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通过博来霉素的二糖部分实现肿瘤细胞的选择性靶向。

Selective tumor cell targeting by the disaccharide moiety of bleomycin.

机构信息

Center for BioEnergetics, Biodesign Institute, and Department of Chemistry & Biochemistry, Arizona State University, Tempe, Arizona 85287, USA.

出版信息

J Am Chem Soc. 2013 Feb 27;135(8):2883-6. doi: 10.1021/ja311090e. Epub 2013 Feb 13.

Abstract

In a recent study, the well-documented tumor targeting properties of the antitumor agent bleomycin (BLM) were studied in cell culture using microbubbles that had been derivatized with multiple copies of BLM. It was shown that BLM selectively targeted MCF-7 human breast carcinoma cells but not the "normal" breast cell line MCF-10A. Furthermore, it was found that the BLM analogue deglycobleomycin, which lacks the disaccharide moiety of BLM, did not target either cell line, indicating that the BLM disaccharide moiety is necessary for tumor selectivity. Not resolved in the earlier study were the issues of whether the BLM disaccharide moiety alone is sufficient for tumor cell targeting and the possible cellular uptake of the disaccharide. In the present study, we conjugated BLM, deglycoBLM, and BLM disaccharide to the cyanine dye Cy5**. It was found that the BLM and BLM disaccharide conjugates, but not the deglycoBLM conjugate, bound selectively to MCF-7 cells and were internalized. The same was also true for the prostate cancer cell line DU-145 (but not for normal PZ-HPV-7 prostate cells) and for the pancreatic cancer cell line BxPC-3 (but not for normal SVR A221a pancreas cells). The targeting efficiency of the disaccharide was only slightly less than that of BLM in MCF-7 and DU-145 cells and comparable to that of BLM in BxPC-3 cells. These results establish that the BLM disaccharide is both necessary and sufficient for tumor cell targeting, a finding with obvious implications for the design of novel tumor imaging and therapeutic agents.

摘要

在最近的一项研究中,使用经过衍生化处理的、带有多个拷贝抗肿瘤药物博来霉素(BLM)的微泡,在细胞培养中研究了 BLM 的明确肿瘤靶向特性。结果表明,BLM 选择性地靶向 MCF-7 人乳腺癌细胞,而不靶向“正常”乳腺细胞系 MCF-10A。此外,还发现缺乏 BLM 二糖部分的 BLM 类似物去糖博来霉素也不靶向任何一种细胞系,这表明 BLM 二糖部分对于肿瘤选择性是必需的。在早期的研究中,尚未解决的问题是,BLM 二糖部分本身是否足以用于肿瘤细胞靶向,以及二糖是否可能被细胞摄取。在本研究中,我们将 BLM、去糖 BLM 和 BLM 二糖与菁染料 Cy5**缀合。结果发现,BLM 和 BLM 二糖缀合物,但不是去糖 BLM 缀合物,选择性地与 MCF-7 细胞结合并被内化。这对于前列腺癌细胞系 DU-145(但不是正常 PZ-HPV-7 前列腺细胞)和胰腺癌细胞系 BxPC-3(但不是正常 SVR A221a 胰腺细胞)也是如此。二糖的靶向效率在 MCF-7 和 DU-145 细胞中仅略低于 BLM,与 BxPC-3 细胞中的 BLM 相当。这些结果表明,BLM 二糖对于肿瘤细胞靶向既是必需的,也是充分的,这对于新型肿瘤成像和治疗剂的设计具有明显的意义。

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