Mickan Arite, Sarko Dikran, Haberkorn Uwe, Mier Walter
Department of Nuclear Medicine, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.
Curr Pharm Biotechnol. 2014;15(3):200-9. doi: 10.2174/138920101503140822101814.
Therapeutics are restricted from cellular internalization due to the biological barrier formed by the cell membrane. Especially for therapeutics with high molecular weight, strategies are required to enable delivery to intracellular targets. Cell-penetrating peptides (CPPs) represent a powerful tool to mediate the entry of large cargos such as proteins, siRNA and nanoparticles. The high diversity of CPPs is the prerequisite to use this class of carriers for various applications. However, therapies based on CPPs are hampered by their unfavorable pharmacokinetics, mainly dominated by their rapid renal clearance and their lack of specificity. Rational design is required to overcome these disadvantages and thereby exploits the actual potential of CPPs. We summarize and highlight the current state of knowledge with special emphasis on pharmacokinetics. The unclear internalization pathways of CPPs remain one of the main obstacles and therefore have been in the focus of research. In this review, several promising strategies such as the combination with targeting sequences, activatable CPPs and adjustment of the molecular weight are described. In addition, new absorption pathways such as nasal, pulmonary or transdermal uptake expand the applicability of CPPs and may be a promising prospect for clinical application.
由于细胞膜形成的生物屏障，治疗药物难以实现细胞内化。特别是对于高分子量的治疗药物，需要采取策略以实现向细胞内靶点的递送。细胞穿透肽（CPPs）是介导蛋白质、小干扰RNA和纳米颗粒等大分子货物进入细胞的有力工具。CPPs的高度多样性是将这类载体用于各种应用的前提条件。然而，基于CPPs的疗法受到其不良药代动力学的阻碍，主要表现为快速的肾脏清除和缺乏特异性。需要进行合理设计以克服这些缺点，从而发挥CPPs的实际潜力。我们总结并强调了当前的知识状态，特别关注药代动力学。CPPs尚不明确的内化途径仍然是主要障碍之一，因此一直是研究的重点。在本综述中，描述了几种有前景的策略，如与靶向序列结合、可激活的CPPs以及分子量的调整。此外，鼻内、肺部或经皮吸收等新的吸收途径扩展了CPPs的适用性，可能是临床应用的一个有前景的方向。
