Collaborative Research: Design and mechanistic studies on microenvironment-sensitive polymeric nanoparticles for simultaneous contents release and ultrasound imaging

非技术描述：许多疾病，如癌症，是可怕的，因为往往是在治疗无效时才被诊断出来。此外，当治疗可行时，它会产生使人虚弱的副作用，包括其他危及生命的疾病。因此，主要的医疗保健目标是早期、非侵入性的准确诊断和无有害副作用的有效治疗干预。在这里，一个由来自两所大学的药物化学家和工程师领导的跨学科科学团队将开发和研究单一临床设备背后的基础科学，其双重目标是改进诊断超声成像和靶向治疗，仅在目标区域有效。该团队的目标是合成纳米尺寸的聚合物颗粒。它们在结构上与人体细胞相似，可以携带治疗药物避开人体的防御系统到达目标区域。这些粒子经过化学改造，在特定的化学环境中爆炸，只有在患病的情况下才会爆炸，并运送它们的货物。该研究将通过实验和理论系统地研究这些纳米粒子的化学性质，以优化它们的预期效果和它们的超声反射率背后的机制。主要研究人员提出了一系列的教育活动，包括高中实习生、本科生和博士生，他们参与了多学科项目的实际临床应用，为进入21世纪的劳动力做好准备。技术描述：本提案的目的是对聚合物纳米颗粒（聚合体）进行基础研究，这些聚合物纳米颗粒被编程为在疾病中常见的特定生化环境下释放其封装内容物，同时对超声有反应，从而允许成像和超声辅助释放。它使用降低的氧分压作为释放的模型触发器。这些研究将发展多模态聚合物纳米颗粒的设计原则，用于未来的肿瘤药物输送和同时超声成像。该团队将优化聚合物设计，使聚合体对降低的氧气水平做出反应，并释放被封装的内容物。纳米粒子将被制造成能在空气中捕获空气，从而在它们被破坏之前同时进行超声成像。这些带有回声的聚合体将在含有缺氧壁龛的癌细胞的三维（3D）培养中进行测试。该奖项将支持扩大代表性不足的少数民族参与研究和教育的活动。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Non-technical Description:Many diseases, such as cancer, are dreadful because often, they are diagnosed late when therapy proves ineffective. Moreover, when therapy is available, it involves debilitating side effects, including other life-threatening conditions. The primary healthcare objectives, therefore, are early, noninvasive accurate diagnosis and effective therapeutic intervention without harmful side effects. Here a cross-disciplinary scientific team led by a pharmaceutical chemist and an engineer from two universities will develop and study the fundamental science behind a single clinical implement with the dual aim of improved diagnostic ultrasound imaging and targeted therapy which becomes active only in the target region. The team aims at synthesizing nanometer-size polymeric particles. They are similar in structure to body cells and can carry therapeutics to target areas evading the body’s defense system. The particles are chemically engineered to implode in a specific chemical environment found only in diseased conditions and deliver their cargo. The proposed research will systematically investigate the chemistry of these nanoparticles through experiments and theory to optimize their desired effects and the mechanism behind their ultrasound reflectivity. The principal investigators have proposed an array of educational activities involving high school interns, undergraduates, and Ph.D. students in multi-disciplinary projects with real-life clinical applications preparing them to enter the twenty-first-century workforce.Technical Description:The objective of this proposal is to conduct foundational studies on polymer nanoparticles (polymersomes) that are programmed to release their encapsulated contents under specific biochemical environments common in diseases and simultaneously are responsive to ultrasound to allow imaging and ultrasound-assisted release. It uses reduced oxygen partial pressure as a model trigger for release. The proposed studies will develop the design principles of multimodal polymer nanoparticles for future applications in drug delivery to tumors and simultaneous ultrasound imaging. The team will optimize polymer design so that the resultant polymersomes become responsive to the reduced oxygen levels and release the encapsulated contents. The nanoparticles will be made to entrap air allowing simultaneous ultrasound imaging before their destruction. These echogenic content-bearing polymersomes will be tested in three-dimensional (3D) cultures of cancer cells containing hypoxic niches. The award will support activities that broaden participation of underrepresented minorities in research and education.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.