Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.
Int J Radiat Biol. 2023;99(1):28-38. doi: 10.1080/09553002.2020.1815889. Epub 2020 Sep 14.
The most attractive features of Auger electrons (AEs) in cancer therapy are their extremely short range and sufficiently high linear energy transfer (LET) for a majority of them. The cytotoxic effects of AE emitters can be realized only in close vicinity to sensitive cellular targets and they are negligible if the emitters are located outside the cell. The nucleus is considered the compartment most sensitive to high LET particles. Therefore, the use of AE emitters could be most useful in specific recognition of a cancer cell and delivery of AE emitters into its nucleus.
This review describes the studies aimed at developing effective anticancer agents for the delivery of AE emitters to the nuclei of target cancer cells. The use of peptide-based conjugates, nanoparticles, recombinant proteins, and other constructs for AE emitter targeted intranuclear delivery as well as their advantages and limitations are discussed.
Transport from the cytoplasm to the nucleus along with binding to the cancer cell is one of the key stages in the delivery of AE emitters; therefore, several constructs for exploitation of this transport have been developed. The transport is carried out through a nuclear pore complex (NPC) with the use of specific amino acid nuclear localization sequences (NLS) and carrier proteins named importins, which are located in the cytosol. Therefore, the effectiveness of NLS-containing delivery constructs designed to provide energy-dependent transport of AE emitter into the nuclei of cancer cells also depends on their efficient entry into the cytosol of the target cell.
在癌症治疗中，俄歇电子（Auger electrons，AEs）最吸引人的特点是它们的射程极短，而且大多数俄歇电子的线性能量转移（linear energy transfer，LET）都足够高。只有在靠近敏感的细胞靶标时，AE 发射器的细胞毒性作用才能实现，而如果发射器位于细胞之外，则这种作用可以忽略不计。细胞核被认为是对高 LET 粒子最敏感的隔室。因此，AE 发射器的使用可以在特定识别癌细胞和将 AE 发射器递送至其细胞核方面发挥最大作用。
本综述描述了旨在开发将 AE 发射器有效递送至靶癌细胞核的抗癌药物的研究。讨论了基于肽的缀合物、纳米颗粒、重组蛋白和其他用于 AE 发射器靶向核内递送的构建体及其优缺点。
沿着细胞质到细胞核的运输以及与癌细胞的结合是将 AE 发射器递送至靶细胞的关键步骤之一；因此，已经开发了几种利用这种运输的构建体。该运输是通过核孔复合物（nuclear pore complex，NPC）进行的，使用特定的氨基酸核定位序列（nuclear localization sequence，NLS）和称为importin 的载体蛋白，这些蛋白位于细胞质中。因此，设计用于提供 AE 发射器能量依赖性运输进入癌细胞核的包含 NLS 的递送构建体的有效性也取决于其有效进入靶细胞的细胞质。
