Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
Department of Biomedical Science and Biofilms - Research Center for Biointerfaces, Faculty of Health and Society, Malmö University, Per Albin Hanssons väg 35, 214 32, Malmö, Sweden.
Sci Rep. 2018 Apr 20;8(1):6327. doi: 10.1038/s41598-018-24154-z.
The demand for highly efficient macromolecular drugs, used in the treatment of many severe diseases, is continuously increasing. However, the hydrophilic character and large molecular size of these drugs significantly limit their ability to permeate across cellular membranes and thus impede the drugs in reaching their target sites in the body. Cell-penetrating peptides (CPP) have gained attention as promising drug excipients, since they can facilitate drug permeation across cell membranes constituting a major biological barrier. Fluorophores are frequently covalently conjugated to CPPs to improve detection, however, the ensuing change in physico-chemical properties of the CPPs may alter their biological properties. With complementary biophysical techniques, we show that the mode of biomembrane interaction may change considerably upon labeling of the CPP penetratin (PEN) with a fluorophore. Fluorophore-PEN conjugates display altered modes of membrane interaction with increased insertion into the core of model cell membranes thereby exerting membrane-thinning effects. This is in contrast to PEN, which localizes along the head groups of the lipid bilayer, without affecting the thickness of the lipid tails. Particularly high membrane disturbance is observed for the two most hydrophobic PEN conjugates; rhodamine B or 1-pyrene butyric acid, as compared to the four other tested fluorophore-PEN conjugates.
对于用于治疗许多严重疾病的高效大分子药物的需求不断增加。然而，这些药物的亲水性和较大的分子尺寸极大地限制了它们穿过细胞膜的能力，从而阻碍了药物到达体内的靶部位。细胞穿透肽 (CPP) 作为有前途的药物赋形剂引起了人们的关注，因为它们可以促进药物穿过构成主要生物屏障的细胞膜的渗透。荧光团通常与 CPP 共价连接以提高检测效果，然而，CPP 的物理化学性质的这种变化可能会改变它们的生物学性质。通过互补的生物物理技术，我们表明，在将荧光团标记到 CPP penetratin (PEN) 上后，生物膜相互作用的模式可能会发生很大变化。荧光团-PEN 缀合物显示出与模型细胞膜相互作用的模式发生改变，插入到细胞膜的核心中，从而产生膜变薄的效果。这与 PEN 形成对比，PEN 沿脂质双层的头基团定位，而不影响脂质尾部的厚度。与其他四种测试的荧光团-PEN 缀合物相比，对于两种疏水性最高的 PEN 缀合物（罗丹明 B 或 1-对苯丁酸），观察到特别高的膜干扰。
