Herceptin (an anti-HER2 antibody) and platinum drug via a cathepsin B cleavable dipetide for enhancing drug accumulation and HER2-positive cancer cell specific delivery. This conjugate is believed to be cleaved by cathepsin B, leading to a 1,6-elimination reaction and activation of drug release. Herceptin-Pt(II) is evaluated to have approximately loaded with 6.4 moles platinum drugs per mole of antibody. We demonstrate that Herceptin-Pt(II) retain high and selective binding affinity for HER2 protein and HER2-positive SK-BR-3 cancer cells. The in vitro cytotoxicity tests indicate that Herceptin-Pt(II) exhibits much higher cytotoxicity than oxaliplatin against SK-BR-3 cells. More importantly, Herceptin-Pt(II) shows no obvious inhibition against the growth of both MCF-7 and MDA-MB-231 cells, which express lower levels of HER2. Furthermore, compared with free oxaliplatin, Herceptin significantly improved the cellular uptake of platinum drugs in SK-BR-3 cells. In summary, Herceptin-platinum (II) conjugate is a remarkable and potent platform for efficient and cancer cell specific delivery.
铂类药物已被广泛用于治疗恶性肿瘤。然而，由于其对癌细胞缺乏选择性，其应用受到严重副作用的限制。抗体药物偶联物（ADCs）的发展提供了一个降低药物毒性和提高药物疗效的平台。在此，我们描述了一种新型偶联物，它由赫赛汀（一种抗HER2抗体）和铂类药物通过组织蛋白酶B可裂解的二肽组成，用于增强药物积累和HER2阳性癌细胞的特异性递送。这种偶联物被认为可被组织蛋白酶B裂解，导致1,6-消除反应并激活药物释放。经评估，每摩尔抗体的赫赛汀-Pt(II)大约负载了6.4摩尔铂类药物。我们证明赫赛汀-Pt(II)对HER2蛋白和HER2阳性SK-BR-3癌细胞保持高选择性结合亲和力。体外细胞毒性试验表明，赫赛汀-Pt(II)对SK-BR-3细胞的细胞毒性比奥沙利铂高得多。更重要的是，赫赛汀-Pt(II)对HER2表达水平较低的MCF-7和MDA-MB-231细胞的生长没有明显抑制作用。此外，与游离奥沙利铂相比，赫赛汀显著提高了SK-BR-3细胞中铂类药物的细胞摄取。总之，赫赛汀-铂(II)偶联物是一个用于高效和癌细胞特异性递送的卓越且有效的平台。
