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

基本信息

批准号：
8655176
负责人：
MADHAVAN P. NAIR
金额：
$ 20.63万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-22 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8655176
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

项目摘要

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（由申请人提供）：高效抗逆转录病毒疗法（HAART）已导致艾滋病患者的发病率和死亡率显着下降。然而，抗逆转录病毒（ARV）药物穿过血脑屏障（BBB）的能力不足或为零，导致病毒在大脑藏身处中储存。近年来，纳米技术在医学中的应用显示出开发新型药物输送系统的令人兴奋的前景。然而，现有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，并且纳米载体到达大脑时药物从载体中释放的不确定性。因此，从药物输送的角度来看，非常需要一种快速有效的方法，根据需要从大脑中的载体输送和释放药物，以根除艾滋病毒储存库。磁场或电场已被分别证明对包括脑部疾病在内的生物系统产生有益的影响。因此，我们假设使用磁电纳米粒子（MENP）将这两种特性耦合起来将作为有效的载体来递送，最重要的是，根据大脑的需要释放药物。我们的初步研究表明，AZTTP 与 MENP 结合，并且结合的药物可以通过交流触发（频率小于 100 Hz、强度为 65 Oe 的磁场）按需释放，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粒子（20-40 nm），其具有与HIV药物（在大脑中不可检测/难以检测到）结合的ME特性，例如奈非那韦(PI)、5'-三磷酸-AZT (AZTTP) (NRTI)、利匹韦林 (NNRTI) 和恩夫韦肽 (FI)，并评估结合、药代动力学、动力学、稳定性和毒性。在具体目标#2中，所开发的制剂将在体外测试其穿越血脑屏障的能力，以及通过外部ME力释放药物的能力，并研究释放药物的抗病毒活性。根据本发明的ME纳米技术（正在申请专利），直流和交流外部磁场（通过微型线圈芯片）分别用于快速递送药物结合的纳米载体和按需释放药物。因此，这种低能耗要求使得设备实现具有极高的便携性。这项新技术实现了前所未有的 3D 诊断和药物输送，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 纳米粒子从大脑清除到外周。我们期望最终的设备用户友好、重量足够轻、尺寸相对较小，并由便携式电池供电。这项利用 MENP 靶向大脑的特定药物的跨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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Technobiology's Enabler: The Magnetoelectric Nanoparticle.

技术生物学的推动者：磁电纳米粒子。

DOI：
10.1101/cshperspect.a034207
发表时间：
2018-10-05
期刊：
Cold Spring Harbor perspectives in medicine
影响因子：
0
作者：
S. Khizroev
通讯作者：
S. Khizroev

Coupling of transient near infrared photonic with magnetic nanoparticle for potential dissipation-free biomedical application in brain.

瞬态近红外光子与磁性纳米粒子的耦合，用于脑中潜在的无耗散生物医学应用。

DOI：
发表时间：
2016-07-28
期刊：
影响因子：
4.6
作者：
Sagar, Vidya;Atluri, V S R;Tomitaka, A;Shah, P;Nagasetti, A;Pilakka;El;McGoron, A;Takemura, Y;Nair, M
通讯作者：
Nair, M

Magnetic nanotherapeutics for dysregulated synaptic plasticity during neuroAIDS and drug abuse.

磁性纳米疗法治疗神经艾滋病和药物滥用期间突触可塑性失调。