Orally Administrable Therapeutic Synthetic Nanoparticle for Zika Virus
Orally Administrable Therapeutic Synthetic Nanoparticle for Zika Virus
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DOI：
10.1021/acsnano.9b02807
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发表时间：
2019-10-01
期刊：
影响因子：
17.1
通讯作者：
Dhar, Shanta
中科院分区：
文献类型：
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作者：
Surnar, Bapurao;Kamran, Mohammad Z.;Dhar, Shanta
寨卡病毒（ZIKV）感染在过去三年中在美国和各个国家的传播不仅对美国的医疗保健系统产生直接影响，而且也引起了国际关注。ZIKV感染的最终影响仍有待了解。目前，没有治疗或疫苗选择可用于保护ZIKV感染者。发现药物伊维菌素（IVM）是用于预防ZIKV传播的可行药剂。伊维菌素在水的存在下不稳定，并且在人血流中不能保持足够的浓度以有效治疗ZIKV。可生物降解的纳米颗粒将通过提供足够高的药物浓度并确保药物逐渐释放以维持体内适当的水平来帮助伊维菌素的递送。本研究的总体目标是开发和优化IVM的可口服纳米制剂，其可以在血液中长时间循环以进行有效递送。为了实现这一目标，我们合成并优化了一种用于口服的IVM合成纳米制剂，该制剂可以穿过肠上皮屏障进入血流。我们的研究证明，当用合成纳米颗粒（NP）递送时，IVM可以以更高的浓度积累在血液中，并且初步研究强调了NP递送的IVM具有靶向ZIKV的非结构1蛋白的能力。对于潜在的临床相关性，用于包含在胶囊形式和含有冷冻保护剂的冷冻形式中的干粉状态的IVM-纳米颗粒的长期可储存制剂显示出有希望的发现。此外，我们的初步体外研究记录了伊维菌素穿过胎盘屏障，因此使其对于怀孕的ZIKV群体不安全，而负载伊维菌素的纳米颗粒未显示任何显著的胎盘屏障穿过，因此表明其对此类群体的潜在适用性。我们设想，这项工作将通过开发更安全，更有效的治疗病毒感染（包括ZIKV）的疗法来填补巨大的未满足的需求。
The spread of Zika virus (ZIKV) infection across the USA and various countries in the last three years will not only have a direct impact on the U.S. health care system but has caused international concerns as well. The ultimate impact of ZIKV infection remains to be understood. Currently, there are no therapeutic or vaccine options available to protect those infected by ZIKV. The drug ivermectin (IVM) was found to be a viable agent for the prevention of transmission of ZIKV. Ivermectin is unstable in the presence of water and does not remain in adequate concentration in the human bloodstream to be effective in treatment for ZIKV. Biodegradable nanoparticles would aid in the delivery of ivermectin by providing a high enough concentration of drug and ensuring the drug is gradually released to maintain an appropriate level in the body. The overall goal of this study was to develop and optimize an orally administrable nanoformulation of IVM which can circulate in the blood for a long period for efficient delivery. To achieve the goal, we synthesized and optimized a synthetic nanoformulation of IVM for oral use which can cross the intestinal epithelial barrier to enter the bloodstream. Our studies documented that when delivered with the synthetic nanoparticle (NP), IVM can be accumulated in the blood at a higher concentration and preliminary studies highlighted that NP delivered IVM has the ability to target nonstructural 1 protein of ZIKV. For potential clinical relevance, long-term storable formulation of IVM-nanoparticle in dry powder state for inclusion in a capsule form and cryoprotectant containing frozen forms revealed promising findings. Further, our preliminary in vitro studies documented that ivermectin crosses the placental barrier, thus making it unsafe for the pregnant ZIKV population, whereas the ivermectin-loaded nanoparticle did not show any significant placental barrier crossing, thus indicating its potential suitability for such population. We envision that this work will fill a great unmet need by developing safer and more effective therapies for the treatment of viral infections, including ZIKV.