Biological evaluation of a novel Herceptin-platinum (II) conjugate for efficient and cancer cell specific delivery
Biological evaluation of a novel Herceptin-platinum (II) conjugate for efficient and cancer cell specific delivery
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对新型赫赛汀-铂 (II) 缀合物进行高效和癌细胞特异性递送的生物学评价
DOI：
10.1016/j.biopha.2015.05.013
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发表时间：
2015-07-01
影响因子：
7.5
通讯作者：
Zhu, Jin
中科院分区：
文献类型：
--
作者：
Huang, Rong;Sun, Yu;Zhu, Jin
铂类药物已广泛用于治疗恶性肿瘤。然而，由于缺乏对癌细胞的选择性，它们的应用受到严重副作用的限制。抗体药物偶联物（ADC）的发展为降低药物毒性和提高药物疗效提供了平台。在这里，我们描述了一种由赫赛汀（一种抗 HER2 抗体）和铂类药物通过组织蛋白酶 B 可裂解二肽组成的 nover 缀合物，用于增强药物积累和 HER2 阳性癌细胞特异性递送。这种结合物被认为被组织蛋白酶 B 裂解，导致 1,6-消除反应并激活药物释放。据评估，赫赛汀-Pt(II) 每摩尔抗体大约负载 6.4 摩尔铂类药物。我们证明 Herceptin-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，Herceptin-Pt(II) 对 SK-BR-3 细胞的细胞毒性远高于奥沙利铂。更重要的是，Herceptin-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的抑制作用。此外，与游离奥沙利铂相比，赫赛汀显着提高了SK-BR-3细胞对铂类药物的细胞摄取。总之，赫赛汀-铂 (II) 缀合物是一个卓越且有效的平台，可用于高效且癌细胞特异性的递送。 (C) 2015 Elsevier Masson SAS。版权所有。
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. (C) 2015 Elsevier Masson SAS. All rights reserved.