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.

纳米粒子将抗癌药物运送到肿瘤中。它们可以防止身体其他部位接触到这些有毒药物。穿透肿瘤很困难。了解控制肿瘤内药物纳米载体行为的因素可以帮助改善药物的递送。改善输送的一种策略是尝试消化肿瘤周围的基质物质。所用的酶被称为基质金属蛋白酶（MMPs）。不幸的是，MMPs可能对周围的细胞和组织有毒。这项研究的主要目标是创造“智能”MMPs，其活性仅针对肿瘤基质材料。推广和教育工作旨在吸引学生从事工程职业，提高技术素养。计划大学预科科研实习、当地一所中学药物传递教学模块、蛋白质工程和药物传递新课程模块。纳米载体在药物递送方面提供了许多潜在的好处。这包括它们精确靶向药物递送、控制释放、延长体内循环时间和提供刺激反应特性的能力。由于肿瘤间质/基质的特性导致的穿透力差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/蛋白质工程和药物输送/生物材料方面的各种专业知识，以创建肿瘤可驱动的亲mmps，并揭示控制其位点选择性揭开、蛋白质水解活性和增强肿瘤相关细胞外基质内纳米载体运输能力的机制。某些MMPs（例如MMP-9）在肿瘤微环境中的浓度升高。将设计被升高的MMPs有条件激活的合成pro-MMPs。这些有条件的亲mmps为蛋白质纳米结构提供mmp特异性迁移增强的能力将被评估。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。