Modular Nanotransporters for Nuclear-Targeted Delivery of Auger Electron Emitters

Соболев, А. С.

doi:10.3389/fphar.2018.00952

Cited by 29 publications

(19 citation statements)

References 57 publications

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“…They showed superior uptake and cytotoxicity over 67 Ga-hEGF, which was attributed to improved nuclear retention. This MNT has been used with various other ligand modules (melanocortin receptor and folate receptor ligands) and radionuclides ( 111 In, 125 I) ( Slastnikova et al, 2012 , 2017a , b ), and has recently been reviewed by Sobolev (2018) .…”

Section: Subcellular Targets For Radionuclide Therapymentioning

confidence: 99%

Subcellular Targeting of Theranostic Radionuclides

et al. 2018

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The last decade has seen rapid growth in the use of theranostic radionuclides for the treatment and imaging of a wide range of cancers. Radionuclide therapy and imaging rely on a radiolabeled vector to specifically target cancer cells. Radionuclides that emit β particles have thus far dominated the field of targeted radionuclide therapy (TRT), mainly because the longer range (μm–mm track length) of these particles offsets the heterogeneous expression of the molecular target. Shorter range (nm–μm track length) α- and Auger electron (AE)-emitting radionuclides on the other hand provide high ionization densities at the site of decay which could overcome much of the toxicity associated with β-emitters. Given that there is a growing body of evidence that other sensitive sites besides the DNA, such as the cell membrane and mitochondria, could be critical targets in TRT, improved techniques in detecting the subcellular distribution of these radionuclides are necessary, especially since many β-emitting radionuclides also emit AE. The successful development of TRT agents capable of homing to targets with subcellular precision demands the parallel development of quantitative assays for evaluation of spatial distribution of radionuclides in the nm–μm range. In this review, the status of research directed at subcellular targeting of radionuclide theranostics and the methods for imaging and quantification of radionuclide localization at the nanoscale are described.

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Section: Subcellular Targets For Radionuclide Therapymentioning

confidence: 99%

Subcellular Targeting of Theranostic Radionuclides

et al. 2018

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“…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). Locally acting cytotoxic agents, in particular Auger electron emitters, have great therapeutic potential that can be used to antitumor treatment.…”

Section: Introductionmentioning

confidence: 99%

“…EGFR, upon binding to its ligand, is not only capable to activate other signaling proteins, but is also transported inside endosomes from the surface of the cell membrane (Sorkin and Goh, 2009). It has been shown for tumor cells that part of ligand-bound EGF translocates into the cell nuclei (Reilly et al, 2000;Hicks et al, 2006;De Angelis Campos et al, 2011;Sobolev, 2018). Based on the data obtained, numerous attempts have been made to create a drug where EGFR would be used as a vehicle for various agents, such as, for example, Auger-electron emitter 111 In, Staphylococcal enterotoxin A, etc.…”

Section: Introductionmentioning

confidence: 99%

“…One of these developments is the modular nanotransporters (MNT) designed in our laboratory (Gilyazova et al, 2006;Rosenkranz et al, 2018). MNT were designed to deliver locally acting drugs such as photosensitizers and radionuclide-emitting short-range particles to the nuclei of the target cells (Sobolev, 2008;Sobolev et al, 2016;Sobolev, 2018). We used Auger electron emitters, because they combine two important characteristics.…”

Section: Introductionmentioning

confidence: 99%

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Targeted Delivery of 111In Into the Nuclei of EGFR Overexpressing Cells via Modular Nanotransporters With Anti-EGFR Affibody

et al. 2020

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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 (MNT N-affibody ) effectively delivered the Auger electron emitter 111 In 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), MNT N-affibody and MNT with EGF on the C-terminus did not stimulate cancer cell proliferation.

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“…When an antigen of interest is localized within another compartment (e.g., the nucleus or mitochondria), additional signal peptides for specific compartment delivery are required. The delivery system that can serve an appropriate candidate to accomplish this step-by-step targeted cell-specific delivery of antibody (or its derivative/mimic) into the designated intracellular compartment (e.g., the nucleus) is the modular nanotransporters platform ( Sobolev, 2009 ; Sobolev et al, 2016 ). Modular nanotransporters are recombinant polypeptide-based delivery vehicles, consisting of a ligand module for cell-specific recognition and subsequent internalization, the translocation domain of Diphtheria toxin as an endosomolytic module for successful endosomal escape, and the optimized SV-40 large T-antigen nuclear localization sequence for nuclear import.…”

Section: Strategies For Intracellular Targeting Of Antibodies Their mentioning

confidence: 99%

Targeted Intracellular Delivery of Antibodies: The State of the Art

et al. 2018

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A dominant area of antibody research is the extension of the use of this mighty experimental and therapeutic tool for the specific detection of molecules for diagnostics, visualization, and activity blocking. Despite the ability to raise antibodies against different proteins, numerous applications of antibodies in basic research fields, clinical practice, and biotechnology are restricted to permeabilized cells or extracellular antigens, such as membrane or secreted proteins. With the exception of small groups of autoantibodies, natural antibodies to intracellular targets cannot be used within living cells. This excludes the scope of a major class of intracellular targets, including some infamous cancer-associated molecules. Some of these targets are still not druggable via small molecules because of large flat contact areas and the absence of deep hydrophobic pockets in which small molecules can insert and perturb their activity. Thus, the development of technologies for the targeted intracellular delivery of antibodies, their fragments, or antibody-like molecules is extremely important. Various strategies for intracellular targeting of antibodies via protein-transduction domains or their mimics, liposomes, polymer vesicles, and viral envelopes, are reviewed in this article. The pitfalls, challenges, and perspectives of these technologies are discussed.

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Modular Nanotransporters for Nuclear-Targeted Delivery of Auger Electron Emitters

Cited by 29 publications

References 57 publications

Subcellular Targeting of Theranostic Radionuclides

Subcellular Targeting of Theranostic Radionuclides

Targeted Delivery of 111In Into the Nuclei of EGFR Overexpressing Cells via Modular Nanotransporters With Anti-EGFR Affibody

Targeted Intracellular Delivery of Antibodies: The State of the Art

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