Abstract
Since cell nucleus is one of the most vulnerable compartments, the maximum therapeutic effect from a variety of locally acting agents, such as photosensitizers, alfa-emitters, Auger electron emitters, will be expected when they get there. Therefore, the targeted delivery of these agents into the nuclei of target tumor cells is necessary for their anticancer effects and minimization of side effects. Modular nanotransporters (MNT) are artificial polypeptides comprising several predefined modules that recognize target cell, launching their subsequent internalization, escape from endosomes, and transport the drug load to the nucleus. This technology significantly enhances the cytotoxicity of locally acting drugs in vitro and in vivo. Epidermal growth factor receptors (EGFR) are useful molecular targets as they are overexpressed in glioblastoma, head-and-neck cancer, bladder cancer, and other malignancies. Here, we examined the possibility of using internalizable anti-EGFR affibody as an EGFR-targeting MNT module for drug transport into the cancer cell nuclei. It binds to both murine and human EGFR facilitating preclinical studies. We showed that MNT with affibody on the N-terminus (MNTN-affibody) effectively delivered the Auger electron emitter 111In to target cell nuclei and had pronounced cytotoxic efficacy against EGFR-overexpressing human A431 epidermoid carcinoma cells. Using EGFR-expressing human adenocarcinoma MCF-7 cells, we demonstrated that in contrast to MNT with N-terminal epidermal growth factor (EGF), MNTN-affibody and MNT with EGF on the C-terminus did not stimulate cancer cell proliferation.
Highlights
Today a great interest in pharmacology sphere is the design of drugs that have a local damaging effect and are able to selectively uptake by the target cells (Rosenblum et al, 2018; Sobolev, 2018)
Purity of isolated and purified MNTN-affibody, MNTC-epidermal growth factor (EGF) and MNTN-EGF was evaluated by Laemmli SDS PAGE, it was > 85% for all Modular nanotransporters (MNT)
We showed that the growth rate of MCF-7 cancer cell line greatly increased after a few days incubation with EGF and MNTN-EGF compared to control cells
Summary
Today a great interest in pharmacology sphere is the design of drugs that have a local damaging effect and are able to selectively uptake by the target cells (Rosenblum et al, 2018; Sobolev, 2018). Different cell compartments have different resistance to certain damaging agents; the cell nucleus is the most vulnerable compartments to many of them It determines the importance of development targeted systems for their delivery to reach a significant effect without damaging non-target cells. This approach would minimize side effects and increase the effectiveness of treatment with reducing the minimum required concentration of the drug. Research in this area, in particular, is aimed at creating different intranuclear delivery systems conjugated with locally acting cytotoxic compounds (such as Auger electron emitters, photosensitizers, etc.) (Pan et al, 2018). One such approach is the creation of conjugates with EGF, one of the natural ligands to EGFR (Reilly et al, 2000; Cornelissen et al, 2013)
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