Tumor targeting with RGD peptide Ligands-Design of new molecular conjugates for Imaging and therapy of cancers
Tumor targeting with RGD peptide Ligands-Design of new molecular conjugates for Imaging and therapy of cancers
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DOI：
10.2174/187152007781668706
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发表时间：
2007-09-01
影响因子：
2.8
通讯作者：
Dumy, Pascal
中科院分区：
文献类型：
--
作者：
Garanger, Elisabeth;Boturyn, Didier;Dumy, Pascal
具有肿瘤靶向功能和携带细胞毒性成分的分子装置的发展将使化疗药物能够特异性地输送到恶性肿瘤组织，从而提高其局部疗效，同时限制其外周毒性。这样的分子载体可以为开发新的治疗方法铺平道路，对抗肿瘤发展的主角。根据这一概念，含有精氨酸-甘氨酸-天冬氨酸(RGD)三联体的多肽配体已被开发出来，它们对αvβ(3)整合素具有很强的亲和力和选择性，以靶向表达αvβ(3)受体的肿瘤相关细胞。在已确认的配体中，先导化合物是Kessler等人开发的环五肽c[-RGDf(NME)V-](Cilengitie)。(J.Med.化学，1999，42,3033-3040)。该化合物作为一种抗血管生成剂已进入临床试验阶段。进一步的研究方向是开发母体c[-RGDfK-]与常规化疗或与非侵入性成像技术的标记的分子偶合物。最近，含有RGD的多聚体化合物已被利用来通过受体介导的内吞作用来改善靶向潜力以及细胞膜的破裂。后者被构建在各种支架上(多聚赖氨酸或多谷氨酸、脂质体、纳米颗粒……)。我们的团队开发了一种结合了所有这些性质的化学系统，其中多价RGD靶向功能通过环肽模板与功能分子相关联。后者代表了一种用于肿瘤靶向、成像和治疗的相关非病毒载体。这篇综述描述了到目前为止开发的各种RGD配体的设计考虑，并概述了这些结构在癌症研究中的主要应用。
Development of molecular devices endowed with tumor-targeting functions and carrying cytotoxic components should enable the specific delivery of chemotherapeutics to malignant tissues, thus increasing their local efficacy while limiting their peripheral toxicity. Such molecular vectors can pave the way for the development of new classes of therapeutics, fighting against protagonists of neoplastic development. In line with this concept, peptide ligands containing the Arginine-Glycine-Aspartate (RGD) triad, which display a strong affinity and selectivity to the alpha v beta(3) integrin, have been developed to target the tumor-associated cells expressing the alpha v beta(3) receptors. Among the validated ligands, the leader compound is the cyclic pentapeptide c[-RGDf(NMe)V-] (Cilengitide) developed by kessler et al. (J. Med. Chem., 1999, 42, 3033-3040). This compound has entered phase If clinical trials as an anti-angiogenic agent. Further studies have been directed to develop molecular conjugates of the parent c[-RGDfK-] with conventional chemotherapeuties or with labels for non-invasive imaging technologies. More recently, multimeric RGD containing compounds have been exploited to improve the targeting potential as well as cell-membrane breaching, through receptor-mediated endocytosis. The latter have been constructed on various scaffolds (polylysines or polyglutamates, liposomes, nanoparticles...). Our group has developed a chemical system combining all these properties where multivalent RGD targeting functions are associated with functional molecules through a cyclopeptide template. The latter represents a relevant non-viral vector for tumor targeting, imaging and therapy. This review describes the considerations for the design of the diverse RGD ligands developed so far and reports an overview of the main applications of these structures in cancer research.