Logic-gated pro-MMP activation for tumor-specific motility in nanocarriers

纳米载体中肿瘤特异性运动的逻辑门控 MMP 前体激活

• 批准号: 2220667
• 负责人: Wilfred Chen
• 金额: $ 52.1万
• 依托单位: University of Delaware
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2220667&HistoricalAwards=false
• 关键词: Logic; gated; pro; MMP; activation

Nanoparticles deliver anti-cancer drugs to tumors. They prevent exposure of the rest of the body to these toxic drugs. Penetrating the tumor is difficult. Understanding the factors that govern the behavior of drug nanocarriers within the tumor could help improve delivery. One strategy to improve delivery has been to try digesting the matrix material surrounding tumors. The enzymes used are referred to as matrix metalloproteinases (MMPs). Unfortunately, MMPs can be toxic to surrounding cells and tissue. The major objective of this research is to create ‘smart’ MMPs whose activity is specific for tumor matrix material only. Outreach and educational efforts are designed to attract students to careers in engineering and improve technological literacy. Pre-college research internships, drug delivery teaching modules for a local middle school, and new course modules in protein engineering and drug delivery are planned.Nanocarriers offer numerous potential benefits in drug delivery. These include their abilities to precisely target drug delivery, to control release, extend circulation time within the body, and offer stimulus-responsive features. Poor penetration caused by the features of the tumor stroma/matrix is cited as a primary challenge to drug delivery effectiveness. This project fuses diverse expertise in synthetic biology/protein engineering and drug delivery/biomaterials to create tumor-actuatable pro-MMPs and uncover mechanisms governing their site-selective unmasking, proteolytic activity, and capacity to enhance nanocarrier transport within tumor-relevant extracellular matrix. Certain MMPs (MMP-9 for example) have elevated concentrations in tumor microenvironments. Synthetic pro-MMPs that are conditionally activated by the elevated MMPs will be designed. The ability of these conditional pro-MMPs to provide MMP-specific mobility enhancements to protein nanostructures will be evaluated.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.

纳米颗粒向肿瘤提供抗癌药物。它们防止身体其他部位暴露于这些有毒药物中。穿透肿瘤很困难。了解控制肿瘤中药物纳米载体行为的因素可以帮助改善递送。改善分娩的一种策略是尝试消化周围肿瘤周围的基质材料。所使用的酶称为基质金属蛋白酶（MMP）。不幸的是，MMP可能对周围的细胞和组织有毒。这项研究的主要目的是创建“智能” MMP，其活动仅针对肿瘤基质材料。外展和教育工作旨在吸引学生从事工程学的职业并提高技术素养。计划在蛋白质工程和药物输送的新课程模块中进行预科研究实习，提供蛋白质工程和药物输送的新课程模块。纳米载体为肿瘤基质/基质的特征造成的许多优势提供了许多优势，这是对药物输送的主要挑战。这些包括它们精确靶向药物输送，控制释放，延长体内循环时间并提供刺激反应性特征的能力。由肿瘤基质/基质的特征引起的渗透不良被认为是药物递送有效性的主要挑战。该项目融合了合成生物学/蛋白质工程和药物递送/生物材料方面的分歧专业知识，以创建可肿瘤的促疾病促进症，并揭示控制其现场选择性液化，蛋白水解活动，蛋白水解活性的机制，以及增强肿瘤 - 纳米载体运输的能力，以增强肿瘤 - 利用细胞外的细胞外胞外矩阵。某些MMP（例如，MMP-9）在肿瘤微环境中的浓度升高。将设计由高架MMP有条件激活的合成Pro-MMP。将评估这些有条件的Pro-MMP对蛋白质纳米结构提供MMP特异性移动性增强功能的能力。该奖项反映了NSF的法定任务，并通过使用该基金会的知识分子的优点和更广泛的影响来审查标准，通过评估来诚实地支持支持。