Pharmaceutics

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20 pages, 3138 KiB

Open AccessArticle

Triphenylphosphonium Analogs of Short Peptide Related to Bactenecin 7 and Oncocin 112 as Antimicrobial Agents

by Andrey G. Tereshchenkov, Zimfira Z. Khairullina, Inna A. Volynkina, Dmitrii A. Lukianov, Pavel A. Nazarov, Julia A. Pavlova, Vadim N. Tashlitsky, Elizaveta A. Razumova, Daria A. Ipatova, Yury V. Timchenko, Dmitry A. Senko, Olga V. Efremenkova, Alena Paleskava, Andrey L. Konevega, Ilya A. Osterman, Igor A. Rodin, Petr V. Sergiev, Olga A. Dontsova, Alexey A. Bogdanov and Natalia V. Sumbatyan

Pharmaceutics 2024, 16(1), 148; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics16010148 - 22 Jan 2024

Viewed by 995

Abstract

Antimicrobial peptides (AMPs) have recently attracted attention as promising antibacterial agents capable of acting against resistant bacterial strains. In this work, an approach was applied, consisting of the conjugation of a peptide related to the sequences of bactenecin 7 (Bac7) and oncocin (Onc112) [...] Read more.

Antimicrobial peptides (AMPs) have recently attracted attention as promising antibacterial agents capable of acting against resistant bacterial strains. In this work, an approach was applied, consisting of the conjugation of a peptide related to the sequences of bactenecin 7 (Bac7) and oncocin (Onc112) with the alkyl(triphenyl)phosphonium (alkyl-TPP) fragment in order to improve the properties of the AMP and introduce new ones, expand the spectrum of antimicrobial activity, and reduce the inhibitory effect on the eukaryotic translation process. Triphenylphosphonium (TPP) derivatives of a decapeptide RRIRPRPPYL were synthesized. It was comprehensively studied how the modification of the AMP affected the properties of the new compounds. It was shown that while the reduction in the Bac7 length to 10 a.a. residues dramatically decreased the affinity to bacterial ribosomes, the modification of the peptide with alkyl-TPP moieties led to an increase in the affinity. New analogs with structures that combined a decapeptide related to Bac7 and Onc112—Bac(1–10, R/Y)—and TPP attached to the C-terminal amino acid residue via alkylamide linkers, inhibited translation in vitro and were found to be more selective inhibitors of bacterial translation compared with eukaryotic translation than Onc112 and Bac7. The TPP analogs of the decapeptide related to Bac7 and Onc112 suppressed the growth of both Gram-negative bacteria, similar to Onc112 and Bac7, and Gram-positive ones, similar to alkyl-TPP derivatives, and also acted against some resistant laboratory strains. Bac(1–10, R/Y)-C2-TPP, containing a short alkylamide linker between the decapeptide and TPP, was transferred into the E. coli cells via the SbmA transporter protein. TPP derivatives of the decapeptide Bac(1–10, R/Y) containing either a decylamide or ethylamide linker caused B. subtilis membrane depolarization, similar to alkyl-TPP. The Bac(1–10, R/Y)-C2-TPP analog was proven to be non-toxic for mammalian cells using the MTT test. Full article

(This article belongs to the Special Issue Design, Development, and Characterization of Drug and Gene Delivery Systems in the Russian Federation)

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20 pages, 4937 KiB

Open AccessArticle

Obtaining Gene-Modified HLA-E-Expressing Feeder Cells for Stimulation of Natural Killer Cells

by Nadezhda A. Alekseeva, Maria A. Streltsova, Julia D. Vavilova, Maria O. Ustiuzhanina, Anastasia I. Palamarchuk, Anna A. Boyko, Nikita D. Timofeev, Alexey I. Popodko and Elena I. Kovalenko

Pharmaceutics 2024, 16(1), 133; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics16010133 - 19 Jan 2024

Viewed by 808

Abstract

Human cytomegalovirus (HCMV)-specific adaptive NK cells are capable of recognizing viral peptides presented by HLA-E on infected cells via the NKG2C receptor. Using retroviral transduction, we have generated a K562-cell-based line expressing HLA-E in the presence of the HLA-E-stabilizing peptide, which has previously [...] Read more.

Human cytomegalovirus (HCMV)-specific adaptive NK cells are capable of recognizing viral peptides presented by HLA-E on infected cells via the NKG2C receptor. Using retroviral transduction, we have generated a K562-cell-based line expressing HLA-E in the presence of the HLA-E-stabilizing peptide, which has previously shown the capacity to enhance adaptive NK cell response. The obtained K562-21E cell line was employed to investigate proliferative responses of the CD57⁻ NK cell subset of HCMV-seropositive and seronegative donors. Stimulation of CD57⁻ NK cells with K562-21E/peptide resulted in an increased cell expansion during the 12-day culturing period, regardless of the serological HCMV status of the donor. The enhanced proliferation in response to the peptide was associated with a greater proportion of CD56^brightHLA-DR⁺ NK cells. In later stages of cultivation, the greatest proliferative response to K562-21E/peptide was shown for a highly HCMV-seropositive donor. These expanded NK cells were characterized by the accumulation of CD57⁻KIR2DL2/3⁺NKG2C⁺NKG2A⁻ cells, which are hypothesized to represent adaptive NK cell progenitors. The K562-21E feeder cells can be applied both for the accumulation of NK cells as therapeutic effectors, and for the study of NK cell maturation into the adaptive state after the HLA-E peptide presentation. Full article

(This article belongs to the Special Issue Design, Development, and Characterization of Drug and Gene Delivery Systems in the Russian Federation)

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13 pages, 2143 KiB

Open AccessArticle

Evaluation of the Immunosafety of Cucurbit[n]uril In Vivo

by Ekaterina Pashkina, Alina Aktanova, Olga Boeva, Maria Bykova, Elena Gavrilova, Elena Goiman, Ekaterina Kovalenko, Na’il Saleh, Lyubov Grishina and Vladimir Kozlov

Pharmaceutics 2024, 16(1), 127; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics16010127 - 19 Jan 2024

Cited by 2 | Viewed by 774

Abstract

Cucurbiturils are a family of macrocyclic oligomers capable of forming host–guest complexes with various molecules. Due to noncovalent binding to drug molecules and low toxicity, cucurbiturils has been extensively investigated as potential carriers for drug delivery. However, the immune system’s interactions with different [...] Read more.

Cucurbiturils are a family of macrocyclic oligomers capable of forming host–guest complexes with various molecules. Due to noncovalent binding to drug molecules and low toxicity, cucurbiturils has been extensively investigated as potential carriers for drug delivery. However, the immune system’s interactions with different drug carriers, including cucurbiturils, are still under investigation. In this study, we focused on cucurbiturils’ immunosafety and immunomodulation properties in vivo. We measured blood counts and lymphocyte subpopulations in blood, spleen, and bone marrow, and assessed the in vivo toxicity to spleen and bone marrow cells after intraperitoneal administration to BALB/c mice. When assessing the effect of cucurbit[6]uril on blood parameters after three intraperitoneal injections within a week in laboratory animals, a decrease in white blood cells was found in mice after injections of cucurbit[6]util, but the observed decrease in the number of white blood cells was within the normal range. At the same time, cucurbit[7]uril and cucurbit[8]uril did not affect the leukocyte counts of mice after three injections. Changes in the number of platelets, erythrocytes, and monocytes, as well as in several other indicators, such as hematocrit or erythrocyte volumetric dispersion, were not detected. We show that cucurbiturils do not have immunotoxicity in vivo, with the exception of a cytotoxic effect on spleen cells after сucurbit[7]uril administration at a high dosage. We also evaluated the effect of cucurbiturils on cellular and humoral immune responses. We founded that cucurbiturils in high concentrations affect the immune system in vivo, and the action of various cucurbiturils differs in different homologues, which is apparently associated with different interactions in the internal environment of the body. Full article

(This article belongs to the Special Issue Design, Development, and Characterization of Drug and Gene Delivery Systems in the Russian Federation)

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20 pages, 4239 KiB

Open AccessArticle

Self-Penetrating Oligonucleotide Derivatives: Features of Self-Assembly and Interactions with Serum and Intracellular Proteins

by Irina Bauer, Ekaterina Ilina, Timofey Zharkov, Evgeniya Grigorieva, Olga Chinak, Maxim Kupryushkin, Victor Golyshev, Dmitry Mitin, Alexey Chubarov, Svetlana Khodyreva and Elena Dmitrienko

Pharmaceutics 2023, 15(12), 2779; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics15122779 - 14 Dec 2023

Viewed by 1191

Abstract

Lipophilic oligonucleotide derivatives are a potent approach to the intracellular delivery of nucleic acids. The binding of these derivatives to serum albumin is a determinant of their fate in the body, as its structure contains several sites of high affinity for hydrophobic compounds. [...] Read more.

Lipophilic oligonucleotide derivatives are a potent approach to the intracellular delivery of nucleic acids. The binding of these derivatives to serum albumin is a determinant of their fate in the body, as its structure contains several sites of high affinity for hydrophobic compounds. This study focuses on the features of self-association and non-covalent interactions with human serum albumin of novel self-penetrating oligonucleotide derivatives. The study revealed that the introduction of a triazinyl phosphoramidate modification bearing two dodecyl groups at the 3′ end region of the oligonucleotide sequence has a negligible effect on its affinity for the complementary sequence. Dynamic light scattering verified that the amphiphilic oligonucleotides under study can self-assemble into micelle-like particles ranging from 8 to 15 nm in size. The oligonucleotides with dodecyl groups form stable complexes with human serum albumin with a dissociation constant of approximately 10⁻⁶ M. The oligonucleotide micelles are simultaneously destroyed upon binding to albumin. Using an electrophoretic mobility shift assay and affinity modification, we examined the ability of DNA duplexes containing triazinyl phosphoramidate oligonucleotides to interact with Ku antigen and PARP1, as well as the mutual influence of PARP1 and albumin or Ku antigen and albumin upon interaction with DNA duplexes. These findings, together with the capability of dodecyl-containing derivatives to effectively penetrate different cells, such as HEK293 and T98G, indicate that the oligonucleotides under study can be considered as a platform for the development of therapeutic preparations with a target effect. Full article

(This article belongs to the Special Issue Design, Development, and Characterization of Drug and Gene Delivery Systems in the Russian Federation)

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14 pages, 6533 KiB

Open AccessArticle

Magnetic and Fluorescent Dual-Labeled Genetically Encoded Targeted Nanoparticles for Malignant Glioma Cell Tracking and Drug Delivery

by Anna N. Gabashvili, Nelly S. Chmelyuk, Vera V. Oda, Maria K. Leonova, Viktoria A. Sarkisova, Polina A. Lazareva, Alevtina S. Semkina, Nikolai A. Belyakov, Timur R. Nizamov and Petr I. Nikitin

Pharmaceutics 2023, 15(10), 2422; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics15102422 - 04 Oct 2023

Cited by 1 | Viewed by 1186

Abstract

Human glioblastoma multiforme (GBM) is a primary malignant brain tumor, a radically incurable disease characterized by rapid growth resistance to classical therapies, with a median patient survival of about 15 months. For decades, a plethora of approaches have been developed to make GBM [...] Read more.

Human glioblastoma multiforme (GBM) is a primary malignant brain tumor, a radically incurable disease characterized by rapid growth resistance to classical therapies, with a median patient survival of about 15 months. For decades, a plethora of approaches have been developed to make GBM therapy more precise and improve the diagnosis of this pathology. Targeted delivery mediated by the use of various molecules (monoclonal antibodies, ligands to overexpressed tumor receptors) is one of the promising methods to achieve this goal. Here we present a novel genetically encoded nanoscale dual-labeled system based on Quasibacillus thermotolerans (Qt) encapsulins exploiting biologically inspired designs with iron-containing nanoparticles as a cargo, conjugated with human fluorescent labeled transferrin (Tf) acting as a vector. It is known that the expression of transferrin receptors (TfR) in glioma cells is significantly higher compared to non-tumor cells, which enables the targeting of the resulting nanocarrier. The selectivity of binding of the obtained nanosystem to glioma cells was studied by qualitative and quantitative assessment of the accumulation of intracellular iron, as well as by magnetic particle quantification method and laser scanning confocal microscopy. Used approaches unambiguously demonstrated that transferrin-conjugated encapsulins were captured by glioma cells much more efficiently than by benign cells. The resulting bioinspired nanoplatform can be supplemented with a chemotherapeutic drug or genotherapeutic agent and used for targeted delivery of a therapeutic agent to malignant glioma cells. Additionally, the observed cell-assisted biosynthesis of magnetic nanoparticles could be an attractive way to achieve a narrow size distribution of particles for various applications. Full article

(This article belongs to the Special Issue Design, Development, and Characterization of Drug and Gene Delivery Systems in the Russian Federation)

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20 pages, 2457 KiB

Open AccessEditor’s ChoiceArticle

Purification Process of a Recombinant Human Follicle Stimulating Hormone Biosimilar (Primapur^®) to Yield a Pharmaceutical Product with High Batch-to-Batch Consistency

by Maria Sinegubova, Ivan Vorobiev, Anatoly Klishin, Dmitry Eremin, Nadezhda Orlova, Natalya Orlova and Mikhail Polzikov

Pharmaceutics 2022, 14(1), 96; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14010096 - 01 Jan 2022

Cited by 3 | Viewed by 3615

Abstract

Recombinant human follicle stimulating hormone (r-hFSH) is widely used for infertility treatment and is subject to the development of biosimilars. There are different purification strategies that can yield r-hFSH of pharmaceutical quality from Chinese hamster ovary cell culture broth. We developed a purification [...] Read more.

Recombinant human follicle stimulating hormone (r-hFSH) is widely used for infertility treatment and is subject to the development of biosimilars. There are different purification strategies that can yield r-hFSH of pharmaceutical quality from Chinese hamster ovary cell culture broth. We developed a purification process for r-hFSH centered on immunoaffinity chromatography with single-domain recombinant camelid antibodies. The resulting downstream process is simple and devoid of ultrafiltration operations. Studies on chromatography resin resource and ligand leakage showed that the immunoaffinity matrix employed was suitable for industrial use and stable for at least 40 full chromatography cycles, and the leaked single-domain antibody ligand was completely removed by subsequent purification steps. All chromatography resins employed withstood the same 40 cycles of use without significant changes in separation efficiency and product binding capacity. The resulting industrial purification process yielded batches of r-hFSH with consistent levels of purity and bioactivity. Full article

(This article belongs to the Special Issue Design, Development, and Characterization of Drug and Gene Delivery Systems in the Russian Federation)

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19 pages, 3478 KiB

Open AccessArticle

Reprogramming Extracellular Vesicles for Protein Therapeutics Delivery

by Leyla A. Ovchinnikova, Stanislav S. Terekhov, Rustam H. Ziganshin, Dmitriy V. Bagrov, Ioanna N. Filimonova, Arthur O. Zalevsky and Yakov A. Lomakin

Pharmaceutics 2021, 13(6), 768; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13060768 - 21 May 2021

Cited by 18 | Viewed by 3565

Abstract

Delivering protein therapeutics specifically into target cells and tissues is a promising avenue in medicine. Advancing this process will significantly enhance the efficiency of the designed drugs. In this regard, natural membrane-based systems are of particular interest. Extracellular vesicles (EVs), being the bilayer [...] Read more.

Delivering protein therapeutics specifically into target cells and tissues is a promising avenue in medicine. Advancing this process will significantly enhance the efficiency of the designed drugs. In this regard, natural membrane-based systems are of particular interest. Extracellular vesicles (EVs), being the bilayer lipid particles secreted by almost all types of cells, have several principal advantages: biocompatibility, carrier stability, and blood–brain barrier penetrability, which make them a perspective tool for protein therapeutic delivery. Here, we evaluate the engineered genetically encoded EVs produced by a human cell line, which allow efficient cargo loading. In the devised system, the protein of interest is captured by self-assembling structures, i.e., “enveloped protein nanocages” (EPN). In their turn, EPNs are encapsulated in fusogenic EVs by the overexpression of vesicular stomatitis virus G protein (VSV-G). The proteomic profiles of different engineered EVs were determined for a comprehensive evaluation of their therapeutic potential. EVs loading mediated by bio-safe Fos–Jun heterodimerization demonstrates an increased efficacy of active cargo loading and delivery into target cells. Our results emphasize the outstanding technological and biomedical potential of the engineered EV systems, including their application in adoptive cell transfer and targeted cell reprogramming. Full article

(This article belongs to the Special Issue Design, Development, and Characterization of Drug and Gene Delivery Systems in the Russian Federation)

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Review

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15 pages, 1762 KiB

Open AccessReview

Development of Peptide Biopharmaceuticals in Russia

by Vladislav I. Deigin, Elena A. Poluektova, Allan G. Beniashvili, Sergey A. Kozin and Yuri M. Poluektov

Pharmaceutics 2022, 14(4), 716; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040716 - 27 Mar 2022

Cited by 5 | Viewed by 3186

Abstract

Peptides are low-molecular-weight substances that participate in numerous important physiological functions, such as human growth and development, stress, regulation of the emotional state, sexual behavior, and immune responses. Their mechanisms of action are based on receptor–ligand interactions, which result in highly selective effects. [...] Read more.

Peptides are low-molecular-weight substances that participate in numerous important physiological functions, such as human growth and development, stress, regulation of the emotional state, sexual behavior, and immune responses. Their mechanisms of action are based on receptor–ligand interactions, which result in highly selective effects. These properties and low toxicity enable them to be considered potent drugs. Peptide preparations became possible at the beginning of the 20th century after a method was developed for selectively synthesizing peptides; however, after synthesis of the first peptide drugs, several issues related to increasing the stability, bioavailability, half-life, and ability to move across cell membranes remain unresolved. Here, we briefly review the history of peptide production and development in the biochemical industry and outline potential areas of peptide biopharmaceutical applications and modern approaches for creating pharmaceuticals based on synthetic peptides and their analogs. We also focus on original peptide drugs and the approaches used for their development by the Russian Federation. Full article

(This article belongs to the Special Issue Design, Development, and Characterization of Drug and Gene Delivery Systems in the Russian Federation)

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