Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, 1985 Zonal Ave, Los Angeles, CA 90033, United States.
J Control Release. 2012 Mar 28;158(3):357-61. doi: 10.1016/j.jconrel.2012.01.039. Epub 2012 Feb 1.
A recently designed nanoconstruct was engineered using recombinant technology to contain a cell-penetrating peptide (CPP), i.e. Model Amphipathic Peptide (MAP), attached to a pH-sensitive masking peptide sequence. CPPs such as MAP exhibit unique internalization properties which enable them to deliver attached bioactive molecules, including proteins and peptides, into the cytosolic or nuclear compartment of cells. However, their application in drug delivery is limited due to lack of specificity, as they are widely distributed in most tissues following in vivo administration. In order to overcome this hurdle, a highly pH-sensitive histidine-glutamic acid (HE) copolymer sequence was linked to MAP to prevent non-specific internalization of the construct in non-target cells. Our results show that this nanoconstruct is highly pH-sensitive in a mildly acidic pH, exhibiting high binding and internalization at pH 6.8 and below, but low binding and internalization at pH>7. This unique sensitivity in the mildly acidic pH range can be applied to targeting the activation of membrane permeable properties in mildly acidic pH environments, such as the surface of tumor cells or in the early endosomes of target cells. Therefore, the design could lead to a significant advancement in the application of CPPs and in the therapeutic potential of the biotechnology field.
最近设计的一种纳米结构是使用重组技术制造的，其中包含一个穿透细胞的肽（CPP），即模型两亲肽（MAP），连接到 pH 敏感的掩蔽肽序列上。MAP 等 CPP 具有独特的内化特性，使它们能够将附着的生物活性分子，包括蛋白质和肽，递送到细胞的细胞质或核区室中。然而，由于缺乏特异性，它们在药物输送中的应用受到限制，因为它们在体内给药后广泛分布在大多数组织中。为了克服这一障碍，将高度 pH 敏感的组氨酸-谷氨酸（HE）共聚物序列连接到 MAP 上，以防止构建体在非靶细胞中发生非特异性内化。我们的结果表明，这种纳米结构在轻度酸性 pH 下具有高度的 pH 敏感性，在 pH 6.8 及以下时表现出高结合和内化，但在 pH>7 时结合和内化较低。这种在轻度酸性 pH 范围内的独特敏感性可用于靶向在轻度酸性 pH 环境中激活膜通透性特性，例如肿瘤细胞表面或靶细胞的早期内体。因此，该设计可能会在 CPP 的应用和生物技术领域的治疗潜力方面取得重大进展。
