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Hamideh Parhiz, Vladimir V Shuvaev, Norbert Pardi, Makan Khoshnejad, Raisa Yu Kiseleva, Jacob S Brenner, Thomas Uhler, Steven Tuyishime, Barbara L Mui, Ying K Tam, Thomas D Madden, Michael J Hope, Drew Weissman, Vladimir R Muzykantov
Systemic administration of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) leads predominantly to hepatic uptake and expression. Here, we conjugated nucleoside-modified mRNA-LNPs with antibodies (Abs) specific to vascular cell adhesion molecule, PECAM-1. Systemic (intravenous) administration of Ab/LNP-mRNAs resulted in profound inhibition of hepatic uptake concomitantly with ~200-fold and 25-fold elevation of mRNA delivery and protein expression in the lungs compared to non-targeted counterparts...
October 15, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Patrick N Lawlor, Matthew G Perich, Lee E Miller, Konrad P Kording
Prominent models of spike trains assume only one source of variability - stochastic (Poisson) spiking - when stimuli and behavior are fixed. However, spike trains may also reflect variability due to internal processes such as planning. For example, we can plan a movement at one point in time and execute it at some arbitrary later time. Neurons involved in planning may thus share an underlying time course that is not precisely locked to the actual movement. Here we combine the standard Linear-Nonlinear-Poisson (LNP) model with Dynamic Time Warping (DTW) to account for shared temporal variability...
October 8, 2018: Journal of Computational Neuroscience
Pablo Hervella, Johan HygumDam, Helge Thisgaard, Christina Baun, Birgitte Brinkmann Olsen, Poul Flemming Høilund-Carlsen, David Needham
BACKGROUND AND MOTIVATION: While small molecules can be used in cancer diagnosis there is a need for imageable diagnostic NanoParticles (NPs) that act as surrogates for the therapeutic NPs. Many NPs are composed of hydrophobic materials so the challenge is to formulate hydrophobic imaging agents. To develop individualized medical treatments based on NP, a first step should be the selection of patients who are likely responders to the treatment as judged by imaging tumor accumulation of NPs...
October 3, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Harvinder Saggi, Dhiman Maitra, An Jiang, Rong Zhang, Pengcheng Wang, Pamela Cornuet, Sucha Singh, Joseph Locker, Xiaochao Ma, Harry Dailey, Marc Abrams, M Bishr Omary, Satdarshan P Monga, Kari Nejak-Bowen
BACKGROUND & AIMS: Porphyrias occur from anomalies of heme biosynthetic enzymes and can lead to cirrhosis and hepatocellular cancer. In mice, these diseases can be modeled by administration of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) containing diet, which causes accumulation of porphyrin intermediates, resulting in hepatobiliary injury. Wnt/β-catenin signaling has been shown to be a modulatable target in models of biliary injury; thus, we investigated its role in DDC-driven injury...
October 1, 2018: Journal of Hepatology
Mika H Sipponen, Heiko Lange, Mariko Ago, Claudia Crestini
The mechanism of lignin nanoprecipitation and subsequent self-assembly was elucidated by studying generation of lignin nanoparticles (LNPs) from aqueous ethanol. LNP formation was found to follow a kinetically controlled nucleation-growth mechanism in which large lignin molecules formed the initial critical nuclei. Using this information, we demonstrate entrapment of budesonide in LNPs and subsequent pH-triggered and surfactant-responsive release of this synthetic anti-inflammatory corticosteroid. Overall, our results not only provide a promising intestinal delivery system for budesonide but also deliver fundamental mechanistic understanding for the entrapment of actives in LNPs with controlled size and release properties...
July 2, 2018: ACS Sustainable Chemistry & Engineering
Zhiyu He, Yizong Hu, Tianqi Nie, Haoyu Tang, Jinchang Zhu, Kuntao Chen, Lixin Liu, Kam W Leong, Yongming Chen, Hai-Quan Mao
Lipid-based nanoparticles (LNPs) have been developed to address the transport and uptake barriers to enhance the delivery efficiency of plasmid DNA therapeutics. In these systems, plasmid DNA can be encapsulated through condensation by a cationic lipid to form lipo-complexes, or polycation following complexation into cationic liposomes to form lipo-polyplexes. Conventional methods for achieving these two DNA-delivering LNP vehicles suffer from significant batch-to-batch variation, poor scalability and complicated multi-step preparation procedures...
September 27, 2018: Acta Biomaterialia
Cory D Sago, Melissa P Lokugamage, Gwyneth N Lando, Naima Djeddar, Nirav N Shah, Chris Syed, Anton V Bryksin, James E Dahlman
Nanoparticles are often targeted to receptors expressed on specific cells, but few receptors are (i) highly expressed on one cell type and (ii) involved in endocytosis. One unexplored alternative is manipulating an endocytic gene expressed on multiple cell types; an ideal gene would inhibit delivery to cell type A more than cell type B, promoting delivery to cell type B. This would require a commonly expressed endocytic gene to alter nanoparticle delivery in a cell type-dependent manner in vivo; whether this can occur is unknown...
September 20, 2018: Nano Letters
Minori Kawai, Takashi Nakamura, Naoya Miura, Mio Maeta, Hiroki Tanaka, Keisuke Ueda, Kenjirou Higashi, Kunikazu Moribe, Kota Tange, Yuta Nakai, Hiroki Yoshioka, Hideyoshi Harashima, Hidetaka Akita
Cytoplasmic DNA triggers cellular immunity via activating the stimulator of interferon genes pathway. Since DNA is degradable and membrane impermeable, delivery system would permit cytoplasmic delivery by destabilizing the endosomal membrane for the use as an adjuvant. Herein, we report on the development of a plasmid DNA (pDNA)-encapsulating lipid nanoparticle (LNP). The structural components include an SS-cleavable and pH-activated lipid-like material that mounts vitamin E as a hydrophobic scaffold, and dual sensing motifs that are responsive to the intracellular environment (ssPalmE)...
August 29, 2018: Nanomedicine: Nanotechnology, Biology, and Medicine
Kyuri Lee, Bora Jang, You-Ri Lee, Eun-Young Suh, Ji-Seon Yoo, Mi-Jin Lee, Joo-Young Lee, Hyukjin Lee
siRNA therapeutics allows precise regulation of disease specific gene expression to treat various diseases. Although gene silencing approaches using siRNA therapeutics shows some promising results in the treatment of gene-related diseases, the practical applications has been limited by problems such as inefficient in vivo delivery to target cells and nonspecific immune responses after systemic or local administration. To overcome these issues, various in vivo delivery platforms have been introduced. Here we provide an overview for three different platform technologies for the in vivo delivery of therapeutic siRNAs (siRNA-GalNAc conjugate, SAMiRNA technology, and LNP-based delivery method) and their applications in the treatment of various diseases...
September 2018: Archives of Pharmacal Research
Owen S Fenton, Kevin J Kauffman, Rebecca L McClellan, James C Kaczmarek, Manhao D Zeng, Jason L Andresen, Luke H Rhym, Michael W Heartlein, Frank DeRosa, Daniel G Anderson
RNAs are a promising class of therapeutics given their ability to regulate protein concentrations at the cellular level. Developing safe and effective strategies to deliver RNAs remains important for realizing their full clinical potential. Here, we develop lipid nanoparticle formulations that can deliver short interfering RNAs (for gene silencing) or messenger RNAs (for gene upregulation). Specifically, we study how the tail length, tail geometry, and linker spacing in diketopiperazine lipid materials influences LNP potency with siRNAs and mRNAs...
October 8, 2018: Angewandte Chemie
Kendra A Turk-Kubo, Paige Connell, David Caron, Mary E Hogan, Hanna M Farnelid, Jonathan P Zehr
Major advances in understanding the diversity, distribution, and activity of marine N2 -fixing microorganisms (diazotrophs) have been made in the past decades, however, large gaps in knowledge remain about the environmental controls on growth and mortality rates. In order to measure diazotroph net growth rates and microzooplankton grazing rates on diazotrophs, nutrient perturbation experiments and dilution grazing experiments were conducted using free-floating in situ incubation arrays in the vicinity of Station ALOHA in March 2016...
2018: Frontiers in Microbiology
Jesse H Erasmus, Amit P Khandhar, Jeff Guderian, Brian Granger, Jacob Archer, Michelle Archer, Emily Gage, Jasmine Fuerte-Stone, Elise Larson, Susan Lin, Ryan Kramer, Rhea N Coler, Christopher B Fox, Dan T Stinchcomb, Steven G Reed, Neal Van Hoeven
Since the first demonstration of in vivo gene expression from an injected RNA molecule almost two decades ago,1 the field of RNA-based therapeutics is now taking significant strides, with many cancer and infectious disease targets entering clinical trials.2 Critical to this success has been advances in the knowledge and application of delivery formulations. Currently, various lipid nanoparticle (LNP) platforms are at the forefront,3 but the encapsulation approach underpinning LNP formulations offsets the synthetic and rapid-response nature of RNA vaccines...
October 3, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Sam Chen, Josh Zaifman, Jayesh A Kulkarni, Igor V Zhigaltsev, Ying K Tam, Marco A Ciufolini, Yuen Yi C Tam, Pieter R Cullis
Lipid nanoparticles (LNPs) are playing a leading role in enabling clinical applications of gene therapies based on DNA or RNA polymers. One factor impeding clinical acceptance of LNP therapeutics is that LNP formulations of nucleic acid polymers can be immunostimulatory, necessitating co-administration of potent corticosteroid immunosuppressive agents. Here, we describe the development of hydrophobic prodrugs of a potent corticosteroid, dexamethasone, that can be readily incorporated into LNP systems. We show that the presence of the dexamethasone prodrug LD003 effectively suppresses production of cytokines such as KC-GRO, TNFα, IL-1β and IL-6 following intravenous administration of LNP loaded with immune stimulatory oligodeoxynucleotides containing cytosine-guanine dinucleotide motifs...
September 28, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Kalina Paunovska, Carmen J Gil, Melissa P Lokugamage, Cory D Sago, Manaka Sato, Gwyn N Lando, Marielena Gamboa Castro, Anton V Bryksin, James E Dahlman
Lipid nanoparticles (LNPs) are formulated using unmodified cholesterol. However, cholesterol is naturally esterified and oxidized in vivo, and these cholesterol variants are differentially trafficked in vivo via lipoproteins including LDL and VLDL. We hypothesized that incorporating the same cholesterol variants into LNPs-which can be structurally similar to LDL and VLDL-would alter nanoparticle targeting in vivo. To test this hypothesis, we quantified how >100 LNPs made with six cholesterol variants delivered DNA barcodes to 18 cell types in wild-type, LDLR-/- , and VLDLR-/- mice that were both age-matched and female...
August 28, 2018: ACS Nano
Haruko Ueda, Natsumi Ohta, Yoshitaka Kimori, Teruka Uchida, Tomoo Shimada, Kentaro Tamura, Ikuko Hara-Nishimura
The endoplasmic reticulum (ER) is a large network made of membranous cisternae and tubules, which accounts for a large proportion of the total lipid bilayer endomembrane of the cell. In mammals and yeast, LUNAPARK proteins are preferentially localized at the three-way junctions of the ER network, stabilizing the junctions and establishing the ER architecture. We identified two Arabidopsis homologs and designated them LNPA and LNPB. Subcellular localization analysis with a non-dimerizable type of green fluorescent protein (GFP) revealed that both LNPA and LNPB are predominantly distributed throughout the ER, but not preferentially localized at the three-way junctions...
October 1, 2018: Plant & Cell Physiology
Yueping Jiang, Wen Zi, Zhifang Pei, Shao Liu
Two novel polysaccharides, Plumula nelumbinis (P. nelumbinis) polysaccharide I (LNP I) and P. nelumbinis polysaccharide II (LNP II), were extracted and purified from P. nelumbinis , and a sulfated polysaccharide, P. nelumbinis polysaccharide III (LNP III), with a substitution degree of 0.62 was prepared from LNPI. The structures of the LNPs were preliminarily characterized using high performance size exclusion chromatography (HPSEC), gas chromatography-mass spectrometry (GC-MS), Fourier transformed infrared spectrometry (FT-IR), and nuclear magnetic resonance (NMR) spectrometry...
July 2018: Saudi Pharmaceutical Journal: SPJ: the Official Publication of the Saudi Pharmaceutical Society
Piotr S Kowalski, Umberto Capasso Palmiero, Yuxuan Huang, Arnab Rudra, Robert Langer, Daniel G Anderson
The utility of messenger RNA (mRNA) as a therapy is gaining a broad interest due to its potential for addressing a wide range of diseases, while effective delivery of mRNA molecules to various tissues still poses a challenge. This study reports on the design and characterization of new ionizable amino-polyesters (APEs), synthesized via ring opening polymerization (ROP) of lactones with tertiary amino-alcohols that enable tissue and cell type selective delivery of mRNA. With a diverse library of APEs formulated into lipid nanoparticles (LNP), structure-activity parameters crucial for efficient transfection are established and APE-LNPs are identified that can preferentially home to and elicit effective mRNA expression with low in vivo toxicity in lung endothelium, liver hepatocytes, and splenic antigen presenting cells, including APE-LNP demonstrating nearly tenfold more potent systemic mRNA delivery to the lungs than vivo-jetPEI...
July 5, 2018: Advanced Materials
Jian Zhang, Joseph R Lakowicz
Background: Near-field fluorescence (NFF) effects were employed to develop a novel near-infrared (NIR) luminescent nanoparticle (LNP) with superior brightness. The LNP is used as imaging contrast agent for cellular and small animal imaging and furthermore suggested to use for detecting voltage-sensitive calcium in living cells and animals with high sensitivity. Results: NIR Indocyanine green (ICG) dye was conjugated with human serum albumin (HSA) followed by covalently binding to gold nanorod (AuNR)...
2018: Cell & Bioscience
Ann E Almazar, Joseph Y Chang, Joseph J Larson, Elizabeth J Atkinson, G Richard Locke, Nicholas J Talley, Yuri A Saito
GOALS: To evaluate agreement of MCM6-13910 with self-report of dairy sensitivity (DS) and lactose hydrogen methane breath test (LHMBT) results in subjects with irritable bowel syndrome (IBS). BACKGROUND: IBS is a functional gastrointestinal disorder with symptoms including abdominal pain, variable bowel habits, and bloating. Adult patients with lactose malabsorption may present with similar symptoms. Patients with lactose malabsorption have a lactase nonpersistent (LNP) phenotype...
June 16, 2018: Journal of Clinical Gastroenterology
Ema Robinson, Kelvin D MacDonald, Kai Slaughter, Madison McKinney, Siddharth Patel, Conroy Sun, Gaurav Sahay
The promise of gene therapy for the treatment of cystic fibrosis has yet to be fully clinically realized despite years of effort toward correcting the underlying genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR). mRNA therapy via nanoparticle delivery represents a powerful technology for the transfer of genetic material to cells with large, widespread populations, such as airway epithelia. We deployed a clinically relevant lipid-based nanoparticle (LNP) for packaging and delivery of large chemically modified CFTR mRNA (cmCFTR) to patient-derived bronchial epithelial cells, resulting in an increase in membrane-localized CFTR and rescue of its primary function as a chloride channel...
August 1, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
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