磁性纳米颗粒的靶向输运及其在肺靶向中的应用研究
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摘要
磁性载药颗粒的靶向治疗由于其非侵入性和高靶向性等特点而成为目前最具热点且大有前途的技术之一。磁性载药颗粒的靶向递送是将药物装载到高磁响应的磁性纳米颗粒上，利用外磁场使其移动并在靶部位聚焦的方法。它能提高靶部位药物的浓度，降低药物对正常组织的毒副作用，从而减少总用药量。磁性药物靶向治疗可以用来治疗各种疾病，特别是癌症。如果与吸入雾化剂相结合，可以治疗呼吸道和肺部的各种疾病，具有广泛的用途和潜在的巨大市场需求。
本文以优化磁性载药颗粒在气道内的靶向输运行为为目的，首先采用以蒙特卡罗（Monte Carlo）为基础的Metropolis算法分析了磁性纳米颗粒在均匀磁场下的团聚行为。在外磁场作用下，磁性纳米颗粒会在外磁场的方向上形成一些团状、分叉状或链状的团簇结构；然后设计并构造了具有单边磁场特性的准Halbach永磁磁体阵列，然后使之作为引导磁性纳米颗粒在靶目标区域聚集的外磁场发生装置；然后以磁场—流体场耦合计算为基础研究了在不同外磁场应用环境下，Y形管道内磁性气雾颗粒流的定向流动和聚集情况，并且进行了相应的体外实验和动物实验来验证我们得到的结论。主要的研究工作包括：
①用蒙特卡罗方法模拟了纳米磁性粒子在均匀磁场下的团聚行为，得到了不同作用能量和浓度下的团聚外貌，粒子的团聚形貌由高能量的链状逐渐向低能量的分支状、圆团状形貌变化，并且在高浓度下形成大片团聚。还分析了粒子系统的总能量随蒙特卡罗步变化特点。
②准Halbach磁体阵列的提出和构造。准Halbach磁体阵列周围的磁场具有明显的单边特点，磁场大部分分布在磁体阵列的一侧而另一侧很少，这就大大提高了磁场能量的利用效率。我们考察了磁场力、磁场力效能参数和磁场力横向均匀度参数等三个评价参数，准Halbach磁体阵列比普通磁体均提高两个数量级以上。作为靶向磁体具有产生的磁场强度和磁场梯度高、对磁性纳米颗粒的有效作用距离长和聚集性好等特点，同时本文提出的三个评价参数，对于构造和评价一个磁靶向磁体的性能有一定指导作用。
③提出以稀疏固相气—固两相流为基础的磁场-流体场耦合计算模型。分析了流速和流量的关系、流速和压强的关系，得出如下结论：在靠近磁体的一侧，磁性气雾颗粒流体的轴向速度降低，并且径向速度加大，流量增大，从而提高了磁性气雾颗粒在靠近磁体侧的聚集浓度；随着目标距离的增加，磁性气雾流的定向性变差。然而，如果距离太近，反而由于目标以及周围大片区域的磁场都较大，而破坏定向性；体积分数的变化引起的相对流速差的变化不大，基本上在1左右，这说明相对差和距离参数关系更大；单个磁体和Halbach磁体阵列在使磁性气雾流定向流动上的差异明显，Halbach磁体对流体的加速作用是单个磁体的2-3倍。
④进行了相应的体外和动物实验。从体外实验的结果得出，在距离3.5cm时Halbach磁体阵列，可以提供2倍以上的聚集差异，而且随着雾化时间的增长，聚集差异更加明显。从对大鼠的吸入实验结果来看，加磁场组大鼠左右两侧肺组织内的铁含量比正常组和未加磁场组均高，组间铁含量有显著性差异（P<0.01），并且左右两侧差异明显，差值达2倍以上。从大鼠的肺部组织切片的分析，可以清楚的看到磁性纳米颗粒在左右两侧肺叶组织沉积的差异。
The magnetic targeted drug delivery system is one of the most attractive strategiesdue to its non-invasiveness, high targeting efficiency and minimizing the toxic sideeffects on healthy cells and tissues. Magnetic drug targeting therapy can be used for themedical treatment of various diseases, especially cancer. If combined with theinhalation aerosol, this technique can cure the diseases of the respiratory tract and lungs.It could result in wide range of uses and the huge potential market demand.
The purpose of the dissertation is to optimize the targeting delivery of magneticdrug-loaded particles in respiratory tract. First, we used Metropolis Monte Carlo methodto simulate the magnetic nanoparticles aggregation in uniform magnetic field. Theparticles will form the chain-like clusters, branched clusters and looped clusters aligningin the orientation external magnetic field. Then the quasi-Halbach permanent magnetarray was designed and constructed, which used to magnetic particle aggregation asexternal magnetic field generation device. Based on the coupled physics field ofmagnetic field and fluid field, the motion of magnetic aerosol particles in Y-shape tubewas studied in different condition of external field.
The main research works of the dissertation include:
(1) We used Metropolis Monte Carlo method to simulate the magneticnanoparticles aggregation in uniform magnetic field. From small to large diameters thedistribution of orientations approach the orientation of magnetic field direction step bystep, the larger one forms chain-like clusters, smaller size forms clusters with branchedand looped shapes. An analysis of total particles system energy with Monte Carlo stepswas conducted.
(2) The magnetic field distribution around Halbach magnet has single-sided feature,which could improve the utilization efficiency of magnetic field energy. We examinedthree evaluation factors，such as magnetic field strength, the effectiveness of magneticfield strength parameters and lateral uniformity of magnetic force parameters. Theresults demonstrate the Halbach magnet array than normal magnet is more than twoorders of magnitude improvement for the three factors. And, the three evaluation factorspresented in thesis can provide methods available for performance evaluation of a typetargeting delivery magnet system.
(3) The calculation model of coupled magneto-fluid field was introduction based on based on gas-solid two-phase flow model with sparse solid-phase. The methodologyof our research is based on analysis of relationship of between flow velocity and flowrate, flow rate and pressure analysis. In summary, after imposing a magnetic field thevelocity decreases and the pressure drop increases at the target position as the magneticfield intensity increases. Thus concentration of magnetic aerosol particles near themagnet side has risen. The directed flow of magnetic aerosol particle flow is changedwith the distance with magnet. Volume fraction of different can also cause changes inthe velocity difference. After the comparisons of single magnet and Halbach magnetarray, the Halbach magnet is2-3times that of a single magnet about the capacity offluid acceleration.
(4) Derived from3.5cm Halbach magnet array can provide a difference of morethan2times the aggregation, and along with the atomizing time of growth, aggregationdifference is more obvious from the results of in vitro experiments. Judging from theexperimental results on rat inhalation, add field group the iron content of the right andleft sides of the lungs than in the normal group and without magnetic field group, thegroups iron content was significant difference (P <0.01), and the left and rightsignificantly different on both sides, the difference is more than2times. From thehistology of rat lung lobe analysis, we can clearly see the difference of the magneticnanoparticles deposited on different the lung tissue.
本文以优化磁性载药颗粒在气道内的靶向输运行为为目的，首先采用以蒙特卡罗（Monte Carlo）为基础的Metropolis算法分析了磁性纳米颗粒在均匀磁场下的团聚行为。在外磁场作用下，磁性纳米颗粒会在外磁场的方向上形成一些团状、分叉状或链状的团簇结构；然后设计并构造了具有单边磁场特性的准Halbach永磁磁体阵列，然后使之作为引导磁性纳米颗粒在靶目标区域聚集的外磁场发生装置；然后以磁场—流体场耦合计算为基础研究了在不同外磁场应用环境下，Y形管道内磁性气雾颗粒流的定向流动和聚集情况，并且进行了相应的体外实验和动物实验来验证我们得到的结论。主要的研究工作包括：
①用蒙特卡罗方法模拟了纳米磁性粒子在均匀磁场下的团聚行为，得到了不同作用能量和浓度下的团聚外貌，粒子的团聚形貌由高能量的链状逐渐向低能量的分支状、圆团状形貌变化，并且在高浓度下形成大片团聚。还分析了粒子系统的总能量随蒙特卡罗步变化特点。
②准Halbach磁体阵列的提出和构造。准Halbach磁体阵列周围的磁场具有明显的单边特点，磁场大部分分布在磁体阵列的一侧而另一侧很少，这就大大提高了磁场能量的利用效率。我们考察了磁场力、磁场力效能参数和磁场力横向均匀度参数等三个评价参数，准Halbach磁体阵列比普通磁体均提高两个数量级以上。作为靶向磁体具有产生的磁场强度和磁场梯度高、对磁性纳米颗粒的有效作用距离长和聚集性好等特点，同时本文提出的三个评价参数，对于构造和评价一个磁靶向磁体的性能有一定指导作用。
③提出以稀疏固相气—固两相流为基础的磁场-流体场耦合计算模型。分析了流速和流量的关系、流速和压强的关系，得出如下结论：在靠近磁体的一侧，磁性气雾颗粒流体的轴向速度降低，并且径向速度加大，流量增大，从而提高了磁性气雾颗粒在靠近磁体侧的聚集浓度；随着目标距离的增加，磁性气雾流的定向性变差。然而，如果距离太近，反而由于目标以及周围大片区域的磁场都较大，而破坏定向性；体积分数的变化引起的相对流速差的变化不大，基本上在1左右，这说明相对差和距离参数关系更大；单个磁体和Halbach磁体阵列在使磁性气雾流定向流动上的差异明显，Halbach磁体对流体的加速作用是单个磁体的2-3倍。
④进行了相应的体外和动物实验。从体外实验的结果得出，在距离3.5cm时Halbach磁体阵列，可以提供2倍以上的聚集差异，而且随着雾化时间的增长，聚集差异更加明显。从对大鼠的吸入实验结果来看，加磁场组大鼠左右两侧肺组织内的铁含量比正常组和未加磁场组均高，组间铁含量有显著性差异（P<0.01），并且左右两侧差异明显，差值达2倍以上。从大鼠的肺部组织切片的分析，可以清楚的看到磁性纳米颗粒在左右两侧肺叶组织沉积的差异。
The magnetic targeted drug delivery system is one of the most attractive strategiesdue to its non-invasiveness, high targeting efficiency and minimizing the toxic sideeffects on healthy cells and tissues. Magnetic drug targeting therapy can be used for themedical treatment of various diseases, especially cancer. If combined with theinhalation aerosol, this technique can cure the diseases of the respiratory tract and lungs.It could result in wide range of uses and the huge potential market demand.
The purpose of the dissertation is to optimize the targeting delivery of magneticdrug-loaded particles in respiratory tract. First, we used Metropolis Monte Carlo methodto simulate the magnetic nanoparticles aggregation in uniform magnetic field. Theparticles will form the chain-like clusters, branched clusters and looped clusters aligningin the orientation external magnetic field. Then the quasi-Halbach permanent magnetarray was designed and constructed, which used to magnetic particle aggregation asexternal magnetic field generation device. Based on the coupled physics field ofmagnetic field and fluid field, the motion of magnetic aerosol particles in Y-shape tubewas studied in different condition of external field.
The main research works of the dissertation include:
(1) We used Metropolis Monte Carlo method to simulate the magneticnanoparticles aggregation in uniform magnetic field. From small to large diameters thedistribution of orientations approach the orientation of magnetic field direction step bystep, the larger one forms chain-like clusters, smaller size forms clusters with branchedand looped shapes. An analysis of total particles system energy with Monte Carlo stepswas conducted.
(2) The magnetic field distribution around Halbach magnet has single-sided feature,which could improve the utilization efficiency of magnetic field energy. We examinedthree evaluation factors，such as magnetic field strength, the effectiveness of magneticfield strength parameters and lateral uniformity of magnetic force parameters. Theresults demonstrate the Halbach magnet array than normal magnet is more than twoorders of magnitude improvement for the three factors. And, the three evaluation factorspresented in thesis can provide methods available for performance evaluation of a typetargeting delivery magnet system.
(3) The calculation model of coupled magneto-fluid field was introduction based on based on gas-solid two-phase flow model with sparse solid-phase. The methodologyof our research is based on analysis of relationship of between flow velocity and flowrate, flow rate and pressure analysis. In summary, after imposing a magnetic field thevelocity decreases and the pressure drop increases at the target position as the magneticfield intensity increases. Thus concentration of magnetic aerosol particles near themagnet side has risen. The directed flow of magnetic aerosol particle flow is changedwith the distance with magnet. Volume fraction of different can also cause changes inthe velocity difference. After the comparisons of single magnet and Halbach magnetarray, the Halbach magnet is2-3times that of a single magnet about the capacity offluid acceleration.
(4) Derived from3.5cm Halbach magnet array can provide a difference of morethan2times the aggregation, and along with the atomizing time of growth, aggregationdifference is more obvious from the results of in vitro experiments. Judging from theexperimental results on rat inhalation, add field group the iron content of the right andleft sides of the lungs than in the normal group and without magnetic field group, thegroups iron content was significant difference (P <0.01), and the left and rightsignificantly different on both sides, the difference is more than2times. From thehistology of rat lung lobe analysis, we can clearly see the difference of the magneticnanoparticles deposited on different the lung tissue.
引文
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