Department of Biotechnology and Bioengineering, Sandia National Laboratories, Livermore, CA, USA.
Advanced Materials Laboratory, Sandia National Laboratories, Albuquerque, NM, USA.
Sci Rep. 2018 Sep 18;8(1):13990. doi: 10.1038/s41598-018-32033-w.
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.
委内瑞拉马脑炎病毒（VEEV）具有作为生物恐怖主义制剂的适用性以及对人类健康的严重后果，因此构成了重大的公共卫生风险。ML336 是一种新开发的 VEEV 化学抑制剂，已被证明可有效降低体外和体内的 VEEV 感染。然而，其有限的溶解度和稳定性可能会阻碍其临床转化。为了克服这些限制，使用了脂质包覆介孔硅纳米粒子（LC-MSNs）。MSN 核的大表面积促进了疏水性药物的负载，而脂质体涂层保留了药物并使循环时间和生物相容性增强，提供了理想的 ML336 传递平台。LC-MSNs 负载了 20±3.4μg/ml336/mg LC-MSN，并在 24 小时内释放了 6.6±1.3μg/mg ML336。与未负载的 LC-MSN 对照相比，负载 ML336 的 LC-MSN 在体外以剂量依赖性方式显著抑制了 VEEV。此外，基于细胞的研究表明，在细胞内吞作用后会额外释放 ML336。在小鼠中进行了体内安全性研究，当以 0.11g LC-MSN/kg/天的剂量连续给药 4 天时，LC-MSNs 没有毒性。与 PBS 对照相比，负载 ML336 的 LC-MSNs 使感染 VEEV 的小鼠脑中的病毒滴度显著降低。总的来说，这些结果突出了 LC-MSNs 作为治疗 VEEV 的药物递送载体的效用。
