Istituto di Scienze e Tecnologie Molecolari (ISTM), CNR, Via C. Golgi 19, I-20133 Milan, Italy.
Università degli Studi di Milano, Dipartimento di Chimica, Via C. Golgi 19, I-20133 Milan, Italy.
Adv Drug Deliv Rev. 2016 Feb 1;97:111-43. doi: 10.1016/j.addr.2015.12.001. Epub 2015 Dec 10.
The research of integrin-targeted anticancer agents has recorded important advancements in ingenious design of delivery systems, based either on the prodrug approach, or on nanoparticle carriers, but for now, none of these has reached a clinical stage of development. Past work in this area has been extensively reviewed by us and others. Thus, the purpose and scope of the present review is to survey the advancement reported in the last 3years, with focus on innovative delivery systems that appear to afford openings for future developments. These systems exploit the labelling with conventional and novel integrin ligands for targeting the interface of cancer cells and of endothelial cells involved in cancer angiogenesis, with the proteins of the extracellular matrix, in the circulation, in tissues, and in tumour stroma, as the site of progression and metastatic evolution of the disease. Furthermore, these systems implement the expertise in the development of nanomedicines to the purpose of achieving preferential biodistribution and uptake in cancer tissues, internalisation in cancer cells, and release of the transported drugs at intracellular sites. The assessment of the value of controlling these factors, and their combination, for future developments requires support of biological testing in appropriate mechanistic models, but also imperatively demand confirmation in therapeutically relevant in vivo models for biodistribution, efficacy, and lack of off-target effects. Thus, among many studies, we have tried to point out the results supported by relevant in vivo studies, and we have emphasised in specific sections those addressing the medical needs of drug delivery to brain tumours, as well as the delivery of oligonucleotides modulating gene-dependent pathological mechanism. The latter could constitute the basis of a promising third branch in the therapeutic armamentarium against cancer, in addition to antibody-based agents and to cytotoxic agents.
整合素靶向抗癌药物的研究在设计基于前药方法或纳米颗粒载体的递药系统方面取得了重要进展，但到目前为止，这些方法都没有达到临床开发阶段。我们和其他人已经对该领域的过去工作进行了广泛的综述。因此，本综述的目的和范围是调查过去 3 年报告的进展，重点是具有创新性的递药系统，这些系统似乎为未来的发展提供了机会。这些系统利用传统和新型整合素配体进行标记，以靶向参与癌症血管生成的癌细胞和内皮细胞与细胞外基质蛋白的界面，以及在循环、组织和肿瘤基质中的进展和转移演变的部位。此外，这些系统将纳米医学的专业知识应用于实现优先在癌症组织中分布和摄取、在癌细胞中内化以及在细胞内部位释放运输药物的目的。评估控制这些因素及其组合对未来发展的价值需要在适当的机制模型中进行生物测试的支持，但也迫切需要在治疗相关的体内模型中进行生物分布、疗效和无脱靶效应的确认。因此，在许多研究中，我们试图指出得到相关体内研究支持的结果，并在特定部分强调那些针对向脑肿瘤输送药物以及输送调节基因依赖性病理机制的寡核苷酸的研究。除了基于抗体的药物和细胞毒性药物之外，后者可能成为癌症治疗武器库中的一个有前途的第三条分支的基础。
