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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Targeted drug delivery to tumor vasculature by a carbohydrate mimetic peptide
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Targeted drug delivery to tumor vasculature by a carbohydrate mimetic peptide

机译：碳水化合物模拟肽靶向药物递送至肿瘤血管

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摘要

Although n umerous carbohydrates play significant roles in mammalian cells, carbohydrate-based drug discovery has not been explored due to the technical difficulty of chemically synthesizing complex carbohydrate structures. Previously, we identified a series of carbohydrate mimetic peptides and found that a 7-mer peptide, designated I-peptide, inhibits hematogenous carbohydrate-dependent cancer cell colonization, During analysis of the endothelial surface receptor for l-peptide, we found that l-peptide bound to annexin 1 (Anxa 1). Because Anxal is a highly specific tumor vasculature surface marker, we hypothesized that an I-peptide-like peptide could target anticancer drugs to the tumor vasculature. This study identifies IFLLWQR peptide, designated IF7, as homing to tumors. When synthetic IF7 peptide was conjugated to fluorescent Alexa 488 (A488) and injected intravenously into tumor-bearing mice, IF7-A488 targeted tumors within minutes. IF7 conjugated to the potent anticancer drug SN-38 and injected intravenously into nude mice carrying human colon HCT116 tumors efficiently suppressed tumor growth at low dosages with no apparent side effects. These results suggest that IF7 serves as an efficient drug delivery vehicle by targeting Anxal expressed on the surface of tumor vasculature. Given its extremely specific tumor-targeting activity, IF7 may represent a clinically relevant vehicle for anticancer drugs.
机译：尽管许多碳水化合物在哺乳动物细胞中起重要作用，但是由于化学合成复杂碳水化合物结构的技术难度，尚未探索基于碳水化合物的药物发现。以前，我们鉴定了一系列碳水化合物模拟肽，并发现称为I肽的7-mer肽抑制血源性碳水化合物依赖性癌细胞的定殖。在分析L-肽的内皮表面受体时，我们发现L-与膜联蛋白1（Anxa 1）结合的多肽。因为Anxal是高度特异性的肿瘤血管表面标记，所以我们假设I肽样肽可以将抗癌药物靶向肿瘤血管。这项研究确定了IFLLWQR肽，称为IF7，归巢于肿瘤。将合成的IF7肽与荧光Alexa 488（A488）偶联并静脉注射到荷瘤小鼠中后，IF7-A488在几分钟内即可靶向肿瘤。 IF7与有效的抗癌药物SN-38结合并静脉注射到携带人结肠HCT116肿瘤的裸鼠体内，以低剂量有效抑制了肿瘤的生长，没有明显的副作用。这些结果表明IF7通过靶向在肿瘤脉管系统表面表达的Anxal而充当有效的药物递送载体。鉴于其极具针对性的肿瘤靶向活性，IF7可能代表了抗癌药物的临床相关载体。

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  • 作者

    Shingo Hatakeyama; Kazuhiro Sugihara; Toshiaki K. Shibata; Jun Nakayama; Tomoya O. Akama; Naoaki Tamura; Shuk-Man Wong; Andrey A. Bobkov; Yutaka Takano; Chikara Ohyama; Minoru Fukuda; Michiko N. Fukuda;

  • 作者单位

    Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;

    Department of Gynecology and Obstetrics, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan;

    Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;

    Department of Molecular Pathology, Shinshu University Graduate School of Medicine, Matsumoto 390-8621, Japan;

    Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;

    Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;

    Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;

    Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;

    Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;

    Department of Urology, Hirosaki University School of Medicine, Hirosaki 036-8243, Japan;

    Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;

    Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    angiogenesis; carbohydrate binding protein; geldanamycin; phage display; chemiluminescence;

    机译：血管生成;碳水化合物结合蛋白格尔德霉素噬菌体展示;化学发光;

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