Multifunctional methionine based materials for therapeutic use

用于治疗用途的多功能蛋氨酸基材料

• 批准号: 1308081
• 负责人: Timothy Deming
• 金额: $ 42万
• 依托单位: University of California-Los Angeles
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1308081&HistoricalAwards=false
• 关键词: Multifunctional; methionine; based; materials; therapeutic

Technical: There is a need for polymeric drug carriers that can be prepared using a versatile method that allows fine tuning of chemical composition and structure, and use building blocks that are biocompatible and easily functionalized. The goal of this project is to develop and study multifunctional amphiphilic block copolypeptides containing modified poly(L-methionine) segments, MMOD, that can be assembled into vehicles for intracellular drug delivery. Recent synthetic advances in this lab now allow the development of entirely new polypeptide amphiphiles utilizing MMOD domains that are designed so that individual segments can play unprecedented multiple functional roles in the resulting nanocarrier assemblies. This innovative approach provides a new method for introducing functionality into polymeric nanocarriers and will develop and test a new class of methionine based biomaterials. The incorporation of methionine segments and their subsequent modification is a straightforward, scalable process, and allows unprecedented control in the ability to add complex functionality and biological activity to polypeptides. Some MMOD residues also occur naturally in biological systems and these will be used strategically to promote release of therapeutics, and may also provide other therapeutic benefits. The MMOD segments will be utilized as new, functional hydrophilic domains capable of providing multiple combinations of solubility, biocompatibility, therapeutic binding, cell uptake, enzyme-response, pH response, and chemoselective bioconjugation. Specifically, the project will design, prepare, and characterize vesicle forming block copolypeptides containing MMOD segments as carriers for therapeutics with low cytotoxicity and capability for cell uptake, endosomal release and intracellular carrier disruption. In addition, it will test the capabilities of these carriers using in vitro cell culture and trafficking studies. The knowledge gained from these studies will allow fine tuning of carrier properties for downstream specific uses in encapsulation and delivery of drugs, and will lay groundwork for development of a new class of functional biomaterials for medical applications.Non-Technical: In this project, the PIs will continue their successful inclusion of underrepresented groups, teaching and training of graduate and undergraduate students, and dissemination of their research findings in publications and presentations. Some examples of these efforts from the previous grant period are: development and improvement of bioengineering courses incorporating concepts from the project such as intracellular trafficking and bioconjugation methods; recruitment of a Hispanic female student (Ph.D. granted in March 2013) and an African American female student for this project (1st year); PI and student presentations of research results at national and local meetings (ACS, BMES, MRS, Society for Advancement of Hispanics, Chicanos, and Native Americans in Science (SACNAS) national meeting); and presentations incorporating this research by the PI to encourage students to pursue careers in science (2010 UCSB Summer School on materials synthesis; 2011 NAE Grand Challenges Summit for graduate students; 2012 International Young Scientist Symposium, Bordeaux, France). Professor Kamei has also made annual visits to elementary and high schools in East Los Angeles (one is 90% Hispanic) to inspire youth in this system to become scientists and engineers. Ph.D. students trained under this program are valuable in the industrial job force (both pharmaceutical and materials science areas) since they will learn fundamentals of polymer synthesis using catalysis and self-assembly, cell culture and drug trafficking, as well as more applied areas of materials characterization and property evaluation. These undergraduate students have also done well by being admitted into prestigious Ph.D. (Washington, MIT, UCSB) and MD (Cornell, Texas A&M) programs, and obtaining NSF graduate fellowships.

技术支持：需要可以使用允许微调化学组成和结构的通用方法制备的聚合物药物载体，并且使用生物相容性和容易官能化的结构单元。 本项目的目标是开发和研究含有修饰的聚（L-甲硫氨酸）片段的多功能两亲性嵌段共聚肽，MMOD，可以组装成细胞内药物递送载体。 该实验室最近的合成进展现在允许开发利用MMOD结构域的全新多肽两亲物，所述MMOD结构域被设计成使得各个片段可以在所得纳米载体组装体中发挥前所未有的多种功能作用。 这种创新的方法提供了一种将功能引入聚合物纳米载体的新方法，并将开发和测试一类新的基于蛋氨酸的生物材料。 甲硫氨酸区段的掺入及其随后的修饰是直接的、可扩展的过程，并且允许对向多肽添加复杂功能性和生物活性的能力进行前所未有的控制。 一些MMOD残基也天然存在于生物系统中，并且这些将策略性地用于促进治疗剂的释放，并且还可以提供其他治疗益处。 MMOD片段将用作新的功能性亲水结构域，能够提供溶解性、生物相容性、治疗结合、细胞摄取、酶响应、pH响应和化学选择性生物缀合的多种组合。 具体而言，该项目将设计，制备和表征含有MMOD片段的囊泡形成嵌段共聚肽，作为具有低细胞毒性和细胞摄取，内体释放和细胞内载体破坏能力的治疗剂的载体。 此外，它将使用体外细胞培养和贩运研究来测试这些载体的能力。 从这些研究中获得的知识将允许微调载体特性，以用于药物的封装和递送的下游特定用途，并将为开发用于医疗应用的新型功能生物材料奠定基础。非技术：在这个项目中，项目执行机构将继续成功地纳入代表性不足的群体，继续对研究生和本科生进行教学和培训，并在出版物和演讲中传播其研究成果。 这些努力的一些例子，从上一个赠款期：发展和改进生物工程课程纳入概念的项目，如细胞内贩运和生物共轭方法;招聘西班牙裔女学生（博士），2013年3月获得）和一名非裔美国女学生参加该项目（第一年）; PI和学生在国家和地方会议上介绍研究成果（ACS，BMES，MRS，社会促进西班牙裔，奇卡诺人和美洲原住民在科学（SACNAS）全国会议）;以及由PI结合这项研究的演示文稿，以鼓励学生追求科学事业（2010年UCSB材料合成暑期学校; 2011年NAE研究生大挑战峰会; 2012年国际青年科学家研讨会，法国波尔多）。 龟井教授还每年访问东洛杉矶的小学和高中（其中90%是西班牙裔），以激励这个系统中的年轻人成为科学家和工程师。 博士根据该计划培训的学生在工业就业队伍（包括制药和材料科学领域）中很有价值，因为他们将学习使用催化和自组装的聚合物合成，细胞培养和毒品贩运的基础知识，以及材料表征和性能评估的更多应用领域。 这些本科生也取得了很好的成绩，被著名的博士学位录取。（华盛顿，麻省理工学院，UCSB）和MD（康奈尔大学，得克萨斯州A M）计划，并获得NSF研究生奖学金。