Nanodiscs as a therapeutic delivery agent: Inhibition of respiratory syncytial virus infection in the lung

Department of Medicine, Program in Cell Biology, National Jewish Health, Denver, CO, USA.
International Journal of Nanomedicine (Impact Factor: 4.38). 04/2013; 8:1417-1427. DOI: 10.2147/IJN.S39888
Source: PubMed


There is increasing interest in the application of nanotechnology to solve the difficult problem of therapeutic administration of pharmaceuticals. Nanodiscs, composed of a stable discoidal lipid bilayer encircled by an amphipathic membrane scaffold protein that is an engineered variant of the human Apo A-I constituent of high-density lipoproteins, have been a successful platform for providing a controlled lipid composition in particles that are especially useful for investigating membrane protein structure and function. In this communication, we demonstrate that nanodiscs are effective in suppressing respiratory syncytial viral (RSV) infection both in vitro and in vivo when self-assembled with the minor pulmonary surfactant phospholipid palmitoyloleoylphosphatidylglycerol (POPG). Preparations of nanodiscs containing POPG (nPOPG) antagonized interleukin-8 production from Beas2B epithelial cells challenged by RSV infection, with an IC50 of 19.3 μg/mL. In quantitative in vitro plaque assays, nPOPG reduced RSV infection by 93%. In vivo, nPOPG suppressed inflammatory cell infiltration into the lung, as well as IFN-γ production in response to RSV challenge. nPOPG also completely suppressed the histopathological changes in lung tissue elicited by RSV and reduced the amount of virus recovered from lung tissue by 96%. The turnover rate of nPOPG was estimated to have a halftime of 60-120 minutes (m), based upon quantification of the recovery of the human Apo A-I constituent. From these data, we conclude that nPOPG is a potent antagonist of RSV infection and its inflammatory sequelae both in vitro and in vivo.

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    • "In this regard, future modifications of the SMA copolymer (size, pendant group stoichiometry and functionalization with molecular tags) will likely be useful in the development of novel experimental applications. In addition to their utility in basic research, these nanoscale bilayers have vast potential for applied technologies, including the development of biocompatible systems for hydrophobic drug delivery and diagnostic applications (Murakami, 2012; Ng, Lovell, Vedadi, Hajian, & Zheng, 2013; Numata et al., 2013), nanoelectronic devices (Goldsmith et al., 2011; Ham et al., 2010), and multiplexed sensor arrays to detect protein interactions (Sloan, Marty, Sligar, & Bailey, 2013). Given the commercial availability of all components required for the synthesis of nanodiscs and SMAPLs/Lipodisqs®, we are sure to see these systems applied to an ever-expanding repertoire of MPs by many independent groups in the coming years. "
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    ABSTRACT: Within the last decade, nanoscale lipid bilayers have emerged as powerful experimental systems in the analysis of membrane proteins (MPs) for both basic and applied research. These discoidal lipid lamellae are stabilized by annuli of specially engineered amphipathic polypeptides (nanodiscs) or polymers (SMALPs/Lipodisqs®). As biomembrane mimetics, they are well suited for the reconstitution of MPs within a controlled lipid environment. Moreover, because they are water-soluble, they are amenable to solution-based biochemical and biophysical experimentation. Hence, due to their solubility, size, stability, and monodispersity, nanoscale lipid bilayers offer technical advantages over more traditional MP analytic approaches such as detergent solubilization and reconstitution into lipid vesicles. In this article, we review some of the most recent advances in the synthesis of polypeptide- and polymer-bound nanoscale lipid bilayers and their application in the study of MP structure and function.
    Biotechnology & genetic engineering reviews 07/2014; 30(1):79-93. DOI:10.1080/02648725.2014.921502 · 1.39 Impact Factor
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    ABSTRACT: Respiratory syncytial virus (RSV) infects nearly all children under age 2, and reinfection occurs throughout life, seriously impacting adults with chronic pulmonary diseases. Recent data demonstrate the anionic pulmonary surfactant lipid, phosphatidylglycerol (PG), exerts a potent anti-viral effect against RSV in vitro and in vivo. Phosphatidylinositol (PI) is also an anionic pulmonary surfactant phospholipid, and we tested its anti-viral activity. PI liposomes completely suppress interleukin 8 production from BEAS2B epithelial cells challenged with RSV. The presence of PI during viral challenge in vitro reduces infection by a factor of >103. PI binds RSV with high affinity, preventing virus attachment to epithelial cells. Intranasal inoculation with PI along with RSV in mice, reduces the viral burden 30-fold, eliminates the influx of inflammatory cells, and reduces tissue histopathology. Pharmacological doses of PI persist for >6 hrs in mouse lung. Pretreatment of mice with PI at 2 hrs prior to viral infection effectively suppresses inflammation and reduces the viral burden by 85%. These data demonstrate PI has potent anti-viral properties, a long residence time in the extracellular bronchoalveolar compartment, and a significant prophylaxis window. The findings demonstrate the PG and PI have complementary roles as intrinsic, innate immune anti-viral mediators in the lung. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    The Journal of Lipid Research 01/2015; 56(3). DOI:10.1194/jlr.M055723 · 4.42 Impact Factor
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    ABSTRACT: Nanodiscs are monodisperse, self-assembled discoidal particles that consist of a lipid bilayer encircled by membrane scaffold proteins (MSP). Nanodiscs have been used to solubilize membrane proteins for structural and functional studies and deliver therapeutic phospholipids. Herein, we report on tetramethylrhodamine (TMR) tagged Nanodiscs that solubilize lipophilic MR contrast agents for generation of multimodal nanoparticles for cellular imaging. We incorporate both multimeric and monomeric Gd(III)-based contrast agents into Nanodiscs and show that particles containing the monomeric agent (ND2) label cells with high efficiency and generate significant image contrast at 7 T compared to Nanodiscs containing the multimeric agent (ND1) and Prohance®, a clinically approved contrast agent.
    Bioconjugate Chemistry 04/2015; 26(5). DOI:10.1021/acs.bioconjchem.5b00107 · 4.51 Impact Factor

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