Modular Nanotransporters for Nuclear-Targeted Delivery of Auger Electron Emitters

Abstract

This review describes artificial modular nanotransporters (MNTs) delivering their cargos into target cells and then into the nuclei - the most vulnerable cell compartment for most anticancer agents and especially for radionuclides emitting short-range particles. The MNT strategy uses natural subcellular transport processes inherent in practically all cells including cancer cells. The MNTs use these processes just as a passenger who purchased tickets for a multiple-transfer trip making use of different kinds of public transport to reach the desired destination. The MNTs are fusion polypeptides consisting of several parts, replaceable modules, accomplishing binding to a specific receptor on the cell and subsequent internalization, endosomal escape and transport into the cell nucleus. Radionuclides emitting short-range particles, like Auger electron emitters, acquire cell specificity and significantly higher cytotoxicity both in vitro and in vivo when delivered by the MNTs into the nuclei of cancer cells. MNT modules are interchangeable, allowing replacement of receptor recognition modules, which permits their use for different types of cancer cells and, as a cocktail of several MNTs, for targeting several tumor-specific molecules for personalized medicine.

Keywords: Auger electron emitters; cancer; cell nucleus; modular nanotransporters; nuclear medicine; subcellular drug delivery.

FIGURE 1

Schematic presentation of MNTs – their structure, functions, and subcellular transport [from (Slastnikova et al., 2017a) with permission]. (A) Principal scheme of MNTs, their structure and function of each module. (B) A scheme of MNT transport within the target cell. An MNT recognizes and binds to internalizable receptors, overexpressed on the target cancer cells, with the use of its ligand module; following subsequent receptor-mediated endocytosis, the endosomolytic module of the MNT performs escape from the endocytotic vesicles into the hyaloplasm; finally, the MNT is transported into the target cell nucleus due to its nuclear localization signal module. Ligand modules, MSH, EGF, and FA are targeted at melanocortin receptor-1, EGF receptor, and folate receptor, respectively. DTox is the endosomolytic module, the module with optimized SV-40 large T-antigen NLS is responsible for delivery into the nucleus of a target cell, and Escherichia coli HMP is a carrier module.

FIGURE 2

Scheme of MNTs discussed in this review. MNT targeted at (A) melanocortin receptors-1, (B) epidermal growth factor receptors, and (C) folate receptors. FA, folic acid.