Intrathecal magnetic drug targeting to the central nervous system with superparamagnetic nanoparticles

使用超顺磁性纳米颗粒靶向中枢神经系统的鞘内磁性药物

• 批准号: 1403409
• 负责人: Andreas Linninger
• 金额: $ 29.88万
• 依托单位: University of Illinois at Chicago
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1403409&HistoricalAwards=false
• 关键词: Intrathecal; magnetic; drug; targeting; central

Proposal Number: CBET - 1403409 Principal Investigator: Andreas A. LinningerInstitution: University of Illinois at ChicagoTitle: Intrathecal magnetic drug targeting to the central nervous system with superparamagnetic nanoparticlesFor a family of diseases of the central nervous system (CNS), especially brain tumors and spinal metastases, few effective treatment options exist. Existing treatments have serious side effects including acute pain, nausea and even paralysis, due to lack of a targeted drug delivery strategy. In order to localize drug molecules in specific diseased target sites within the CNS, the investigator proposes a novel nanoparticle drug delivery technique termed Intrathecal Magnetic Drug Targeting (IT-MDT). It combines traditional intrathecal drug administration with magnetic drug targeting for highly localized treatment of neurological disorders. In this technique, magnetic nanoparticles (MNPs) conjugated to therapeutic agents are directly infused into the cerebrospinal fluid (CSF) and collected at the desired target site via an external magnetic field. The drug then desorbs from the MNPs to begin its therapeutic mechanism of action. The most notable benefit of MDT resides in highly confined local drug action in the desired region such as the tumor site. At the same time, systemic side effects are minimal because of the limited drug spread. The project will advance the fundamental understanding of magnetically targeted nanoparticle transport within the CNS and develop fundamental insights about biotransport phenomena within the intrathecal space. This study will also create intellectual advancements necessary to elevate MNP based carriers from a research subject to a clinically useful technology.The Blood Brain Barrier (BBB) regulates molecular transport and protects the CNS against harmful compounds, but also hinders therapeutic interventions by preventing drugs from reaching the brain or spinal cord. Therefore, there is a critical need for developing drug delivery techniques for guiding and localizing therapeutic agents at specific target cells in the CNS. The proposed IT-MDT delivery technique uses magnetic forces to guide and confine intrathecally delivered, superparamagnetic drug functionalized MNPs to any desired target location within the CNS. This mode of drug administration offers the following advantages: it (i) bypasses the BBB, (ii) reduces toxicity while enhancing treatment efficiency in the target site, and (iii) enables active external control over the spatial and temporal distribution of the drug inside the CNS. To establish this novel mechanism, it is planned to (1)design and synthesize magnetic nanoparticle based drug delivery vehicles, (2) conduct IT-MDT experiments in a physiologically relevant 3D live cell spine model,(3) perform IT-MDT treatment of in vitro spinal cord tumors using doxorubicin loaded magnetic nanoparticles. This study will establish a novel technique for effectively conjugating tumor drug molecules to MNPs, build and validate a 3D live tumor cell spine model to demonstrate cellular uptake and tumor cell death from the drug functionalized nanoparticles. The experiments will study cellular uptake of MNPs at the cerebrospinal fluid (CSF)-pia interface in the presence of pulsatile CSF motion and eddies caused by the spinal micro-anatomy. The results will enable to select critical parameters such as MNP infusate concentration, flow rate and duration to achieve desired therapeutic concentrations of MNPs at specific target locations along the CNS. Optimal magnetic field parameters for steering nanoparticles to desired locations in the CNS will be established both by experiments and by computational fluid dynamic methods and magnetostatics.This award by the Biotechnology, Biochemical, and Biomass Engineering Program of the CBET Division is co-funded by the Instrument Development for Biological Research Program of the Division of Biological Infrastructure.

提案编号：CBET - 1403409主要研究者：Andreas A. Linninger机构：题目：利用超顺磁性纳米粒子靶向中枢神经系统的鞘内磁性药物对于中枢神经系统（CNS）疾病家族，尤其是脑肿瘤和脊柱转移瘤，几乎没有有效的治疗选择。现有的治疗方法有严重的副作用，包括急性疼痛，恶心，甚至瘫痪，由于缺乏有针对性的药物输送策略。为了将药物分子定位在中枢神经系统内特定的疾病靶点，研究人员提出了一种新型纳米颗粒药物递送技术，称为鞘内磁性药物靶向（IT-MDT）。它将传统的鞘内给药与磁性药物靶向结合起来，用于神经系统疾病的高度局部化治疗。在该技术中，将与治疗剂缀合的磁性纳米颗粒（MNP）直接注入脑脊液（CSF）中，并通过外部磁场在所需的靶部位收集。然后药物从MNP上解吸，开始其治疗作用机制。MDT最显著的益处在于在所需区域（如肿瘤部位）中高度限制的局部药物作用。同时，由于药物扩散有限，全身副作用很小。 该项目将推进对CNS内磁靶向纳米颗粒运输的基本理解，并开发有关鞘内空间内生物运输现象的基本见解。这项研究还将创造必要的智力进步，以提高MNP为基础的载体从一个研究课题，临床上有用的technology.The血脑屏障（BBB）调节分子运输和保护中枢神经系统免受有害化合物，但也阻碍了治疗干预，阻止药物到达大脑或脊髓。因此，迫切需要开发用于将治疗剂引导和定位在CNS中的特定靶细胞处的药物递送技术。所提出的IT-MDT递送技术使用磁力来引导和限制鞘内递送的超顺磁性药物功能化的MNP至CNS内的任何期望的靶位置。这种给药模式具有以下优点：（i）绕过BBB，（ii）降低毒性，同时提高靶部位的治疗效率，以及（iii）能够对药物在中枢神经系统内的空间和时间分布进行主动外部控制。为了建立这种新的机制，计划（1）设计和合成基于磁性纳米颗粒的药物递送载体，（2）在生理学相关的3D活细胞脊柱模型中进行IT-MDT实验，（3）使用多柔比星负载的磁性纳米颗粒进行体外脊髓肿瘤的IT-MDT治疗。 本研究将建立一种将肿瘤药物分子有效地结合到MNP上的新技术，建立并验证三维活肿瘤细胞脊柱模型，以证明药物功能化纳米颗粒的细胞摄取和肿瘤细胞死亡。实验将研究在存在由脊柱显微解剖结构引起的脉动CSF运动和涡流的情况下，在脑脊液（CSF）-软脑膜界面处的MNP的细胞摄取。结果将使得能够选择关键参数，例如MNP输注液浓度、流速和持续时间，以在沿着CNS的特定靶位置沿着达到所需的MNP治疗浓度。将通过实验和计算流体动力学方法以及静磁学来建立将纳米粒子引导到CNS中所需位置的最佳磁场参数。CBET部门的生物技术，生物化学和生物质工程计划的这项奖励由生物基础设施部门的生物研究计划仪器开发共同资助。