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Kalina Paunovska, Alejandro J Da Silva Sanchez, Cory D Sago, Zubao Gan, Melissa P Lokugamage, Fatima Z Islam, Sujay Kalathoor, Brandon R Krupczak, James E Dahlman
Using mRNA to produce therapeutic proteins is a promising approach to treat genetic diseases. However, systemically delivering mRNA to cell types besides hepatocytes remains challenging. Fast identification of nanoparticle delivery (FIND) is a DNA barcode-based system designed to measure how over 100 lipid nanoparticles (LNPs) deliver mRNA that functions in the cytoplasm of target cells in a single mouse. By using FIND to quantify how 75 chemically distinct LNPs delivered mRNA to 28 cell types in vivo, it is found that an LNP formulated with oxidized cholesterol and no targeting ligand delivers Cre mRNA, which edits DNA in hepatic endothelial cells and Kupffer cells at 0...
February 12, 2019: Advanced Materials
Funing Liu, Hongli Zhang, Junjie Cheng, Jingang Hu, Chenlu He, Qijin Zhang, Gang Zou
Herein, we study the enantioselective cytotoxicity of vesicles self-assembled by optically active linear polymers (LNPs) and hyperbranched polymers (HBPs). Compared to HBP vesicles, LNP vesicles exhibit properties such as a higher surface charge density and more violent interaction with simulated biomembranes which results in larger cytotoxicity against HeLa cells. Specifically, racemic-LNP vesicles exhibit the largest cytotoxicity of all. More interestingly, there is no significant enantioselective dependence of HBP vesicles on the abovementioned properties...
February 8, 2019: Soft Matter
Xu Shu, Yanfen Zhang, Jinxia Jia, Xiaojie Ren, Yufeng Wang
Lepista nuda has high nutritional and medicinal value, especially has high antioxidant, antitumor and antiviral activities. Based on results of single factor experiment, response surface methodology was used to optimize the extraction conditions of polysaccharides (LNP). Macroporous resin D301 was used to decolorization, and its technological conditions were determined by orthogonal experiment. In addition, two novel polysaccharides (LNP-1, LNP-2) were purified by DEAE Cellulose-52 and Sephadex G-150 chromatography...
February 1, 2019: International Journal of Biological Macromolecules
Takara Ohto, Manami Konishi, Hiroki Tanaka, Koji Onomoto, Mitsutoshi Yoneyama, Yuta Nakai, Kota Tange, Hiroki Yoshioka, Hidetaka Akita
While the use of in vitro-transcribed mRNA (IVT-mRNA) in therapeutics is a rapidly expanding area, the transfection of the exogenous IVT-mRNA is accompanied by a risk of immune activation. This immunological defense mechanism suppresses cellular translation process and can reduce transfection efficiency to a considerable extent. In the present study, we investigated the in vitro effects of Integrated Stress Response Inhibitor (ISRIB), and dexamethasone, a steroidal anti-inflammatory drug, on the transfection activity of a lipid nanoparticle (LNP) that was composed of ionizable lipids and IVT-mRNA...
2019: Biological & Pharmaceutical Bulletin
Xiaoyan He, Francesca Luzi, Xiaolong Hao, Weijun Yang, Luigi Torre, Zefang Xiao, Yanjun Xie, Debora Puglia
Lignin nanoparticles (LNP) have been esterified and etherified by citric acid and then blended with poly (vinyl alcohol) (PVA) at various loading levels (up to 10 wt%). Poly(vinyl alcohol) nanocomposite films containing unmodified and modified lignin nanoparticles (LNP and MLNP) were prepared through solvent casting approach. Microscopic investigation of films fractured surfaces confirmed that MLNP could be evenly dispersed in PVA matrix, and no macroscopic phase separation was generated in the nanocomposite films...
January 30, 2019: International Journal of Biological Macromolecules
Ying Chen, Kun Zheng, Li Niu, Yutao Zhang, Yupeng Liu, Chunpeng Wang, Fuxiang Chu
Biorenewable polymers from natural resources have attracted a greater attention of the research for different applications. In this work, renewable lignin nanoparticles (LNP) were employed as cross-linking junctions to prepare high mechanical properties hydrogel, polyacrylamide/lignin nanoparticle (PAM/LNP) nanocomposite hydrogel. The hydrogel exhibits high compressive and tensile strengths as well as excellent recoverability. The fracture strength of the PAM/LNP hydrogel under compressive stress is on the order of megapascals, which is several orders of magnitude higher than those of pure PAM hydrogel...
January 22, 2019: International Journal of Biological Macromolecules
S Novakowski, K Jiang, G Prakash, C Kastrup
Platelets are natural delivery vehicles within the blood, carrying and releasing their contents at sites of vasculature damage. Investigating the biology of platelets, and modifying them for new therapeutic uses, is limited by a lack of methods for efficiently transfecting these cells. The ability of four different classes of lipid nanoparticles (LNPs) to deliver mRNA to platelets was compared using confocal microscopy, flow cytometry and quantitative PCR. The amount of mRNA delivered, mechanism of uptake, and extent of platelet activation depended on the LNP formulation and platelet storage conditions...
January 24, 2019: Scientific Reports
Nour Shobaki, Yusuke Sato, Hideyoshi Harashima
Introduction: The development of targeted drug delivery systems is a rapidly growing area in the field of nanomedicine. Methods: We report herein on optimizing the targeting efficiency of a lipid nanoparticle (LNP) by manipulating the acid dissociation constant ( pKa ) value of its membrane, which reflects its ionization status. Instead of changing the chemical structure of the lipids to achieve this, we used a mixture of two types of pH-sensitive cationic lipids that show different pKa values in a single LNP...
2018: International Journal of Nanomedicine
Laura A VanBlargan, Sunny Himansu, Bryant M Foreman, Gregory D Ebel, Theodore C Pierson, Michael S Diamond
Powassan virus (POWV) is an emerging tick-transmitted flavivirus that circulates in North America and Russia. Up to 5% of deer ticks now test positive for POWV in certain regions of the northern United States. Although POWV infections cause life-threatening encephalitis, there is no vaccine or countermeasure available for prevention or treatment. Here, we developed a lipid nanoparticle (LNP)-encapsulated modified mRNA vaccine encoding the POWV prM and E genes and demonstrated its immunogenicity and efficacy in mice following immunization with one or two doses...
December 18, 2018: Cell Reports
Yamin Li, Alice Chukun Li, Qiaobing Xu
Protein- and peptide-based therapeutics with high tolerance and specificity along with low off-target effects and genetic risks have attracted tremendous attention over the last three decades. Herein, a new type of noncationic lipidoid nanoparticle (LNP) is reported for His-tagged protein delivery. Active lipidoids are synthesized by conjugating a nitrilotriacetic acid group with hydrophobic tails (EC16, O16B, and O17O) and nanoparticles are formulated in the presence of nickel ions and helper lipids (cholesterol, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000])...
November 22, 2018: Advanced Healthcare Materials
Rebecca A Lapides, Dennis A Savaiano
Research evaluating the relationship between lactose intolerance (LI) symptoms and age, gender and race is reviewed. An exhaustive search was conducted on the Google Scholar and PubMed databases. The evidence suggests that women, the elderly or specific racial groups are not more susceptible to LI, but rather dose, body size and genetic differences in lactase non-persistence (LNP) are the primary drivers of intolerance symptoms.
December 11, 2018: Nutrients
Yu Sakurai, Tomoya Hada, Akari Kato, Yuta Hagino, Wataru Mizumura, Hideyoshi Harashima
Although metastatic cancer is a major cause of death for cancer patients, no efficacious treatment for metastasis is available. We previously showed that the growth of a primary tumor could be inhibited by the administration of an anti-angiogenic small interfering RNA (siRNA) that is encapsulated in an RGD peptide-modified lipid nanoparticle (RGD-LNP). We herein report on the delivery of siRNA by an RGD-LNP to the vasculature is also effective for treating metastatic tumors. We compared the RGD-LNP with the polyethylene glycol (PEG)ylated LNP (PEG-LNP) in terms of accumulation in a lung-metastasized model...
December 21, 2018: Molecular Therapy Oncolytics
Xin Zhou, Yu He, Xiaofang Huang, Yuting Guo, Dong Li, Junjie Hu
Three-way junctions are characteristic structures of the tubular endoplasmic reticulum (ER) network. Junctions are formed through atlastin (ATL)-mediated membrane fusion and stabilized by lunapark (Lnp). However, how Lnp is preferentially enriched at three-way junctions remains elusive. Here, we showed that Lnp loses its junction localization when ATLs are deleted. Reintroduction of ATL1 R77A and ATL3, which have been shown to cluster at the junctions, but not wild-type ATL1, relocates Lnp to the junctions...
November 29, 2018: Protein & Cell
Puneet Tyagi, Sergei Pechenov, Jonathan RiosDoria, Luke Masterson, Niall J Dickinson, Philip Howard, Shenlan Mao, Jay Harper, Leslie Wetzel, Kwok Yo, J Anand Subramony
We describe the development and evaluation of pyrrolobenzodiazepines (PBDs) in poly(DL-lactide-co-glycolide) (PLGA) and lipid (LNP) nanoparticle drug delivery systems. We have established that the partition coefficient (LogP) of PBD is a key influencer of the encapsulation efficiency in nanoparticle systems, with higher LogP values associated with higher encapsulation efficiencies toward increased drug payload delivery and better antitumor efficacy. Cytotoxicity assays demonstrated that compounds with higher LogP values demonstrated higher 50% inhibitory concentration values than the free drug...
November 22, 2018: Journal of Pharmaceutical Sciences
Ian Lai, Srividya Swaminathan, Virginie Baylot, Adriane Mosley, Renumathy Dhanasekaran, Meital Gabay, Dean W Felsher
Interleukin-12 (IL-12) is a promising candidate for cancer immunotherapy because of its ability to activate a number of host immune subsets that recognize and destroy cancer cells. We found that human hepatocellular carcinoma (HCC) patients with higher than median levels of IL-12 have significantly favorable clinical outcomes. Here, we report that a messenger RNA (mRNA) lipid nanoparticle delivering IL-12 (IL-12-LNP) slows down the progression of MYC oncogene-driven HCC. IL-12-LNP was well distributed within the HCC tumor and was not associated with significant animal toxicity...
November 20, 2018: Journal for Immunotherapy of Cancer
Songyu Wang, Robert E Powers, Vicki Am Gold, Tom A Rapoport
Lunapark (Lnp) is a conserved membrane protein that localizes to and stabilizes three-way junctions of the tubular ER network. In higher eukaryotes, phosphorylation of Lnp may contribute to the conversion of the ER from tubules to sheets during mitosis. Here, we report on the reconstitution of purified Lnp with phospholipids. Surprisingly, Lnp induces the formation of stacked membrane discs. Each disc is a bicelle, with Lnp sitting in the bilayer facing both directions. The interaction between bicelles is mediated by the cytosolic domains of Lnp, resulting in a constant distance between the discs...
January 2018: Life science alliance
Xin Ye, Chise Tateno, Emily P Thi, Masakazu Kakuni, Nicholas M Snead, Yuji Ishida, Trisha R Barnard, Michael J Sofia, Takashi Shimada, Amy C H Lee
Hepatitis delta virus (HDV) infects 10-20 million individuals worldwide and causes severe fulminant hepatitis with high likelihood of cirrhosis and hepatocellular carcinoma. HDV infection cannot occur in the absence of the surface antigen (HBsAg) of the hepatitis B virus. RNA interference is an effective mechanism by which to inhibit viral transcripts, and siRNA therapeutics sharing this mechanism have begun to demonstrate clinical efficacy. Here we assessed the outcome of HBV-targeting siRNA intervention against HDV and compared it to a direct anti-HDV siRNA approach in dually infected humanized mice...
November 20, 2018: ACS Infectious Diseases
Claire Desfrançois, Rachel Auzély, Isabelle Texier
Several drug delivery systems already exist for the encapsulation and subsequent release of lipophilic drugs that are well described in the scientific literature. Among these, lipid nanoparticles (LNP) have specifically come up for dermal, transdermal, mucosal, intramuscular and ocular drug administration routes in the last twenty years. However, for some of them (especially dermal, transdermal, mucosal), the LNP aqueous dispersions display unsuitable rheological properties. They therefore need to be processed as semi-solid formulations such as LNP-hydrogel composites to turn into versatile drug delivery systems able to provide precise spatial and temporal control of active ingredient release...
November 1, 2018: Pharmaceuticals
Drew M P Peltier, Kiona Ogle
While we often assume tree growth-climate relationships are time-invariant, impacts of climate phenomena such as the El Niño Southern Oscillation (ENSO) and the North American Monsoon (NAM) may challenge this assumption. To test this assumption, we grouped ring-widths (1900-present) in three southwestern US conifers into La Niña periods (LNP) and other years (OY). The four years following each La Niña year are included in LNP, and despite 1-2 year growth declines, compensatory adjustments in tree growth responses result in essentially equal mean growth in LNP and OY, as average growth exceeds OY means 2-4 years after La Niña events...
October 22, 2018: Global Change Biology
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...
December 10, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
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