Lipid-Coated Mesoporous Silica Nanoparticles for the Delivery of the ML336 Antiviral to Inhibit Encephalitic Alphavirus Infection

LaBauve, Annette E.; Rinker, Torri E.; Noureddine, Achraf; Serda, Rita E.; Howe, Jane Y.; Sherman, Michael B.; Rasley, Amy; Brinker, C. Jeffery; Sasaki, Darryl Y.; Negrete, Oscar A.

doi:10.1038/s41598-018-32033-w

Title: Lipid-Coated Mesoporous Silica Nanoparticles for the Delivery of the ML336 Antiviral to Inhibit Encephalitic Alphavirus Infection

Journal Article · Tue Sep 18 00:00:00 EDT 2018 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-018-32033-w· OSTI ID:1469731

LaBauve, Annette E.; Rinker, Torri E.; Noureddine, Achraf; Serda, Rita E.; Howe, Jane Y.; Sherman, Michael B.; Rasley, Amy; Brinker, C. Jeffery; Sasaki, Darryl Y.; Negrete, Oscar A.

Venezuelan equine encephalitis virus (VEEV) poses a major public health risk due to its amenability for use as a bioterrorism agent and its severe health consequences in humans. ML336 is a recently developed chemical inhibitor of VEEV, shown to effectively reduce VEEV infection in vitro and in vivo. However, its limited solubility and stability could hinder its clinical translation. To overcome these limitations, lipid-coated mesoporous silica nanoparticles (LC-MSNs) were employed. The large surface area of the MSN core promotes hydrophobic drug loading while the liposome coating retains the drug and enables enhanced circulation time and biocompatibility, providing an ideal ML336 delivery platform. LC-MSNs loaded 20 ± 3.4 μg ML336/mg LC-MSN and released 6.6 ± 1.3 μg/mg ML336 over 24 hours. ML336-loaded LC-MSNs significantly inhibited VEEV in vitro in a dose-dependent manner as compared to unloaded LC-MSNs controls. Moreover, cell-based studies suggested that additional release of ML336 occurs after endocytosis. Here, in vivo safety studies were conducted in mice, and LC-MSNs were not toxic when dosed at 0.11 g LC-MSNs/kg/day for four days. ML336-loaded LC-MSNs showed significant reduction of brain viral titer in VEEV infected mice compared to PBS controls. Overall, these results highlight the utility of LC-MSNs as drug delivery vehicles to treat VEEV.

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Research Organization:: Sandia National Lab. (SNL-CA), Livermore, CA (United States); Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA); USDOE Laboratory Directed Research and Development (LDRD) Program; Defense Threat Reduction Agency (DTRA)

Grant/Contract Number:: AC04-94AL85000; 190245; NA0003525; 1002720595; AC52-07NA27344

OSTI ID:: 1469731

Alternate ID(s):: OSTI ID: 1474053; OSTI ID: 1871379

Report Number(s):: SAND-2018-10167J; LLNL-JRNL-835547; 13990; PII: 32033

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Vol. 8 Journal Issue: 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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Cited by: 52 works

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