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：生物材料计划在纽约大学材料研究中获得的奖项是为了开发能够双重基因和药物输送系统的生物材料，以便对多药抗性癌细胞进行潜在治疗。该奖项是由化学，生物工程，环境和运输系统（工程局）和生物胶带计划的化学，生物工程，环境和运输系统部门的颗粒和多相过程计划进行的。提出的实验将导致生物医​​学新颖的药物产生，并改变传统的治疗疗法。这些系统还将影响生物技术，因为从这些研究中学到的经验教训可以用于提供其他基因和代理，并应用于非医学行业，包括个人护理，化妆品和农业。这项多学科研究将培训下一代学生，科学家和工程师在生物材料，化学，工程和细胞生物学中采用尖端技术。除了教学和指导研究生和博士后研究人员外，PI还将监督代表性不足的本科生和高中生的实验室研究。 PI还计划将技术和社交媒体整合到本科和研究生课程中，并将这些学生暴露于尖端的研究中。对于外展活动，PI将继续参与科学与工程计划的应用研究创新，以吸引纽约市当地的10年级和11年级学生参与生物材料研究。作为夏季生物工程计划的主任，PI将积极招募人数不足的高中生参加生物学启发的材料课程。技术：核酸和小分子疗法具有关键的指导，以控制生物学过程，在基本细胞和生物学研究和生物技术，生物技术，生物技术，生物技术，生物技术，生物技术，生物技术，生物技术，生物技术，生物技术，生物技术，生物技术，生物技术，生物技术，生物技术，生物技术，生物技术，生物技术，生化，生物技术，生物技术和医学上。然而，核酸和小分子的细胞内递送主要是由于质膜屏障。该项目的目的是开发能够：1）有效与siRNA复合的多功能工程蛋白脂质系统（脂蛋白词）； 2）封装小分子药物（姜黄素，阿霉素等），而无需共价修饰； 3）触发双重有效载荷在单元内释放后，导致编程的细胞结果。为了生产能够交付基因和治疗性小分子的媒介，PI提出了一种创新的方法，以重新工程工程师的软骨寡聚基质基质蛋白的盘绕型圈结构域，以便它能够基于PI的最初源于PI的成功，使其能够与核酸和小分子与核酸和小分子进行复杂化。这些工程脂肪的创新包括：1）整合突变的易于快速优化； 2）双重药物和基因封装； 3）控制交付和自组装。所提出的工程蛋白脂质系统的多功能性不仅可用于传递小分子和siRNA来治疗多药耐药性癌症，还可以单独或单独传递各种化学剂和基因或结合使用以洞悉细胞功能。