Novel Magneto-Electric Nanodelivery of Drugs to Eradicate HIV from CNS

新型磁电纳米递送药物可根除中枢神经系统中的艾滋病毒

• 批准号: 8544686
• 负责人: MADHAVAN P. NAIR
• 金额: $ 18.13万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-22 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544686
• 关键词: 3-Dimensional; Acquired Immunodeficiency Syndrome; Affect; Anti-HIV Agents; Antiviral Agents; Binding; Biocompatible Materials; Biological; Biological Availability; Blood - brain barrier anatomy; Blood Circulation; Body Temperature; Brain; Brain Diseases; Carcinoma; Cells; Consumption; Coupling; Deposition; Development; Devices; Diagnostic; Drug Carriers; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug Targeting; Frequencies; HIV; HIV-1; Highly Active Antiretroviral Therapy; Image; In Vitro; Inflammation; Lead; Legal patent; Liposomes; Liver; Lung; Lymphoid; Magnetic Resonance Imaging; Magnetism; Mediating; Medicine; Methods; Modeling; Morbidity - disease rate; Movement; Nanotechnology; Nelfinavir; Organ; Patients; Penetration; Pharmaceutical Preparations; Property; RGD (sequence); Residual state; Reticuloendothelial System; Site; Specificity; Subgroup; Surface; System; T-20; Technology; Therapeutic; Therapeutic Effect; Toxic effect; Uncertainty; Viral; Virus; Zidovudine; antiretroviral therapy; base; biological systems; clinical application; electric field; functional group; in vitro testing; macrophage; magnetic field; miniaturize; monocyte; mortality; multidisciplinary; nano; nanocarrier; nanodrug; nanoliposome; nanoparticle; new technology; non-nucleoside reverse transcriptase inhibitors; novel; novel strategies; particle; portability; public health relevance; research study; response; tripolyphosphate; uptake; user-friendly; zidovudine triphosphate

DESCRIPTION (provided by applicant): Highly Active Antiretroviral Therapy (HAART) has resulted in remarkable decline in the morbidity and mortality in AIDS Patients. Nevertheless, inadequate or zero reachability of anti-retro viral (ARV) drugs across the blood brain barrier (BBB) results in viral reservoir in the brain hideout. In recent years, use of nanotechnology in medicine has shown exciting prospect for development of novel drug delivery systems. However, the existing technologies suffer from the lack of adequate transendothelial penetration before the drugs are engulfed by the reticuloendothelial system (RES) cells as well as the uncertainty of drug release from the carrier if and when the nanocarrier reaches the brain. So from a drug delivery point of view, a fast and effective way of delivering and releasing the drugs on demand from the carrier in the brain is very much needed to eradicate HIV reservoir. Magnetic or electric fields have been shown separately to exert beneficial effects on the biological systems including brain diseases. Hence we hypothesize that coupling of these two properties using magneto- electric nanoparticles (MENPs) will serve as an effective carrier to deliver and, most importantly, to release the drugs on demand in the brain. Our preliminary studies showed that AZTTP binds to MENPs and the bound drug could be released on demand to almost 100% by AC triggering (magneto-electric field with a 65 Oe magnitude at a frequency of less than 100 Hz). Accordingly in the Specific Aim# 1, we will develop magnetoelectro (ME)-liposome based novel multi-ferrous nanoparticles (20-40 nm) with ME properties bound to HIV drugs, (which are undetectable/less detectable in brain) such as Nelfinavir (PI), 5'-triphosphate-AZT (AZTTP) (NRTI), Rilpivirine (NNRTI) and Enfuvirtide (FI), and evaluate the binding, pharmacokinetics, dynamics, stability and toxicity. In Specific Aim #2, the developed formulation will be tested in vitro for its ability to transmigrate across BBB, and release of the drugs with external ME forces and study the antiviral activity of released drugs. According to this invented ME nanotechnology (patent pending), DC and AC external magnetic fields (by miniaturized coil chips) are used for the purposes of speedy delivery of the drug bound nanocarrier and on demand drug release, respectively. Consequently, such low-energy-consumption requirements enable an extreme portability of the device implementation. The new technology enables an unprecedented 3-D diagnostics and drug delivery and further allows to clear the ME nanoparticles from the brain to the periphery by the reverse external magnetic force once the specific drugs have been released on demand in the brain through AC triggering. We expect the ultimate device to be user-friendly, adequately lightweight, relatively small size, and sourced by a portable battery. This multidisciplinary new break-through in specific drug targeting to the brain using MENPs is in response to the specific RFA and will be useful for complete eradication of the HIV-1 virus reservoir in the brain.

描述(申请人提供)：高效抗逆转录病毒疗法(HAART)使艾滋病患者的发病率和死亡率显著下降。然而，抗逆转录病毒(ARV)药物穿越血脑屏障(BBB)的能力不足或为零，会导致病毒储存在大脑的藏身之处。近年来，纳米技术在医学上的应用为新型药物传递系统的发展展示了令人振奋的前景。然而，现有的技术在药物被网状内皮系统(RES)细胞吞噬之前缺乏足够的跨内皮渗透，以及纳米载体到达大脑后药物从载体释放的不确定性。因此，从药物传递的角度来看，根除HIV储藏库非常需要一种快速有效的方式来从脑内的载体上按需传递和释放药物。已有研究表明，磁场或电场分别对包括大脑疾病在内的生物系统产生有益影响。因此，我们假设利用磁电纳米颗粒(MENPs)将这两种特性结合在一起，将作为一种有效的载体来传递药物，最重要的是，在大脑中按需释放药物。我们的初步研究表明，AZTTP与MENPs结合，通过交流触发(频率小于100赫兹，磁场强度为65Oe)，结合的药物可以按需释放到几乎100%。因此，在具体目标1中，我们将开发基于磁电(ME)脂质体的新型多铁纳米颗粒(20-40 nm)，该纳米颗粒具有与HIV药物(在大脑中检测不到/检测不到)的ME特性，如奈非那韦(PI)、5‘-三磷酸氮卓酮(AZTTP)(NRTI)、利培韦林(NNRTI)和恩福韦肽(FI)，并对其结合、药代动力学、动力学、稳定性和毒性进行评价。在特定目标#2中，开发的配方将在体外测试其跨血脑屏障的转运能力，以及利用外部ME力释放药物的能力，并研究释放的药物的抗病毒活性。根据本发明的ME纳米技术(正在申请专利)，DC和AC外部磁场(通过微型线圈芯片)分别用于药物结合纳米载体的快速输送和按需药物释放的目的。因此，这种低能耗要求实现了设备实施的极端便携性。这项新技术实现了前所未有的3-D诊断和药物输送，并进一步允许一旦特定药物通过交流触发在大脑中按需释放，就可以通过反向外部磁力将ME纳米颗粒从大脑清除到外围。我们预计最终的设备将是用户友好的，足够轻，相对较小的尺寸，并由便携式电池供电。使用MENPs在特定药物靶向大脑方面的这一多学科新突破是对特定RFA的响应，将有助于彻底根除大脑中的HIV-1病毒库。