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: 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
• 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

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著下降。然而，抗逆转录病毒（ARV）药物通过血脑屏障（BBB）的可达性不足或为零，导致病毒在大脑中的藏身之处。近年来，纳米技术在医药领域的应用为新型药物传递系统的开发展示了令人振奋的前景。然而，现有技术的缺点是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，以及如果纳米载体到达大脑以及当纳米载体到达大脑时药物从载体释放的不确定性。因此，从药物递送的角度来看，非常需要一种快速有效的方法来根据需要从大脑中的载体递送和释放药物，以根除HIV宿主。磁场或电场已分别显示出对生物系统（包括脑部疾病）产生有益影响。因此，我们假设使用磁电纳米颗粒（MENP）耦合这两种性质将作为有效的载体来递送，并且最重要的是，在大脑中按需释放药物。我们的初步研究表明，AZTTP结合到电磁纳米颗粒上，并且结合的药物可以通过AC触发（在小于100 Hz的频率下具有65 Oe量级的磁电场）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）具有与HIV药物结合的ME性质，（其在脑中不可检测/较少可检测），如奈非那韦（PI）、5 '-三磷酸-AZT（AZTTP）（NRTI）、阿匹韦林（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，将在体外测试开发的制剂穿过BBB的能力，以及在外部ME力下释放药物的能力，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），DC和AC外部磁场（通过小型化线圈芯片）分别用于快速递送药物结合的纳米载体和按需药物释放的目的。因此，这样的低能耗要求使得设备实现的极端便携性成为可能。这项新技术能够实现前所未有的3D诊断和药物输送，并且一旦特定药物通过AC触发按需在大脑中释放，就可以通过反向外部磁力将ME纳米颗粒从大脑清除到外周。我们希望最终的设备是用户友好的，足够轻，相对小的尺寸，并由便携式电池供电。这一多学科的新突破，在特定的药物靶向大脑使用电磁纳米粒子是响应特定的射频消融，将有助于完全根除艾滋病毒-1病毒水库在大脑中。

项目成果

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。

• DOI: 10.1186/s13041-016-0236-0
• 发表时间: 2016
• 期刊: Molecular brain
• 影响因子: 3.6
• 作者: Sagar,Vidya;Atluri,VenkataSubbaRao;Pilakka-Kanthikeel,Sudheesh;Nair,Madhavan
• 通讯作者: Nair,Madhavan

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

• DOI: 10.1038/srep29792
• 发表时间: 2016-07-28
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Sagar V;Atluri VSR;Tomitaka A;Shah P;Nagasetti A;Pilakka-Kanthikeel S;El-Hage N;McGoron A;Takemura Y;Nair M
• 通讯作者: Nair M

Common gene-network signature of different neurological disorders and their potential implications to neuroAIDS.

• DOI: 10.1371/journal.pone.0181642
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sagar V;Pilakka-Kanthikeel S;Martinez PC;Atluri VSR;Nair M
• 通讯作者: Nair M