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1دورية أكاديمية
المؤلفون: Marina A. Dobrovolskaia, Kirill A. Afonin
المصدر: Molecules, Vol 28, Iss 12, p 4788 (2023)
مصطلحات موضوعية: n/a, Organic chemistry, QD241-441
الوصف: This Special Issue is intended to celebrate Professor Yechezkel Barenholz’s distinguished achievements [...]
وصف الملف: electronic resource
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2دورية أكاديمية
المؤلفون: Hannah S. Newton, Yasmine Radwan, Jie Xu, Jeffrey D. Clogston, Marina A. Dobrovolskaia, Kirill A. Afonin
المصدر: Molecules, Vol 28, Iss 11, p 4484 (2023)
مصطلحات موضوعية: nucleic acid nanoparticles, lipofectamine, cytokine, interferons, Organic chemistry, QD241-441
الوصف: Nucleic acid nanoparticles (NANPs) require a carrier to allow for their intracellular delivery to immune cells. Cytokine production, specifically type I and III interferons, allows for reliable monitoring of the carrier effect on NANP immunostimulation. Recent studies have shown that changes in the delivery platform (e.g., lipid-based carriers vs. dendrimers) can alter NANPs’ immunorecognition and downstream cytokine production in various immune cell populations. Herein, we used flow cytometry and measured cytokine induction to show how compositional variations in commercially available lipofectamine carriers impact the immunostimulatory properties of NANPs with different architectural characteristics.
وصف الملف: electronic resource
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3دورية أكاديمية
المؤلفون: Claire K. Holley, Marina A. Dobrovolskaia
المصدر: Molecules, Vol 26, Iss 23, p 7308 (2021)
مصطلحات موضوعية: immunity, bionanopharmaceuticals, impurities, immunotoxicity, immunogenicity, bioassays, Organic chemistry, QD241-441
الوصف: Innate immunity can be triggered by the presence of microbial antigens and other contaminants inadvertently introduced during the manufacture and purification of bionanopharmaceutical products. Activation of these innate immune responses, including cytokine secretion, complement, and immune cell activation, can result in unexpected and undesirable host immune responses. These innate modulators can also potentially stimulate the activation of adaptive immune responses, including the formation of anti-drug antibodies which can impact drug effectiveness. To prevent induction of these adverse responses, it is important to detect and quantify levels of these innate immunity modulating impurities (IIMIs) that may be present in drug products. However, while it is universally agreed that removal of IIMIs from drug products is crucial for patient safety and to prevent long-term immunogenicity, there is no single assay capable of directly detecting all potential IIMIs or indirectly quantifying downstream biomarkers. Additionally, there is a lack of agreement as to which of the many analytical assays currently employed should be standardized for general IIMI screening. Herein, we review the available literature to highlight cellular and molecular mechanisms underlying IIMI-mediated inflammation and its relevance to the safety and efficacy of pharmaceutical products. We further discuss methodologies used for direct and indirect IIMI identification and quantification.
وصف الملف: electronic resource
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4دورية أكاديمية
المؤلفون: Claire K. Holley, Edward Cedrone, Duncan Donohue, Barry W. Neun, Daniela Verthelyi, Eric S. Pang, Marina A. Dobrovolskaia
المصدر: Molecules, Vol 26, Iss 24, p 7461 (2021)
مصطلحات موضوعية: cytokines, innate immunity, immunogenicity, peptides, teriparatide, Organic chemistry, QD241-441
الوصف: Understanding, predicting, and minimizing the immunogenicity of peptide-based therapeutics are of paramount importance for ensuring the safety and efficacy of these products. The so-called anti-drug antibodies (ADA) may have various clinical consequences, including but not limited to the alteration in the product’s distribution, biological activity, and clearance profiles. The immunogenicity of biotherapeutics can be influenced by immunostimulation triggered by the presence of innate immune response modulating impurities (IIRMIs) inadvertently introduced during the manufacturing process. Herein, we evaluate the applicability of several in vitro assays (i.e., complement activation, leukocyte proliferation, and cytokine secretion) for the screening of innate immune responses induced by ten common IIRMIs (Bacillus subtilis flagellin, FSL-1, zymosan, ODN2006, poly(I:C) HMW, poly(I:C) LMW, CLO75, MDP, ODN2216, and Escherichia coli O111:B4 LPS), and a model biotherapeutic Forteo™ (teriparatide). Our study identifies cytokine secretion from healthy human donor peripheral blood mononuclear cells (PBMC) as a sensitive method for the in vitro monitoring of innate immune responses to individual IIRMIs and teriparatide (TP). We identify signature cytokines, evaluate both broad and narrow multiplex cytokine panels, and discuss how the assay logistics influence the performance of this in vitro assay.
وصف الملف: electronic resource
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5دورية أكاديمية
المصدر: Molecules, Vol 26, Iss 14, p 4231 (2021)
مصطلحات موضوعية: nucleic acid nanoparticles (NANPs), immunorecognition, immunoreaction, Toll-like receptors, cytokine storm syndrome, complement activation-related pseudoallergy, Organic chemistry, QD241-441
الوصف: The relatively straightforward methods of designing and assembling various functional nucleic acids into nanoparticles offer advantages for applications in diverse diagnostic and therapeutic approaches. However, due to the novelty of this approach, nucleic acid nanoparticles (NANPs) are not yet used in the clinic. The immune recognition of NANPs is among the areas of preclinical investigation aimed at enabling the translation of these novel materials into clinical settings. NANPs’ interactions with the complement system, coagulation systems, and immune cells are essential components of their preclinical safety portfolio. It has been established that NANPs’ physicochemical properties—composition, shape, and size—determine their interactions with immune cells (primarily blood plasmacytoid dendritic cells and monocytes), enable recognition by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), and mediate the subsequent cytokine response. However, unlike traditional therapeutic nucleic acids (e.g., CpG oligonucleotides), NANPs do not trigger a cytokine response unless they are delivered into the cells using a carrier. Recently, it was discovered that the type of carrier provides an additional tool for regulating both the spectrum and the magnitude of the cytokine response to NANPs. Herein, we review the current knowledge of NANPs’ interactions with various components of the immune system to emphasize the unique properties of these nanomaterials and highlight opportunities for their use in vaccines and immunotherapy.
وصف الملف: electronic resource
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6دورية أكاديميةInduction of Cytokines by Nucleic Acid Nanoparticles (NANPs) Depends on the Type of Delivery Carrier
المؤلفون: Yelixza I. Avila, Morgan Chandler, Edward Cedrone, Hannah S. Newton, Melina Richardson, Jie Xu, Jeffrey D. Clogston, Neill J. Liptrott, Kirill A. Afonin, Marina A. Dobrovolskaia
المصدر: Molecules, Vol 26, Iss 3, p 652 (2021)
مصطلحات موضوعية: nucleic acid nanoparticles, NANPs, cytokines, vaccines, immunotherapies, immunology, Organic chemistry, QD241-441
الوصف: Recent insights into the immunostimulatory properties of nucleic acid nanoparticles (NANPs) have demonstrated that variations in the shape, size, and composition lead to distinct patterns in their immunostimulatory properties. While most of these studies have used a single lipid-based carrier to allow for NANPs’ intracellular delivery, it is now apparent that the platform for delivery, which has historically been a hurdle for therapeutic nucleic acids, is an additional means to tailoring NANP immunorecognition. Here, the use of dendrimers for the delivery of NANPs is compared to the lipid-based platform and the differences in resulting cytokine induction are presented.
وصف الملف: electronic resource
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7دورية أكاديمية
المؤلفون: Barry W. Neun, Edward Cedrone, Timothy M. Potter, Rachael M. Crist, Marina A. Dobrovolskaia
المصدر: Molecules, Vol 25, Iss 15, p 3367 (2020)
مصطلحات موضوعية: immunology, beta-glucans, contamination, drug safety, nanoparticles, sterility, Organic chemistry, QD241-441
الوصف: Understanding the potential contamination of pharmaceutical products with innate immunity modulating impurities (IIMIs) is essential for establishing their safety profiles. IIMIs are a large family of molecules with diverse compositions and structures that contribute to the immune-mediated adverse effects (IMAE) of drug products. Pyrogenicity (the ability to induce fever) and activation of innate immune responses underlying both acute toxicities (e.g., anaphylactoid reactions or pseudoallergy, cytokine storm) and long-term effects (e.g., immunogenicity) are among the IMAE commonly related to IIMI contamination. Endotoxins of gram-negative bacteria are the best-studied IIMIs in that both methodologies for and pitfalls in their detection and quantification are well established. Additionally, regulatory guidance documents and research papers from laboratories worldwide are available on endotoxins. However, less information is currently known about other IIMIs. Herein, we focus on one such IIMI, namely, beta-glucans, and review literature and discuss the experience of the Nanotechnology Characterization Lab (NCL) with the detection of beta-glucans in nanotechnology-based drug products.
وصف الملف: electronic resource
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8دورية أكاديمية
المؤلفون: Yaelle Bavli, Bing-Mae Chen, Steve R. Roffler, Marina A. Dobrovolskaia, Eldad Elnekave, Shifra Ash, Yechezkel Barenholz, Keren Turjeman
المصدر: Molecules, Vol 25, Iss 3, p 558 (2020)
مصطلحات موضوعية: pegylated nanodrugs, hypersensitive reactions, anti-peg antibodies, complement activation, liposomal steroids, igg4 related disease, Organic chemistry, QD241-441
الوصف: PEGylated nanomedicines are known to induce infusion reactions (IRs) that in some cases can be life-threatening. Herein, we report a case study in which a patient with rare mediastinal and intracardiac IgG4-related sclerosing disease received 8 treatments of intravenously administered PEGylated liposomal methylprednisolone-succinate (NSSL-MPS). Due to the ethical requirements to reduce IRs, the patient received a cocktail of premedication including low dose of steroids, acetaminophen and H2 blockers before each infusion. The treatment was well-tolerated in that IRs, complement activation, anti-PEG antibodies and accelerated blood clearance of the PEGylated drug were not detected. Prior to the clinical study, an in vitro panel of assays utilizing blood of healthy donors was used to determine the potential of a PEGylated drug to activate complement system, elicit pro-inflammatory cytokines, damage erythrocytes and affect various components of the blood coagulation system. The overall findings of the in vitro panel were negative and correlated with the results observed in the clinical phase.
وصف الملف: electronic resource
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9دورية أكاديمية
المؤلفون: Enping Hong, Justin R. Halman, Ankit Shah, Edward Cedrone, Nguyen Truong, Kirill A. Afonin, Marina A. Dobrovolskaia
المصدر: Molecules, Vol 24, Iss 21, p 3852 (2019)
مصطلحات موضوعية: n/a, Organic chemistry, QD241-441
الوصف: The Molecules Editorial Office wishes to make the following erratum to this paper [...]
وصف الملف: electronic resource
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10دورية أكاديمية
المؤلفون: Enping Hong, Justin R. Halman, Ankit Shah, Edward Cedrone, Nguyen Truong, Kirill A. Afonin, Marina A. Dobrovolskaia
المصدر: Molecules, Vol 24, Iss 6, p 1094 (2019)
مصطلحات موضوعية: nanoparticles, nucleic acids, NANPs, infusion reaction, interferon, immunotoxicity, Toll-like receptors, Organic chemistry, QD241-441
الوصف: Infusion reactions (IRs) create a translational hurdle for many novel therapeutics, including those utilizing nanotechnology. Nucleic acid nanoparticles (NANPs) are a novel class of therapeutics prepared by rational design of relatively short oligonucleotides to self-assemble into various programmable geometric shapes. While cytokine storm, a common type of IR, has halted clinical development of several therapeutic oligonucleotides, NANP technologies hold tremendous potential to bring these reactions under control by tuning the particle’s physicochemical properties to the desired type and magnitude of the immune response. Recently, we reported the very first comprehensive study of the structure–activity relationship between NANPs’ shape, size, composition, and their immunorecognition in human cells, and identified the phagolysosomal pathway as the major route for the NANPs’ uptake and subsequent immunostimulation. Here, we explore the molecular mechanism of NANPs’ recognition by primary immune cells, and particularly the contributing role of the Toll-like receptors. Our current study expands the understanding of the immune recognition of engineered nucleic acid-based therapeutics and contributes to the improvement of the nanomedicine safety profile.
وصف الملف: electronic resource
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