Abstract
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. 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.
Highlights
Several small molecule drugs have been developed that inhibit Venezuelan equine encephalitis virus (VEEV), but many are limited by high toxicity or low efficacy[6,7,8,9,10,11]
100 pore diameters were measured on the scanning electron microscopy (SEM) micrograph and their average was found to be 2.65 ± 0.29 nm which is in the same order of magnitude of the average pore size found by N2 sorption using DFT theory (~3.5 nm) (Fig. S1)
We presented the first use of lipid-coated mesoporous silica nanoparticles (LC-Mesoporous silica nanoparticles (MSNs)) to deliver ML336 for TC-83 VEEV inhibition both in vitro and in vivo
Summary
Several small molecule drugs have been developed that inhibit VEEV, but many are limited by high toxicity or low efficacy[6,7,8,9,10,11]. Established methods enable formation of MSNs with tunable pore size, endowing MSNs with a large surface area for drug adsorption (600–1000 m2/g)[12,13,14,15] This property is advantageous for loading water insoluble or unstable drugs, as the large surface area acts as a reservoir for hydrophobic drug in aqueous solution and can improve drug efficacy in vivo[16,17]. In order to overcome these challenges, we investigated the application of a lipid-based coating to the exterior of ML336-loaded MSNs. MSNs coated with supported lipid bilayers (lipid-coated MSNs (LC-MSNs)) have been employed in drug and protein delivery applications to improve colloidal stability and subsequent circulation time, biocompatibility, cargo loading and release, and tissue-specific targeting[19,21,22,23]. LC-MSNs harness the advantages and overcome the obstacles associated with MSNs and liposomes in one versatile platform for small molecule delivery
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