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.
Highlights
Subcellular delivery systems have attracted growing attention of researchers (Jhaveri and Torchilin, 2016; Ulasov et al, 2018)
They comprise: (1) either α-melanocyte stimulating hormone (MSH) (Figure 2A), or epidermal growth factor (EGF) (Figure 2B) as internalizable ligand modules that are targeted either at melanocortin receptors-1 overexpressed on melanoma cells, or at EGFRs overexpressed on bladder, esophageal, glioblastoma, head and neck, and several other types of cancer cells; (2) a modified nuclear localization sequence (NLS) of the SV40 large T-antigen; (3) the translocation domain of diphtheria toxin (DTox) as the endosomolytic module; (4) Escherichia coli hemoglobin-like protein (HMP) as a carrier (Rosenkranz et al, 2003a; Gilyazova et al, 2006)
It was shown that the cytotoxic potency of these 111In-modular nanotransporters (MNTs) was dependent on their specific activity. These effects were observed for 111In delivered by two types of MNTs: one, DTox-HMP-NLS-MSH, targeted at cancer cells overexpressing melanocortin receptors-1 and another, DTox-HMP-NLSEGF, targeted at EGFRs (EGFR; experiments on U87.wtEGFR human glioblastoma and A431 human epidermoid carcinoma cells) (Slastnikova et al, 2017a)
Summary
Subcellular delivery systems have attracted growing attention of researchers (Jhaveri and Torchilin, 2016; Ulasov et al, 2018). This in turn leads to significantly higher cytotoxic efficiency of AEE carried by MNTs than by EGFR ligands (see chapter “Modular Nanotransporters: in vitro Delivery of Auger Electron Emitters”).
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