使用异二肽甘氨酸-药物偶联物进行肿瘤靶向
Tumor Targeting with an isoDGR-Drug Conjugate.
作者信息
Zanella Simone, Angerani Simona, Pina Arianna, López Rivas Paula, Giannini Clelia, Panzeri Silvia, Arosio Daniela, Caruso Michele, Gasparri Fabio, Fraietta Ivan, Albanese Clara, Marsiglio Aurelio, Pignataro Luca, Belvisi Laura, Piarulli Umberto, Gennari Cesare
机构信息
Dipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi 19, 20133, Milano, Italy.
Dipartimento di Scienza e Alta Tecnologia, Università degli Studi dell'Insubria, Via Valleggio 11, 22100, Como, Italy.
出版信息
Chemistry. 2017 Jun 12;23(33):7910-7914. doi: 10.1002/chem.201701844. Epub 2017 May 26.
Herein we report the first example of an isoDGR-drug conjugate (2), designed to release paclitaxel selectively within cancer cells expressing integrin α β . Conjugate 2 was synthesized by connecting the isoDGR peptidomimetic 5 with paclitaxel via the lysosomally cleavable Val-Ala dipeptide linker. Conjugate 2 displayed a low nanomolar affinity for the purified integrin α β receptor (IC =11.0 nm). The tumor targeting ability of conjugate 2 was assessed in vitro in anti-proliferative assays on two isogenic cancer cell lines characterized by different integrin α β expression: human glioblastoma U87 (α β +) and U87 β -KO (α β -). The isoDGR-PTX conjugate 2 displayed a remarkable targeting index (TI=9.9), especially when compared to the strictly related RGD-PTX conjugate 4 (TI=2.4).
在此，我们报道了异天冬酰胺-甘氨酸-精氨酸（isoDGR）-药物偶联物（2）的首个实例，其设计目的是在表达整合素αβ的癌细胞内选择性释放紫杉醇。偶联物2通过可被溶酶体裂解的缬氨酸-丙氨酸二肽接头将异天冬酰胺-甘氨酸-精氨酸（isoDGR）拟肽5与紫杉醇连接而成。偶联物2对纯化的整合素αβ受体表现出低纳摩尔亲和力（IC = 11.0 nM）。在针对两种具有不同整合素αβ表达特征的同基因癌细胞系进行的抗增殖测定中，对体外评估了偶联物2的肿瘤靶向能力：人胶质母细胞瘤U87（αβ +）和U87 β-KO（αβ -）。异天冬酰胺-甘氨酸-精氨酸-紫杉醇（isoDGR-PTX）偶联物2显示出显著的靶向指数（TI = 9.9），特别是与密切相关的RGD-PTX偶联物4（TI = 2.4）相比时。
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