Logic-based Degradation of Stimuli-Responsive Polymeric Materials

非技术性：许多治疗药物已被成功开发用于治疗和治愈疾病，使我们能够过上更快乐，更健康的生活。为了使这些药物按照设计发挥作用，它们必须以精确的剂量到达身体的特定部位;正如成功治疗需要药物的阈值一样，药物在非预期的身体部位积聚可能会产生危险的副作用。为了最大限度地提高治疗效果，同时最大限度地减少有害的副作用，需要新的策略来选择性地将药物靶向递送到患病组织。拟议的研究旨在建立一种可推广的方法来创建携带药物的生物材料，这些材料会响应用户指定的外部刺激组合而降解。通过对材料进行编程以溶解和释放其治疗货物以响应疾病呈现的线索，这种策略有望产生一类具有前所未有的多功能性的新型“智能”药物递送平台。这项研究将通过增强实验室和课堂课程，培训聚合物化学，材料科学，工程和生物学的多学科学生，从而影响教育。将创建和部署以生物材料开发和光化学日常用途为中心的外展计划，以介绍和吸引代表性不足的群体参与聚合物科学，激发学生对科学、技术、工程和数学的兴趣和终身职业。技术：将药物和细胞治疗药物运送到患病部位是临床转化的主要障碍。靶向递送可以通过基于可降解聚合物的载体介导，所述载体利用疾病生物标志物来触发有效载荷释放。拟议的研究旨在建立一个模块化的化学框架，赋予水凝胶生物材料精确的降解响应多种环境线索后，用户可编程的布尔逻辑。通过指定材料交联剂中正交刺激不稳定部分的分子结构和连接性，该项目旨在获得前所未有的聚合物凝胶溶解和治疗递送特异性。为了说明这种方法，将合成17种不同的刺激响应材料，这些材料从涉及酶、还原剂和光的输入组合中共同产生所有可能的YES/OR/AND逻辑输出。通过对交联剂降解响应于环境信号的系统研究，将建立这些动态材料系统的结构-性能关系以及对分子尺度的改变如何转化为宏观响应的完整理解。所提出的策略将使聚合物刺激响应性具有无与伦比的可定制性，将在包括药物输送、诊断和再生医学在内的几个不同领域中发现巨大的实用性。该奖项反映了NSF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:Many therapeutic drugs have been successfully developed to treat and cure disease, allowing us to live happier and healthier lives. For these drugs to work as designed, they must reach a specific part of the body with a precise dosage; just as a threshold of medicine is required for successful treatment, drugs that accumulate at unintended bodily locations can have dangerous side effects. To maximize therapeutic efficacy while minimizing harmful side effects, new strategies are needed to selectively target delivery of medications to diseased tissue. The proposed research seeks to establish a generalizable approach to create drug-carrying biomaterials that degrade in response to user-specified combinations of external stimuli. By programming materials to dissolve and release their therapeutic cargo in response to disease-presented cues, this strategy is expected to yield a new class of "smart" drug-delivery platforms with unprecedented versatility. This research will impact education by training multidisciplinary students in polymer chemistry, material science, engineering, and biology through enhanced laboratory and classroom-based courses. Outreach programs centered on biomaterial development and the everyday uses for photochemistry will be created and deployed to introduce and attract under-represented groups to polymer science, sparking diverse student interest and lifelong careers in science, technology, engineering, and math.Technical:The transport of drug- and cell-based therapeutics to diseased sites represents a major barrier to clinical translation. Targeted delivery can be mediated through degradable polymer-based vehicles that utilize disease biomarkers to trigger payload release. The proposed research seeks to establish a modular chemical framework for imparting hydrogel biomaterials with precise degradative responsiveness to multiple environmental cues following user-programmable Boolean logic. By specifying the molecular architecture and connectivity of orthogonal stimuli-labile moieties within material crosslinkers, this project seeks to gain unprecedented specificity over polymer gel dissolution and therapeutic delivery. To illustrate this methodology, seventeen distinct stimuli-responsive materials will be synthesized that collectively yield all possible YES/OR/AND logical outputs from input combinations involving enzyme, reductant, and light. Through systematic studies of crosslinker degradation in response to environmental signals, structure-property relationships of these dynamic material systems as well as a complete understanding of how molecular-scale alterations translate into macroscopic response will be established. The proposed strategies, which will enable unmatched customizability of polymer stimuli-responsiveness, will find great utility throughout several diverse fields including drug delivery, diagnostics, and regenerative medicine. Research efforts will be complemented by the creation of outreach programs centered on photochemistry and biomaterial development.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.