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

描述（由申请人提供）：高效抗逆转录病毒疗法（HAART）显著降低了艾滋病患者的发病率和死亡率。然而，抗逆转录病毒（ARV）药物通过血脑屏障（BBB）的可及性不足或零可及性导致病毒在脑隐藏处蓄积。近年来，纳米技术在医学上的应用为开发新型给药系统提供了令人兴奋的前景。然而，现有的技术存在药物在被网状内皮系统（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时药物从载体释放的不确定性等问题。因此，从药物输送的角度来看，一种快速有效的方式来输送和释放药物，从大脑中的载体是非常需要的，以消除艾滋病毒库。磁场和电场分别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（MENPs）耦合这两种特性将作为一种有效的载体来递送，最重要的是，在大脑中根据需要释放药物。我们的初步研究表明，AZTTP与MENPs结合，并且结合的药物可以通过交流触发（频率小于100 Hz，频率为65 Oe的磁电场）按需释放几乎100%。因此，在Specific Aim# 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），其ME特性与HIV药物结合（在大脑中无法检测到），如奈非那韦（PI）， 5'-三磷酸- azt (AZTTP) (NRTI)，利匹韦林（NNRTI）和恩福韦肽（FI），并评估其结合，药代动力学，动力学，稳定性和毒性。在Specific Aim #2中，开发的制剂将在体外测试其跨血脑屏障的转运能力，以及体外ME力释放药物的能力，并研究释放药物的抗病毒活性。根据这项发明的ME纳米技术（正在申请专利），直流和交流外部磁场（通过小型化线圈芯片）分别用于药物结合纳米载体的快速递送和按需药物释放。因此，这样的低能耗要求使得设备实现具有极高的可移植性。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纳米颗粒从大脑清除到周围。我们期望最终的设备是用户友好的，足够轻，相对较小的尺寸，并由便携式电池供电。这一多学科的新突破是针对特定的RFA，利用MENPs靶向大脑的特异性药物，将有助于彻底根除大脑中的HIV-1病毒库。

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.