Section of Pharmaceutical Sciences, University of Lausanne, University of Geneva, Geneva, Switzerland.
Curr Med Chem. 2011;18(12):1785-805. doi: 10.2174/092986711795496782.
Clinical studies provide overwhelming evidence for the importance of proteolytic imbalance and the upregulation of diverse protease classes in diseases such as cancer and arthritis. While the complex nature of proteolytic networks has hampered the development of protease inhibitors for these indications, aberrant enzyme activity could be successfully exploited for the development of proteasesensitive drug delivery systems and fluorescent in vivo imaging agents. More recently, these concepts have also been translated into photomedical applications to develop dual modality prodrugs for the simultaneous treatment and imaging of disease. After an introductory overview of proteases and their role in cancer, we present and discuss different strategies to exploit upregulated protease activity for the development of drug delivery systems, fluorescent in vivo reporter probes, and photosensitizer-prodrugs with respect to their potential and limitations. The main approaches used for targeting proteases in all three areas can be roughly divided into peptide-based and macromolecular strategies. Both involve the use of a short, peptide-based protease substrate, which is either directly tagged to the therapeutic agent or dye/quencher pair, or alternatively, serves as a linker between the polymeric carrier and a functional unit. In the latter case, the pharmacokinetic properties of peptide-based protease-sensitive prodrugs and imaging probes can be further ameliorated by the passive targeting capacity of macromolecular drug delivery systems for neoplastic and inflammatory lesions.
临床研究提供了压倒性的证据，证明蛋白水解失衡和多种蛋白酶类别的上调在癌症和关节炎等疾病中的重要性。尽管蛋白水解网络的复杂性阻碍了这些适应症的蛋白酶抑制剂的开发，但异常的酶活性可以成功地用于开发蛋白酶敏感的药物传递系统和荧光体内成像剂。最近，这些概念也被转化为光医学应用，以开发用于疾病的同时治疗和成像的双重模态前药。在介绍蛋白酶及其在癌症中的作用之后，我们提出并讨论了利用上调的蛋白酶活性开发药物传递系统、荧光体内报告探针和光致敏剂前药的不同策略，以及它们的潜力和局限性。用于靶向这三个领域中所有蛋白酶的主要方法大致可以分为基于肽和基于大分子的策略。这两种策略都涉及使用短的基于肽的蛋白酶底物，该底物要么直接标记到治疗剂或染料/猝灭剂对上，要么作为聚合物载体和功能单元之间的连接物。在后一种情况下，基于肽的蛋白酶敏感前药和成像探针的药代动力学性质可以通过大分子药物传递系统对肿瘤和炎症病变的被动靶向能力进一步改善。
