Laboratory of molecular immunology
Molecular Immunology Laboratory at the Moscow River.
Enhancement of the blood-circulation time and performance of nanomedicines via the forced clearance of erythrocytes.
A new approach has been proposed, which makes it possible to significantly extend the circulation time of nanoagents in the bloodstream and, as a consequence, increase their therapeutic activity. The approach called "cytoblockade of the mononuclear phagocytic system" does not require any modification of nanoparticles and consists in the introduction into the body of a relatively small amount of antibodies against its own erythrocytes. As a result, the immune system “focuses” on attacking its own erythrocytes and for some time “stops seeing” the introduced nanomaterials, which during this time are able to find target pathogenic objects and provide a therapeutic effect. An important characteristic feature of this approach is its versatility, i.e. independence from the nature, size and other properties of the nanoparticles used. [Nat Biomed Eng. 2020]. Another developed approach to improving the therapeutic effect of nanoagents, ideologically close to the one mentioned above, consists in the introduction of "inert" nanoagents into the body, causing an attack by the immune system, and only then nanoparticles with the drug [J. Cont. Release. 2020].
- (2020). Fast processes of nanoparticle blood clearance: Comprehensive study. J Control Release 326, 181–191
- (2020). Enhancement of the blood-circulation time and performance of nanomedicines via the forced clearance of erythrocytes. Nat Biomed Eng 4 (7), 717–731
Dual Regioselective Targeting the Same Receptor in Nanoparticle-Mediated Combination Immuno/Chemotherapy for Enhanced Image-Guided Cancer Treatment.
In collaboration with Nursery for laboratory animals
For the first time, a strategy of regiospecific targeting the same receptor of two antitumor toxins with different mechanisms of action – the antibiotic doxorubicin in targeted nanoparticles with diagnostic fluorescent die and protein targeted toxin - has been developed for the enhanced image-guided cancer treatment. A strong synergistic effect of these toxins on the tumor has been shown, which makes it possible to reduce the effective doses of toxins by 1000 times in in vitro experiments and significantly improve the therapeutic effect in vivo.
The genetically modified receptor-selective variant DR5 of cytokine TRAIL demonstrated increased antitumor activity and an improved pharmacokinetic profile
In collaboration with Laboratory of protein engineering
A genetically modified receptor-selective variant DR5-B of the antitumor cytokine TRAIL was developed, which selectively binds only to the apoptosis-inducing death receptor DR5, without affinity for the receptor DR4 and decoy receptors DcR1, DcR2 and OPG. DR5-B showed increased proapoptotic activity in tumor cells both separately and in combination with chemotherapy drugs. DR5-B inhibited tumor growth in HCT116 and Caco-2 xenografts, and its efficacy was 2.5-3 times higher than wild type TRAIL. DR5-B also significantly increased the animal survival. The pharmacokinetic parameters of DR5-B were comparable to those of TRAIL, except that the half-life was 3.5 times higher. Thus, DR5-B can be considered as an effective agent for the treatment of tumor diseases.
- (2020). Chemotherapeutic Agents Sensitize Resistant Cancer Cells to the DR5-Specific Variant DR5-B more Efficiently than to TRAIL by Modulating the Surface Expression of Death and Decoy Receptors. Cancers (Basel) 12 (5),
- (2020). Genetically Modified DR5-Specific TRAIL Variant DR5-B Revealed Dual Antitumor and Protumoral Effect in Colon Cancer Xenografts and an Improved Pharmacokinetic Profile. Transl Oncol 13 (4), 100762
Creation of plants with genetically encoded autoluminescence
In collaboration with Artificial Climate Station “BIOTRON”,  Laboratory of Chemistry of Metabolic Pathways,  Group of synthetic biology,  Group of Plant Metabolic Engineering,  Group of molecular tags for optical nanoscopy,  Department of Biomolecular Chemistry
In Nature Biotechnology, scientists from IBCh RAS have announced the feasibility of creating plants that produce their own visible luminescence. It was revealed that bioluminescence found in some mushrooms is metabolically similar to the natural processes common among plants. By inserting DNA obtained from the mushroom Neonothopanus nambi, the scientists were able to create plants that glow much brighter than previously possible. Plants containing the mushroom DNA glow continuously throughout their lifecycle, from seedling to maturity. This biological light can be used for observing the inner workings of plants. In contrast to other commonly used forms of bioluminescence, such as from fireflies, unique chemical reagents are not necessary for sustaining mushroom bioluminescence.
- (2020). Plants with genetically encoded autoluminescence. Nat Biotechnol 38 (8), 944–946
Gold nanostructures for biomedical applications.
A biosensor-Fourier transducer based on periodic gold nanostructures was created and studied for the first time, which allows achieving ultrahigh sensitivity of the analysis of compounds (10-15 g/ml) in biological matrix. The developed methodology will allow solving the problems of highly sensitive analysis of target compounds in complex matrices, including hormones and other bioregulators acting in very low concentrations (doping control), highly toxic substances (biotoxins), pathogens (for biosafety problems, antibioterrorism protection). For the first time in the world, gold nanorods coated with a tumor-specific addressing module DARPin were obtained, which find tumor cells of a corresponding molecular profile and suppress their growth when irradiated with infrared light in the “Biotissue Transparency Window” (IC50 3.4 nM).
- (2019). DARPin_9-29-Targeted Mini Gold Nanorods Specifically Eliminate HER2-Overexpressing Cancer Cells. ACS Appl Mater Interfaces 11 (38), 34645–34651
- (2019). Phase-Responsive Fourier Nanotransducers for Probing 2D Materials and Functional Interfaces. Adv Funct Mater 29 (26),
Radioactive (90Y) upconversion nanoparticles conjugated with recombinant targeted toxin for synergistic nanotheranostics of cancer
In collaboration with Group of oncanotechnology
We report combined therapy using upconversion nanoparticles (UCNP) coupled to two therapeutic agents: beta-emitting radionuclide yttrium-90 (90Y) fractionally substituting yttrium in UCNP, and a fragment of the exotoxin A derived from Pseudomonas aeruginosa genetically fused with a targeting designed ankyrin repeat protein (DARPin) specific to HER2 receptors. The resultant hybrid complex UCNP-R-T was tested using human breast adenocarcinoma cells SK-BR-3 overexpressing HER2 receptors and immunodeficient mice, bearing HER2-positive xenograft tumors. The photophysical properties of UCNPs enabled background-free imaging of the UCNP-R-T distribution in cells and animals. Specific binding and uptake of UCNP complexes in SK-BR-3 cells was observed,with separate 90Y- and PE40-induced cytotoxic effects characterized by IC50 140 μg/mL (UCNP-R) and 5.2 μg/mL (UCNP-T), respectively. When both therapeutic agents were combined into UCNP-R-T, the synergetic effect increased markedly, ∼2200-fold, resulting in IC50 = 0.0024 μg/mL. The combined therapy with UCNP-R-T was demonstrated in vivo. PNAS USA, 2018. In colaboration with Lobachevsky University.
- (2018). Disassembling a cancer puzzle: Cell junctions and plasma membrane as targets for anticancer therapy. J Control Release 286, 125–136
- (2018). Radioactive (90Y) upconversion nanoparticles conjugated with recombinant targeted toxin for synergistic nanotheranostics of cancer. Proc Natl Acad Sci U S A 115 (39), 9690–9695
- (2018). 3D in vitro models of tumors expressing EGFR family receptors: a potent tool for studying receptor biology and targeted drug development. Drug Discov Today 24 (1), 99–111
- (2018). Versatile Platform for Nanoparticle Surface Bioengineering Based on SiO2-Binding Peptide and Proteinaceous Barnase, Barstar Interface. ACS Appl Mater Interfaces 10 (20), 17437–17447
Plasmonic gold nanoparticles for photothermal therapy of cancer
The new agents for tumor theranostics with different mechanisms of action were constructed on the base of hybrid nanoparticles. The 5 nm gold nanoparticles conjugated with designed ankyrin repeat protein (DARPin), which speciﬁcally targets human epidermal growth factor receptor 2 (HER 2), are of the utmost interest. The high stability under physiological conditions and high a ﬃnity to the receptors overexpressed by cancer cells make conjugates of plasmonic gold nanostructures with DARPin molecules promising candidates for cancer photothermal therapy. This work was supported by the Russian Science Foundation (project no.14-2400106).
- (2017). Synthesis, Characterization, and Selective Delivery of DARPin-Gold Nanoparticle Conjugates to Cancer Cells. Bioconjug Chem 28 (10), 2569–2574
- (2017). Ultraviolet phototoxicity of upconversion nanoparticles illuminated with near-infrared light. Nanoscale 9 (39), 14921–14928
- (2017). Targeting group i p21-activated kinases to control malignant peripheral nerve sheath tumor growth and metastasis. Oncogene 36 (38), 5421–5431
- (2017). HER2-specific recombinant immunotoxin 4D5scFv-PE40 passes through retrograde trafficking route and forces cells to enter apoptosis. Oncotarget 8 (13), 22048–22058
- (2017). Deep-penetrating photodynamic therapy with KillerRed mediated by upconversion nanoparticles. Acta Biomater 51, 461–470