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

纳米颗粒为肿瘤提供抗癌药物。它们可以防止身体其他部位接触到这些有毒药物。穿透肿瘤是很困难的。了解控制药物纳米载体在肿瘤内行为的因素有助于改善给药。改善递送的一个策略是尝试消化肿瘤周围的基质材料。所使用的酶称为基质金属蛋白酶(MMPs)。不幸的是，MMPs可能会对周围的细胞和组织产生毒性。这项研究的主要目标是创造“智能”的MMPs，其活性仅针对肿瘤基质材料。外展和教育努力旨在吸引学生投身工程职业，并提高技术素养。计划进行大学前的研究实习，为当地一所中学提供药物输送教学模块，以及蛋白质工程和药物输送方面的新课程模块。纳米载体在药物输送方面提供了许多潜在的好处。这些能力包括精确靶向药物输送、控制释放、延长体内循环时间和提供刺激反应功能。肿瘤基质/基质的特性导致的穿透性差被认为是药物传递有效性的主要挑战。该项目融合了合成生物学/蛋白质工程和药物输送/生物材料方面的不同专业知识，以创建肿瘤可致动的前MMPs，并揭示控制它们的位置选择性揭开、蛋白分解活性和增强肿瘤相关细胞外基质内纳米载体运输的能力的机制。某些基质金属蛋白酶(如基质金属蛋白酶-9)在肿瘤微环境中的浓度升高。将设计由提升的MMPs有条件地激活的合成的前MMPs。这些有条件的支持MMP的人为蛋白质纳米结构提供特定于基质金属蛋白酶的流动性增强的能力将被评估。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.