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Results: 1 to 10 of 112

Publication Record


Genetic architecture of host proteins involved in SARS-CoV-2 infection.
Pietzner M, Wheeler E, Carrasco-Zanini J, Raffler J, Kerrison ND, Oerton E, Auyeung VPW, Luan J, Finan C, Casas JP, Ostroff R, Williams SA, Kastenmüller G, Ralser M, Gamazon ER, Wareham NJ, Hingorani AD, Langenberg C
(2020) Nat Commun 11: 6397
MeSH Terms: ABO Blood-Group System, Aptamers, Peptide, Blood Coagulation, COVID-19, Drug Delivery Systems, Female, Gene Expression Regulation, Host-Derived Cellular Factors, Host-Pathogen Interactions, Humans, Internet, Male, Middle Aged, Proteins, Quantitative Trait Loci, SARS-CoV-2
Show Abstract · Added December 18, 2020
Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).
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16 MeSH Terms
PEGylated PLGA Nanoparticle Delivery of Eggmanone for T Cell Modulation: Applications in Rheumatic Autoimmunity.
Haycook CP, Balsamo JA, Glass EB, Williams CH, Hong CC, Major AS, Giorgio TD
(2020) Int J Nanomedicine 15: 1215-1228
MeSH Terms: Animals, Autoimmunity, CD4-Positive T-Lymphocytes, Cytokines, Drug Delivery Systems, Female, Hedgehog Proteins, Immunoglobulin Fragments, Immunologic Factors, Mice, Inbred C57BL, Nanoparticles, Polylactic Acid-Polyglycolic Acid Copolymer, Pyrimidinones, Rheumatic Diseases, T-Lymphocytes, T-Lymphocytes, Helper-Inducer, Thiophenes
Show Abstract · Added March 30, 2020
Background - Helper T cell activity is dysregulated in a number of diseases including those associated with rheumatic autoimmunity. Treatment options are limited and usually consist of systemic immune suppression, resulting in undesirable consequences from compromised immunity. Hedgehog (Hh) signaling has been implicated in the activation of T cells and the formation of the immune synapse, but remains understudied in the context of autoimmunity. Modulation of Hh signaling has the potential to enable controlled immunosuppression but a potential therapy has not yet been developed to leverage this opportunity.
Methods - In this work, we developed biodegradable nanoparticles to enable targeted delivery of eggmanone (Egm), a specific Hh inhibitor, to CD4 T cell subsets. We utilized two FDA-approved polymers, poly(lactic-co-glycolic acid) and polyethylene glycol, to generate hydrolytically degradable nanoparticles. Furthermore, we employed maleimide-thiol mediated conjugation chemistry to decorate nanoparticles with anti-CD4 F(ab') antibody fragments to enable targeted delivery of Egm.
Results - Our novel delivery system achieved a highly specific association with the majority of CD4 T cells present among a complex cell population. Additionally, we have demonstrated antigen-specific inhibition of CD4 T cell responses mediated by nanoparticle-formulated Egm.
Conclusion - This work is the first characterization of Egm's immunomodulatory potential. Importantly, this study also suggests the potential benefit of a biodegradable delivery vehicle that is rationally designed for preferential interaction with a specific immune cell subtype for targeted modulation of Hh signaling.
© 2020 Haycook et al.
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17 MeSH Terms
Endosomolytic and Tumor-Penetrating Mesoporous Silica Nanoparticles for siRNA/miRNA Combination Cancer Therapy.
Wang Y, Xie Y, Kilchrist KV, Li J, Duvall CL, Oupický D
(2020) ACS Appl Mater Interfaces 12: 4308-4322
MeSH Terms: Animals, Breast Neoplasms, Drug Delivery Systems, Endosomes, Female, Genetic Therapy, Humans, Mice, MicroRNAs, Nanoparticles, RNA, Small Interfering, Silicon Dioxide
Show Abstract · Added March 19, 2020
Combination therapies consisting of multiple short therapeutic RNAs, such as small interfering RNA (siRNA) and microRNA (miRNA), have enormous potential in cancer treatment as they can precisely silence a specific set of oncogenes and target multiple disease-related pathways. However, clinical use of siRNA/miRNA combinations is limited by the availability of safe and efficient systemic delivery systems with sufficient tumor penetrating and endosomal escaping capabilities. This study reports on the development of multifunctional tumor-penetrating mesoporous silica nanoparticles (iMSNs) for simultaneous delivery of siRNA (siPlk1) and miRNA (miR-200c), using encapsulation of a photosensitizer indocyanine green (ICG) to facilitate endosomal escape and surface conjugation of the iRGD peptide to enable deep tumor penetration. Increased cell uptake of the nanoparticles was observed in both 3D tumor spheroids in vitro and in orthotopic MDA-MB-231 breast tumors in vivo. Using a galectin-8 recruitment assay, we showed that reactive oxygen species generated by ICG upon light irradiation functioned as an endosomolytic stimulus that caused release of the siRNA/miRNA combination from endosomes. Co-delivery of the therapeutic RNAs displayed combined cell killing activity in cancer cells. Systemic intravenous treatment of metastatic breast cancer with the iMSNs loaded with siPlk1 and miR-200c resulted in a significant suppression of the primary tumor growth and in marked reduction of metastasis upon short light irradiation of the primary tumor. This work demonstrates that siRNA-miRNA combination assisted by the photodynamic effect and tumor penetrating delivery system may provide a promising approach for metastatic cancer treatment.
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12 MeSH Terms
An anionic, endosome-escaping polymer to potentiate intracellular delivery of cationic peptides, biomacromolecules, and nanoparticles.
Evans BC, Fletcher RB, Kilchrist KV, Dailing EA, Mukalel AJ, Colazo JM, Oliver M, Cheung-Flynn J, Brophy CM, Tierney JW, Isenberg JS, Hankenson KD, Ghimire K, Lander C, Gersbach CA, Duvall CL
(2019) Nat Commun 10: 5012
MeSH Terms: Acrylates, Animals, Anions, Cations, Cell Line, Cells, Cultured, Drug Delivery Systems, Endosomes, HEK293 Cells, Humans, Intracellular Space, MCF-7 Cells, Macromolecular Substances, Mice, NIH 3T3 Cells, Nanoparticles, Peptides, Polymers, RAW 264.7 Cells, Rats, Reproducibility of Results
Show Abstract · Added November 7, 2019
Peptides and biologics provide unique opportunities to modulate intracellular targets not druggable by conventional small molecules. Most peptides and biologics are fused with cationic uptake moieties or formulated into nanoparticles to facilitate delivery, but these systems typically lack potency due to low uptake and/or entrapment and degradation in endolysosomal compartments. Because most delivery reagents comprise cationic lipids or polymers, there is a lack of reagents specifically optimized to deliver cationic cargo. Herein, we demonstrate the utility of the cytocompatible polymer poly(propylacrylic acid) (PPAA) to potentiate intracellular delivery of cationic biomacromolecules and nano-formulations. This approach demonstrates superior efficacy over all marketed peptide delivery reagents and enhances delivery of nucleic acids and gene editing ribonucleoproteins (RNPs) formulated with both commercially-available and our own custom-synthesized cationic polymer delivery reagents. These results demonstrate the broad potential of PPAA to serve as a platform reagent for the intracellular delivery of cationic cargo.
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21 MeSH Terms
Preparation, preliminary pharmacokinetic and brain targeting study of metformin encapsulated W/O/W composite submicron emulsions promoted by borneol.
Hong L, Li X, Bao Y, Duvall CL, Zhang C, Chen W, Peng C
(2019) Eur J Pharm Sci 133: 160-166
MeSH Terms: Animals, Brain, Camphanes, Drug Compounding, Drug Delivery Systems, Drug Liberation, Emulsions, Female, Hypoglycemic Agents, Male, Metformin, Rats, Sprague-Dawley
Show Abstract · Added April 10, 2019
Metformin hydrochloride (Met) is the first-line drug to treat type 2 diabetes and has shown high efficiency in reducing Alzheimer's disease in recent studies. Herein, a borneol W/O/W composite submicron emulsion containing Met (B-Met-W/O/W SE) was prepared, expecting longer in-vivo circulation time, better bioavailability and brain targeting of Met drug. In the optimized formulation, the mean droplets size, polydispersity index and encapsulation efficiency of the composite were 386.5 nm, 0.219 and 87.26%, respectively. FTIR analysis confirmed that Met interacted with carriers in B-Met-W/O/W SE. Compared with Met free drug, in-vitro release of Met in B-Met-W/O/W SE delivery system was much slower. In pharmacokinetic studies in rats, the AUC, MRT and t of the B-Met-W/O/W SE system were respectively 1.27, 2.49 and 4.02-fold higher than Met free drug system. The drug-targeting index of B-Met-W/O/W SE system to the brain tissue was also higher than that of Met free drug system and Met-W/O/W SE system. These results indicated that B-Met-W/O/W SE drug delivery system is a promising candidate in treating clinical Alzheimer's disease.
Copyright © 2019 Elsevier B.V. All rights reserved.
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12 MeSH Terms
Gal8 Visualization of Endosome Disruption Predicts Carrier-Mediated Biologic Drug Intracellular Bioavailability.
Kilchrist KV, Dimobi SC, Jackson MA, Evans BC, Werfel TA, Dailing EA, Bedingfield SK, Kelly IB, Duvall CL
(2019) ACS Nano 13: 1136-1152
MeSH Terms: Biological Availability, Biological Products, Drug Carriers, Drug Delivery Systems, Endosomes, Galectins, High-Throughput Screening Assays, Humans
Show Abstract · Added April 10, 2019
Endolysosome entrapment is one of the key barriers to the therapeutic use of biologic drugs that act intracellularly. The screening of prospective nanoscale endosome-disrupting delivery technologies is currently limited by methods that are indirect and cumbersome. Here, we statistically validate Galectin 8 (Gal8) intracellular tracking as a superior approach that is direct, quantitative, and predictive of therapeutic cargo intracellular bioactivity through in vitro high-throughput screening and in vivo validation. Gal8 is a cytosolically dispersed protein that, when endosomes are disrupted, redistributes by binding to glycosylation moieties selectively located on the inner face of endosomal membranes. The quantitative redistribution of a Gal8 fluorescent fusion protein from the cytosol into endosomes is demonstrated as a real-time, live-cell assessment of endosomal integrity that does not require labeling or modification of either the carrier or the biologic drug and that allows quantitative distinction between closely related, endosome-disruptive drug carriers. Through screening two families of siRNA polymeric carrier compositions at varying dosages, we show that Gal8 endosomal recruitment correlates strongly ( r = 0.95 and p < 10) with intracellular siRNA bioactivity. Through this screen, we gathered insights into how composition and molecular weight affect endosome disruption activity of poly[(ethylene glycol)- b-[(2-(dimethylamino)ethyl methacrylate)- co-(butyl methacrylate)]] [PEG-(DMAEMA- co-BMA)] siRNA delivery systems. Additional studies showed that Gal8 recruitment predicts intracellular bioactivity better than current standard methods such as Lysotracker colocalization ( r = 0.35, not significant), pH-dependent hemolysis (not significant), or cellular uptake ( r = 0.73 and p < 10). Importantly, the Gal8 recruitment method is also amenable to fully objective high-throughput screening using automated image acquisition and quantitative image analysis, with a robust estimated Z' of 0.6 (whereas assays with Z' > 0 have high-throughput screening utility). Finally, we also provide measurements of in vivo endosomal disruption based on Gal8 visualization ( p < 0.03) of a nanocarrier formulation confirmed to produce significant cytosolic delivery and bioactivity of siRNA within tumors ( p < 0.02). In sum, this report establishes the utility of Gal8 subcellular tracking for the rapid optimization and high-throughput screening of the endosome disruption potency of intracellular delivery technologies.
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8 MeSH Terms
Platelet-Based Drug Delivery for Cancer Applications.
Ortiz-Otero N, Mohamed Z, King MR
(2018) Adv Exp Med Biol 1092: 235-251
MeSH Terms: Blood Platelets, Drug Delivery Systems, Hemostasis, Humans, Male, Neoplasm Metastasis, Neoplasms
Show Abstract · Added April 15, 2019
Platelets can be considered as the "guardian of hemostasis" where their main function is to maintain vascular integrity. In pathological conditions, the hemostatic role of platelets may be hijacked to stimulate disease progression. In 1865, Armand Trousseau was a pioneer in establishing the platelet-cancer metastasis relationship, which he eventually termed as Trousseau's Syndrome to describe the deregulation of the hemostasis-associated pathways induced by cancer progression (Varki, Blood. 110(6):1723-9, 2007). Since these early studies, there has been an increase in experimental evidence not only to elucidate the role of platelets in cancer metastasis but also to create novel cancer therapies by targeting the platelet's impact in metastasis. In this chapter, we discuss the contribution of platelets in facilitating tumor cell transit from the primary tumor to distant metastatic sites as well as novel cancer therapies based on platelet interactions.
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7 MeSH Terms
Localized low-dose rhBMP-2 is effective at promoting bone regeneration in mandibular segmental defects.
Carlisle P, Guda T, Silliman DT, Burdette AJ, Talley AD, Alvarez R, Tucker D, Hale RG, Guelcher SA, BrownBaer PR
(2019) J Biomed Mater Res B Appl Biomater 107: 1491-1503
MeSH Terms: Animals, Bone Morphogenetic Protein 2, Bone Regeneration, Calcium Phosphates, Drug Delivery Systems, Durapatite, Humans, Mandible, Mandibular Injuries, Recombinant Proteins, Swine, Swine, Miniature, Tomography, X-Ray Computed
Show Abstract · Added March 20, 2020
At least 26% of recent battlefield injuries are to the craniomaxillofacial (CMF) region. Recombinant human bone morphogenetic protein 2 (rhBMP-2) is used to treat CMF open fractures, but several complications have been associated with its use. This study tested the efficacy and safety of a lower (30% recommended) dose of rhBMP-2 to treat mandibular fractures. rhBMP-2 delivered via a polyurethane (PUR) and hydroxyapatite/β-tricalcium phosphate (Mastergraft®) scaffold was evaluated in a 2 cm segmental mandibular defect in minipigs. Bone regeneration was analyzed at 4, 8, and 12 weeks postsurgery using clinical computed tomography (CT) and rhBMP-2, and inflammatory marker concentrations were analyzed in serum and surgery-site drain effluent. CT scans revealed that pigs treated with PUR-Mastergraft® + rhBMP-2 had complete bone bridging, while the negative control group showed incomplete bone-bridging (n = 6). Volumetric analysis of regenerated bone showed that the PUR-Mastergraft® + rhBMP-2 treatment generated significantly more bone than control by 4 weeks, a trend that continued through 12 weeks. Variations in inflammatory analytes were detected in drain effluent samples and saliva but not in serum, suggesting a localized healing response. Importantly, the rhBMP-2 group did not exhibit an excessive increase in inflammatory analytes compared to control. Treatment with low-dose rhBMP-2 increases bone regeneration capacity in pigs with mandibular continuity defects and restores bone quality. Negative complications from rhBMP-2, such as excessive inflammatory analyte levels, were not observed. Together, these results suggest that treatment with low-dose rhBMP-2 is efficacious and may improve safety when treating CMF open fractures. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1491-1503, 2019.
© 2018 Wiley Periodicals, Inc.
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1 Members
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13 MeSH Terms
Macrophage-Targeted Therapeutics for Metabolic Disease.
Peterson KR, Cottam MA, Kennedy AJ, Hasty AH
(2018) Trends Pharmacol Sci 39: 536-546
MeSH Terms: Drug Delivery Systems, Gene Expression, Humans, Macrophages, Metabolic Diseases, Molecular Targeted Therapy, Pharmaceutical Preparations
Show Abstract · Added March 26, 2019
Macrophages are cells of the innate immune system that are resident in all tissues, including metabolic organs such as the liver and adipose tissue (AT). Because of their phenotypic flexibility, they play beneficial roles in tissue homeostasis, but they also contribute to the progression of metabolic disease. Thus, they are ideal therapeutic targets for diseases such as insulin resistance (IR), nonalcoholic fatty liver disease (NAFLD), and atherosclerosis. Recently, discoveries in the area of drug delivery have facilitated phenotype-specific targeting of macrophages. In this review we discuss advances in potential therapeutics for metabolic diseases via macrophage-specific delivery. We highlight micro- and nanoparticles, liposomes, and oligopeptide complexes, and how they can be used to alter macrophage phenotype for a more metabolically favorable tissue environment.
Published by Elsevier Ltd.
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MeSH Terms
Immediate Enhancement of Nerve Function Using a Novel Axonal Fusion Device After Neurotmesis.
Riley DC, Boyer RB, Deister CA, Pollins AC, Cardwell NL, Kelm ND, Does MD, Dortch RD, Bamba R, Shack RB, Thayer WP
(2017) Ann Plast Surg 79: 590-599
MeSH Terms: Animals, Axons, Disease Models, Animal, Drug Delivery Systems, Electromyography, Female, Immunohistochemistry, Male, Nerve Regeneration, Neurosurgical Procedures, Peripheral Nerve Injuries, Polyethylene Glycols, Random Allocation, Rats, Rats, Sprague-Dawley, Recovery of Function, Sciatic Nerve, Trauma, Nervous System
Show Abstract · Added October 24, 2018
BACKGROUND - The management of peripheral nerve injuries remains a large challenge for plastic surgeons. With the inability to fuse axonal endings, results after microsurgical nerve repair have been inconsistent. Our current nerve repair strategies rely upon the slow and lengthy process of axonal regeneration (~1 mm/d). Polyethylene glycol (PEG) has been investigated as a potential axonal fusion agent; however, the percentage of axonal fusion has been inconsistent. The purpose of this study was to identify a PEG delivery device to standardize outcomes after attempted axonal fusion with PEG.
MATERIALS AND METHODS - We used a rat sciatic nerve injury model in which we completely transected and repaired the left sciatic nerve to evaluate the efficacy of PEG fusion over a span of 12 weeks. In addition, we evaluated the effectiveness of a delivery device's ability to optimize results after PEG fusion.
RESULTS - We found that PEG rapidly (within minutes) restores axonal continuity as assessed by electrophysiology, fluorescent retrograde tracer, and diffusion tensor imaging. Immunohistochemical analysis shows that motor axon counts are significantly increased at 1 week, 4 weeks, and 12 weeks postoperatively in PEG-treated animals. Furthermore, PEG restored behavioral functions up to 50% compared with animals that received the criterion standard epineurial repair (control animals).
CONCLUSIONS - The ability of PEG to rapidly restore nerve function after neurotmesis could have vast implications on the clinical management of traumatic injuries to peripheral nerves.
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MeSH Terms