Foerg Christina, Merkle Hans P
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland.
J Pharm Sci. 2008 Jan;97(1):144-62. doi: 10.1002/jps.21117.
The cell membrane poses a substantial hurdle to the use of pharmacologically active biomacromolecules that are not per se actively translocated into cells. An appealing approach to deliver such molecules involves tethering or complexing them with so-called cell penetrating peptides (CPPs) that are able to cross the plasma membrane of mammalian cells. The CPP approach is currently a major avenue in engineering delivery systems that are hoped to mediate the non-invasive import of problematic cargos into cells. The large number of different cargo molecules that have been efficiently delivered by CPPs ranges from small molecules to proteins and even liposomes and particles. With respect to the involved mechanism(s) there is increasing evidence for endocytosis as a major route of entry. Moreover, in terms of intracellular trafficking, current data argues for the transport to acidic early endosomal compartments with cytosolic release mediated via retrograde delivery through the Golgi apparatus and the endoplasmic reticulum. The focus of this review is to revisit the performance of cell penetrating peptides for drug delivery. To this aim we cover both accomplishments and failures and report on new prospects of the CPP approach. Besides a selection of successful case histories of CPPs we also review the limitations of CPP mediated translocation. In particular, we comment on the impact of (i) metabolic degradation, (ii) the cell line and cellular differentiation state dependent uptake of CPPs, as well as (iii) the regulation of their endocytic traffic by Rho-family GTPases. Further on, we aim at the identification of promising niches for CPP application in drug delivery. In this context, as inspired by current literature, we focus on three principal areas: (i) the delivery of antineoplastic agents, (ii) the delivery of CPPs as antimicrobials, and (iii) the potential of CPPs to target inflammatory tissues.
细胞膜对使用本身不能主动转运进入细胞的药理活性生物大分子构成了重大障碍。递送此类分子的一种有吸引力的方法是将它们与所谓的细胞穿透肽（CPP）连接或复合，这些肽能够穿过哺乳动物细胞的质膜。CPP方法目前是工程递送系统的主要途径，有望介导有问题的货物非侵入性地进入细胞。已通过CPP有效递送的大量不同货物分子从小分子到蛋白质，甚至脂质体和颗粒。关于所涉及的机制，越来越多的证据表明内吞作用是主要的进入途径。此外，就细胞内运输而言，目前的数据表明运输到酸性早期内体区室，通过高尔基体和内质网的逆行递送介导胞质释放。本综述的重点是重新审视细胞穿透肽在药物递送方面的性能。为此，我们涵盖了成功与失败，并报告了CPP方法的新前景。除了精选的CPP成功案例外，我们还回顾了CPP介导的易位的局限性。特别是，我们评论了（i）代谢降解、（ii）细胞系和细胞分化状态依赖性CPP摄取以及（iii）Rho家族GTPases对其胞吞运输的调节的影响。此外，我们旨在确定CPP在药物递送中应用的有前景的领域。在这种背景下，受当前文献的启发，我们关注三个主要领域：（i）抗肿瘤药物的递送、（ii）CPP作为抗菌剂的递送以及（iii）CPP靶向炎症组织的潜力。
