Studies on the development and characterization of sonosensitive organic nanoparticles for an ultrasound controlled, local release of pharmaceutical agents

纳米粒子作为药物活性成分的载体，在一定的靶区进行时间和空间的控制释放，即所谓的“给药”，是人们非常感兴趣的。一个重要的应用领域是肿瘤疾病的局部化疗，它可以防止整个身体暴露于治疗剂，从而减少其他令人不快和有害的副作用。由于它们的小尺寸，单个纳米颗粒比以微粒形式存在的更大的载体更有利于EPR效应（增强渗透性和保留性）的优势。这使得活性成分更强地渗透到肿瘤组织中，并对肿瘤组织产生更强的作用。我们的项目专注于“声敏”纳米结构，其中的活性物质可以通过超声波暴露释放。为了将这种影响限制在特定的肿瘤区域，需要聚焦超声波场。到目前为止，在合适尺寸的声敏纳米颗粒上所期望的效果只能在不允许充分聚焦的低超声频率下检测到。然而，最近申请者已经成功地实现了新的声敏纳米颗粒（以球体和胶囊的形式），其中这种效应也发生在具有良好聚焦波场的更高超声波频率下。新开发的纳米颗粒代表了水分散的再水合，冷冻干燥的聚乳酸纳米球，直径为120纳米。宽带噪声是由835 kHz的超声产生的，这是由于瞬态的、有效的成分释放空化。在计划的项目中，纳米颗粒的生产将被优化，以有效释放有效成分。超声引起这些纳米结构惯性空化的机理将被确定。显微方法（光学显微镜，电子显微镜，扫描力显微镜）将用于颗粒的形态表征。为了对颗粒的有效性进行功能表征，必须实现致动器传感器系统，该系统在致动器侧具有用于产生聚焦功率超声的单元，该单元允许通过改变相关超声操作参数来优化空化过程。在传感器端实施和测试了各种用于空化被动和主动检测的超声方法。传感器模式应该在适当的组合中使用，以优化纳米颗粒生产过程，以及有效的、基于空化的有效成分释放。根据项目取得的成果和发现，将制定用于医学应用的概念建议和系统方法。

Nanoparticles are of great interest as carriers for pharmaceutical active ingredients for a time and spatial controlled release in certain target areas as so-called "drug delivery". An important area of application is localized chemotherapy of tumor diseases which prevents the entire body from being exposed to the therapeutic agent and thus reduces otherwise unpleasant and harmful side effects. Because of their small size, the individual nanoparticles favor the advantage of the EPR effect (enhanced permeability and retention) over the substantially larger carriers in the form of microparticles. This allows for a stronger penetration of the active ingredient into and a stronger action on the tumor tissue.Our project focuses on "sonosensitive" nanostructures in which the active substances can be released by ultrasound exposition. In order to limit this effect to specific tumor regions, focused ultrasonic wave fields are required. Until now, the desired effect on sonosensitive nanoparticles of suitable size was detectable only at low ultrasonic frequencies which do not permit sufficient focusing. However, recently the applicants have succeeded in the realization of new sonosensitive nanoparticles (in the form of spheres and capsules) in which the effect also occurs at higher ultrasonic frequencies with well-focused wave fields. The newly developed nanoparticles represent rehydrated, freeze - dried poly(lactic acid) nanospheres in a water dispersion, with a diameter of 120 nm. Broadband noise is generated by sonication at 835 kHz, which is due to transient, active ingredients - releasing cavitation.In the planned project, nanoparticle production is to be optimized with a view to efficient release of active ingredients. The mechanism by which ultrasound causes inertial cavitation of these nanostructures will be determined. Microscopic methods (light microscopy, electron microscopy, scanning force microscopy) will be used for the morphological characterization of the particles. For the functional characterization of the effectiveness of the particles, an actuator sensor system has to be implemented, which on the actuator side has a unit for generating focused power ultrasound, which allows optimization of the cavitation process by variation of relevant ultrasonic operation parameters. Various ultrasonic methods for the passive and the active detection of cavitation are to be implemented and tested on the sensor side. The sensor modalities should be used in a suitable combination for the optimization of the nanoparticle production process as well as for the efficient, cavitation-based release of active ingredients. Based on the results and findings gained in the project, concept proposals and systematic approaches for the application in medicine are to be developed.