Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
Biochemistry (Mosc). 2009 Dec;74(13):1567-74. doi: 10.1134/s0006297909130094.
This review deals with artificial modular nanotransporters (MNT) of polypeptide nature for drug delivery into target cells and then into a specified cell compartment like the nucleus. The developed approach is based on the use of intracellular transport processes characteristic of practically all cells, including cancer cells. The first MNT module ligand carries out a double function: specific recognition of a cancer target cell and penetration into the cell via receptor-mediated endocytosis. The movement of the MNT within the cell along this path specifies the need to supply the MNT with an endosomolytic module making it possible to leave the endocytotic pathway before getting into lysosomes in order to have time for interaction with importins. For this purpose, a polypeptide fragment able to make defects in membranes only at the pH of endosomes is used as the second module. Delivery into the cell nucleus is provided by the third module containing an amino acid sequence of nuclear localization, "recognized" by importins located in the hyaloplasm. And finally, the fourth module, a carrier for joining the transported drug, is incorporated into the MNT. Depending on the type of ligand module, MNT for different target cell types have been produced. Each module retains its activity within the MNT, ligand modules bind target receptors with high affinity, while the module with the nuclear localization sequence binds importins. The endosomolytic module forms pores in lipid membranes through which MNT are able to leave acidifying cell compartments (endosomes). Modules within MNT can be replaced or transposed, which makes it possible to use them for delivery of different drugs into different target cells and their compartments. It was shown that photosensitizers and radionuclides used for cancer therapy acquire pronounced cell specificity as well as the 10-1000-fold higher efficiency resulting from their delivery into the most vulnerable compartment--the cell nucleus.
本文综述了人工多肽类模块化纳米转运体（MNT）用于将药物递送至靶细胞，然后递送至特定的细胞区室，如细胞核。所开发的方法基于利用包括癌细胞在内的几乎所有细胞都具有的细胞内运输过程。第一个 MNT 模块配体执行双重功能：特异性识别癌细胞靶标和通过受体介导的内吞作用穿透细胞。MNT 在细胞内沿着该途径的运动指定需要供应具有内体溶酶体模块的 MNT，使其能够在进入溶酶体之前离开内吞途径，以便有时间与导入蛋白相互作用。为此，使用能够仅在内涵体的 pH 值下在膜上产生缺陷的多肽片段作为第二个模块。通过包含核定位序列的第三个模块提供递送至细胞核的能力，该序列被位于透明质体中的导入蛋白“识别”。最后，将包含运输药物的氨基酸序列的第四模块掺入 MNT 中。根据配体模块的类型，已经生产出用于不同靶细胞类型的 MNT。MNT 中的每个模块都保留其活性，配体模块以高亲和力结合靶受体，而具有核定位序列的模块与导入蛋白结合。内体溶酶体模块在脂质膜中形成孔，MNT 能够通过这些孔离开酸化的细胞区室（内涵体）。MNT 内的模块可以被替换或转位，这使得能够将它们用于将不同的药物递送至不同的靶细胞及其区室。已经表明，用于癌症治疗的光敏剂和放射性核素获得了明显的细胞特异性，以及由于递送至最脆弱的区室 - 细胞核而导致的 10-1000 倍的更高效率。
