Multifunctional methionine based materials for therapeutic use

技术方面：需要一种聚合物药物载体，它可以用一种通用的方法来制备，这种方法允许对化学成分和结构进行微调，并使用生物相容性和易于功能化的构建块。本项目的目标是开发和研究含有修饰的聚l -蛋氨酸片段（MMOD）的多功能两亲性嵌段共肽，这种嵌段共肽可以组装成细胞内药物递送的载体。该实验室最近的合成进展现在允许利用MMOD结构域开发全新的多肽两亲体，这些结构域的设计使得单个片段可以在最终的纳米载体组装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蛋氨酸基生物材料。蛋氨酸片段的掺入及其随后的修饰是一个简单的，可扩展的过程，并且允许前所未有的控制多肽添加复杂功能和生物活性的能力。一些MMOD残基也自然存在于生物系统中，这些残基将战略性地用于促进治疗药物的释放，并可能提供其他治疗益处。MMOD片段将被用作新的功能性亲水性结构域，能够提供溶解度、生物相容性、治疗结合、细胞摄取、酶反应、pH反应和化学选择性生物偶联的多种组合。具体来说，该项目将设计、制备和表征含有MMOD片段的囊泡形成嵌段共肽，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药物的载体。此外，它将使用体外细胞培养和运输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对下游特定用途的载体特性进行微调，用于药物的封装和输送，并将为开发一类新的医疗应用功能生物材料奠定基础。非技术方面：在这个项目中，专业人士将继续成功地吸纳代表性不足的群体，为研究生和本科生提供教学和培训，并在出版物和报告中传播他们的研究成果。这些努力的一些例子来自上一个拨款期：开发和改进生物工程课程，纳入项目的概念，如细胞内运输和生物偶联方法；招募一名西班牙裔女学生（2013年3月获得博士学位）和一名非洲裔女学生参与该项目（第一年）；在国家和地方会议（ACS， BMES， MRS，西班牙裔，奇卡诺裔和美洲原住民科学促进会（SACNAS）全国会议）上的PI和学生研究成果报告；以及PI的研究报告，鼓励学生从事科学事业（2010年UCSB材料合成暑期学校；2011年NAE研究生大挑战峰会；2012年法国波尔多国际青年科学家研讨会）。龟井教授还每年访问东洛杉矶的小学和高中（其中一所90%是西班牙裔），以激励该系统中的年轻人成为科学家和工程师。该项目培养的博士生在工业领域（包括制药和材料科学领域）都很有价值，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，以及更多应用领域的材料表征和性能评估。这些本科生也做得很好，被著名的博士（华盛顿，麻省理工学院，UCSB）和医学博士（康奈尔，德克萨斯a&m）项目录取，并获得NSF研究生奖学金。

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.