The insides of cells can be viewed as a treasure trove of targets for therapeutic intervention of diseases or as deposits for contrasting agents. Increasingly the molecules that need to be delivered to the inside of cells for these purposes are macromolecular and membrane impermeable. Cell penetrating peptides (CPPs) have proven abilities to deliver a range of macromolecular cargo into cells thus raising their profile as potential delivery vectors for wide-ranging applications. There is evidence to suggest that CPPs first enter cells through endocytosis and that cytosolic delivery is mediated across endolysosomal membranes. Their capacity to do this, over direct plasma membrane translocation, is likely to depend on the nature and size of the cargo. Cells use a range of endocytic routes to facilitate entry from well characterised pathways regulated by clathrin to more recently discovered and less characterised pathways regulated by clathrin independent mechanisms. These are likely to determine the intracellular fate of cell delivery vectors including those based on cell penetrating peptides. Thus gaining accurate knowledge of their endocytic uptake and traffic is an important characterisation criteria for progress in this field. This review describes the different endocytic pathways that have been identified in mammalian cells and specific reports that have studied the uptake mechanisms and endocytic traffic of cell penetrating peptides and their associated cargo. These cargoes range from short peptides to an increasing library of nanoparticles such as quantum dots, liposomes and polymeric dendrimers. The studies highlight the effectiveness of cell penetrating peptides for delivering these entities into a diverse array of cell types using different endocytic pathways. This is shown using microscopy based colocalisation analysis with the few specific endocytic probes available, and chemical inhibitors of endocytosis that suffer from lack of specificity. Overall, more specific probes, inhibitors and novel technologies are required for accurate characterisation of cellular dynamics of cell penetrating peptide conjugates thus allowing them to reach their full potential as vectors for therapeutics and other payloads.

译文

细胞内部可以被视为疾病治疗干预靶标的宝库或对比剂的沉积物。为了这些目的,需要递送到细胞内部的分子越来越多地是大分子和膜不可渗透的。细胞穿透肽 (cpp) 已被证明具有将一系列大分子货物递送到细胞中的能力,从而提高了它们作为广泛应用的潜在递送载体的特性。有证据表明,CPPs首先通过胞吞作用进入细胞,并且胞质递送是跨内溶酶体膜介导的。通过直接质膜移位,它们的能力可能取决于货物的性质和大小。细胞使用一系列内吞途径来促进从网格蛋白调节的特征良好的途径进入到最近发现的,由网格蛋白独立机制调节的特征较少的途径。这些可能会确定细胞递送载体 (包括基于细胞穿透肽的载体) 的细胞内命运。因此,获得有关其内吞吸收和流量的准确知识是该领域进展的重要表征标准。这篇综述描述了在哺乳动物细胞中发现的不同的内吞途径,以及研究了细胞穿透肽及其相关货物的摄取机制和内吞运输的具体报道。这些货物的范围从短肽到越来越多的纳米颗粒库,例如量子点,脂质体和聚合物树状大分子。研究强调了细胞穿透肽使用不同的内吞途径将这些实体递送到各种细胞类型的有效性。这是使用基于显微镜的共定位分析和少数可用的特定内吞探针以及缺乏特异性的内吞作用化学抑制剂来显示的。总的来说,需要更具体的探针、抑制剂和新技术来准确表征细胞穿透肽缀合物的细胞动力学,从而使它们能够作为治疗和其他有效载荷的载体达到其全部潜力。

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