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

项目编号：CBET - 1403409项目负责人：Andreas a . linninger机构：伊利诺伊大学芝加哥分校标题：利用超顺磁性纳米颗粒靶向中枢神经系统的鞘内磁性药物对于中枢神经系统（CNS）的一系列疾病，特别是脑肿瘤和脊柱转移瘤，很少有有效的治疗方案存在。由于缺乏靶向给药策略，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。为了将药物分子定位到中枢神经系统内的特定病变靶点，研究者提出了一种新的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相结合，用于神经系统疾病的高度局部治疗。在这项技术中，磁性纳米颗粒（MNPs）与治疗剂结合，直接注入脑脊液（CSF），并通过外部磁场在所需的目标部位收集。然后药物从MNPs中解吸，开始其治疗作用机制。MDT最显著的好处在于药物作用高度局限于所需区域，如肿瘤部位。同时，由于药物扩散有限，全身副作用最小。该项目将促进对中枢神经系统内磁性靶向纳米颗粒运输的基本理解，并对鞘内空间内的生物运输现象产生基本见解。这项研究还将创造必要的智力进步，将基于MNP的载体从研究课题提升到临床有用的技术。血脑屏障（BBB）调节分子运输，保护中枢神经系统免受有害化合物的侵害，但也通过阻止药物到达大脑或脊髓而阻碍治疗干预。因此，迫切需要开发药物递送技术，以指导和定位治疗药物在中枢神经系统的特定靶细胞。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MNPs到中枢神经系统内任何所需的目标位置。这种给药方式具有以下优点：它(i)绕过血脑屏障，（ii）降低毒性，同时提高靶点的治疗效率，（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的外部控制。为了建立这一新机制，我们计划(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)利用负载阿霉素的磁性纳米颗粒对体外脊髓肿瘤进行it - mdt治疗。本研究将建立一种将肿瘤药物分子与MNPs有效结合的新技术，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对细胞的摄取和肿瘤细胞的死亡。实验将研究脑脊液(CSF)-pia界面在脑脊液脉动运动和脊柱微观解剖引起的涡流存在下MNPs的细胞摄取。这些结果将使我们能够选择关键参数，如MNP输注浓度、流速和持续时间，从而在沿中枢神经系统的特定目标位置获得所需的MNP治疗浓度。将通过实验、计算流体动力学方法和静磁学建立将纳米颗粒引导到CNS中所需位置的最佳磁场参数。该奖项由CBET部门的生物技术、生化和生物质工程项目颁发，由生物基础设施部门的生物研究仪器开发项目共同资助。

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.