title: Biological evaluation of a novel Herceptin-platinum (II) conjugate for efficient and cancer cell specific delivery.
abstract: 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.
authors.affiliation: School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210096, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Huang
authors.affiliation: School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210096, China; School of Pharmacy, Wannan Medical College, Wuhu 241002, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Laboratory of Organic Chemistry, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Xiang-yang
authors.initials: XY
authors.lastname: Zhang
authors.affiliation: School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210096, China. Electronic address: chmsunbw@seu.edu.cn.
authors.forename: Bai-wang
authors.initials: BW
authors.lastname: Sun
authors.affiliation: School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210096, China.
authors.forename: Qiu-cui
authors.initials: QC
authors.lastname: Wang
authors.affiliation: Huadong Medical Institute of Biotechniques, Nanjing 210096, China. Electronic address: zhujin1968@njmu.edu.cn.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D017671:Platinum Compounds / Q000008:administration & dosage / Q000138:chemical synthesis*; D000068878:Trastuzumab / Q000008:administration & dosage / Q000737:chemistry*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D017671:Platinum Compounds; D000068878:Trastuzumab
keywords: Drug delivery; ELISA; Herceptin; In vitro cytotoxicity; Platinum drugs