Engineered Protein-Lipid Systems for siRNA and Small Molecule Delivery

用于 siRNA 和小分子递送的工程蛋白质-脂质系统

• 批准号: 1505214
• 负责人: Jin Montclare
• 金额: $ 30万
• 依托单位: New York University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1505214&HistoricalAwards=false
• 关键词: Engineered; Protein; Lipid; Systems; siRNA

Non-Technical: This award by the Biomaterials program in the Divison of Materials Research to New York University is to develop biomaterials capable of dual gene and drug delivery system, for potential treatment of multi-drug resistant cancer cells. This award is cofunded by Particulate and Multiphase Processes program in the Division of Chemical, Bioengineering, Environmental, and Transport Systems (Directorate for Engineering) and the BioMaPS program. The proposed experiments would lead to the generation of novel agents for biomedicine, and transform the traditional view of therapeutics. These systems will also impact biotechnology as the lessons learned from these studies that can be employed for delivery of other genes and agents with applications extending to non-medical industries including personal care, cosmetics and agriculture. This multidisciplinary research will train the next generation students, scientists and engineers to employ cutting edge technologies in biomaterials, chemistry, engineering and cell biology. In addition to teaching and mentoring graduate students and postdoctoral researchers, the PI will supervise underrepresented undergraduates and high-school students in laboratory research. The PI is also planning to integrate technology and social media into both undergraduate and graduate courses, and exposing these students to cutting-edge research. For outreach, the PI will continue to participate in the Applied Research Innovations in Science and Engineering program in engaging local NYC 10th and 11th grade students to biomaterials research. As director of the Summer Bioengineering Program, the PI will be actively recruiting underrepresented high school students to participate in a biologically inspired materials course.Technical: Nucleic acids and small molecule therapeutics possess critical instructions for controlling biological processes with tangible implications in fundamental cell and organismal studies, biotechnology and medicine. However, the intracellular delivery of nucleic acids and small molecules has been a challenge predominantly due to the plasma membrane barrier. The goal of this project is to develop a multifunctional engineered protein-lipid system (lipoproteoplexes) capable of: 1) effectively complexing with siRNA; 2) encapsulating a small molecule drug (curcumin, doxorubicin, etc.) without the need for covalent modification; and 3) triggering release of the dual payload once inside the cell leading to a programmed cellular outcome. In order to produce a vehicle capable of delivering both gene and therapeutic small molecule, the PI proposes an innovative approach to re-engineer the coiled-coil domain of cartilage oligomeric matrix protein so that it is able to complex with nucleic acids and small molecules in conjunction with lipids based on PI's initial success in introducing positive charge on the surface through protein engineering. Innovations in these engineered lipoproteoplexes include: 1) the ease of integrating mutations enabling rapid optimization; 2) dual drug and gene encapsulation; and 3) control over the delivery and self-assembly. The versatility of the proposed engineered protein-lipid systems will not only prove useful for delivering small molecules and siRNA to treat multi-drug resistant cancers, but also for delivering a variety of chemical agents and genes alone or in combination to gain insight into cell functions.

非技术性：纽约大学材料研究部生物材料项目授予的该奖项旨在开发具有双基因和药物输送系统的生物材料，用于潜在治疗多重耐药癌细胞。该奖项由化学、生物工程、环境和运输系统（工程理事会）部门的颗粒和多相过程项目以及 BioMaPS 项目共同资助。拟议的实验将导致生物医​​学新型药物的产生，并改变传统的治疗观点。这些系统还将影响生物技术，因为从这些研究中吸取的经验教训可用于传递其他基因和制剂，其应用范围扩展到包括个人护理、化妆品和农业在内的非医疗行业。这项多学科研究将培训下一代学生、科学家和工程师采用生物材料、化学、工程和细胞生物学领域的尖端技术。除了教学和指导研究生和博士后研究人员外，PI 还将监督实验室研究中代表性不足的本科生和高中生。 PI 还计划将技术和社交媒体整合到本科生和研究生课程中，让这些学生接触到前沿研究。在推广方面，PI 将继续参与科学与工程应用研究创新计划，吸引纽约市当地 10 年级和 11 年级学生参与生物材料研究。作为夏季生物工程项目的主任，PI 将积极招募代表性不足的高中生参加生物启发材料课程。技术：核酸和小分子疗法拥有控制生物过程的关键指令，对基础细胞和有机体研究、生物技术和医学具有实际影响。然而，主要由于质膜屏障，核酸和小分子的细胞内递送一直是一个挑战。该项目的目标是开发一种多功能工程蛋白-脂质系统（lipoproteoplexes），能够：1）有效地与siRNA复合； 2）封装小分子药物（姜黄素、阿霉素等），无需共价修饰； 3) 一旦进入细胞，就会触发双重有效负载的释放，从而导致编程的细胞结果。为了生产能够传递基因和治疗性小分子的载体，PI在通过蛋白质工程在表面引入正电荷的初步成功的基础上，提出了一种创新方法来重新设计软骨寡聚基质蛋白的卷曲螺旋结构域，使其能够与核酸和小分子以及脂质复合。这些工程化脂蛋白复合物的创新包括：1）易于整合突变，从而实现快速优化； 2）药物和基因双重封装； 3）控制交付和自组装。所提出的工程蛋白质-脂质系统的多功能性不仅可用于递送小分子和 siRNA 以治疗多重耐药癌症，而且还可用于单独或组合递送各种化学试剂和基因以深入了解细胞功能。