Engineering Protein-Based Multifinctional Materials

ID：MPS/DMR/BMAT（7623）1205384 PI：Montclare，Jin ORG：纽约理工学院标题：工程蛋白质为基础的多功能材料智力优势：设计和合成的功能性自组装系统能够封装，储存和提供小疏水分子/治疗变得越来越重要。 大多数递送载体来源于脂质和合成聚合物。 然而，自组装肽/蛋白质正在成为潜在的材料，可以很容易地操纵用于治疗递送。 这项工作的目的是定制基因工程蛋白质嵌段聚合物的小疏水分子/治疗剂的交付。 本研究提出以蛋白质为基础的多功能奈米递药，以将多柔比星（dox）与姜黄素（ccm）双重递药至癌细胞。 工程化蛋白质材料可以：（1）通过高温条件靶向，将药剂浓缩在局部疾病部位，（2）结合/包封dox和ccm而不需要进一步化学改变递送药剂或治疗剂，（3）由于增强的渗透保留（EPR）效应而保留在癌症部位，和（4）用癌靶向肽序列修饰以主动靶向乳腺癌细胞。 待测试的中心假设是：（1）蛋白质结构域的适当组合将使得能够在高热温度范围内进行超分子组装，以及（2）将小分子结合能力和癌症特异性靶向结构域定制成单个构建体将使得能够控制递送期望的化学试剂以治疗乳腺癌作为模型。 所提出的递送载体的关键特征是这些蛋白质材料的模块化性质使得能够将上述结构域整合到单个聚合物链中，并且它们的自组装能力允许双重药物包封以及对递送和靶向配体呈递的控制。 这将通过利用分子生物学和蛋白质工程的最强大的方法来实现。 从这些研究中收集到的洞察力可用于确定共同的主题或可预测的规则对工程蛋白质衍生的材料与可调性能的therapeutic delivery.BROADER IMPLEMENTARY：拟议的工作可能会导致封装车辆能够选择性地提供抗癌，和其他，治疗剂。 该项目将培训下一代科学家和工程师，以整合生物学，化学和工程工具，以应对靶向药物输送的生物医学挑战。 本建议的教育和外联部分属于不同但相互关联的活动。 除了教学和指导研究生和博士后，PI已经并将继续监督本科生和高中生从青年工程和科学（YES）计划在实验室研究。 PI将继续与城市议会青年妇女数学和科学研究所（UAI）合作，制定一个分层的指导推广计划，为教师提供课堂支持，并通过现代化的，引人入胜的模块将技术注入课程。 该计划为布鲁克林学校的年轻学生和教师整合了现代技术和跨学科科学。 其他动手，技术先进的模块将与本科研究员一起开发。 例如，他们开发了一个iPad应用程序“刘易斯点”，使化学结构的分子可视化，与基于博客的学习方法一起，已在UAI课堂上实施。

ID: MPS/DMR/BMAT(7623) 1205384 PI: Montclare, Jin ORG: Polytechnic Institute of New YorkTitle: Engineering Protein-Based Multifinctional MaterialsINTELLECTUAL MERIT: The design and synthesis of functional self-assembling systems capable of encapsulating, storing, and delivering small hydrophobic molecules/therapeutics is becoming increasingly important. A majority of the delivery vehicles are derived from lipids and synthetic polymers. However, self-assembling peptides/proteins are emerging as potential materials that can be readily manipulated for therapeutic delivery. This work aims to tailor genetically engineered protein block polymers for the delivery of small hydrophobic molecules/therapeutics. The fabrication of multi-functional, nanoscaled protein-based delivery agents for the dual delivery of doxorubicin (dox) and curcumin (ccm) to cancer cells is proposed. The engineered protein materials can: (1) be targeted via hyperthermia conditions, concentrating the agents at the localized disease site, (2) bind/encapsulate dox and ccm without the need for further chemical alteration of the delivery agent or the therapeutic agent, (3) be retained at the cancer site due to the enhanced permeation retention (EPR) effect, and (4) be decorated with cancer targeting peptide sequences for active targeting of breast cancer cells. The central hypotheses to be tested are that (1) appropriate combinations of protein domains will enable supramolecular assembly in the hyperthermia temperature range and (2) tailoring small molecule-binding abilities and cancer specific targeting domains into a single construct will enable the controlled delivery of desired chemical agents to treat breast cancer as a model. Critical features of the proposed delivery vehicle are that the modular nature of these protein materials enables integration of the above domains into a single polymer chain and that their ability to self-assemble allows dual drug encapsulation as well as control over the delivery and targeting ligand presentation. This will be accomplished by exploiting the most powerful methods of molecular biology and protein engineering. The insight gleaned from these studies may be used to identify common themes or predictable rules towards engineering protein-derived materials with tunable properties for therapeutic delivery.BROADER IMPACTS: The proposed work may lead to encapsulating vehicles capable of selectively delivering anticancer, and other, therapeutic agents. This project will train the next generation scientists and engineers to integrate tools from biology, chemistry, and engineering to address the biomedical challenge of targeted drug delivery. The educational and outreach components of this proposal fall into distinct but interrelated activities. In addition to teaching and mentoring graduate students and postdocs, the PI has and continues to supervise both undergraduates and high-school students from the Youth in Engineering and Science (YES) program in laboratory research. The PI will continue, in partnership with the Urban Assembly Institute for Math and Science for Young Women (UAI), to develop a tiered mentoring outreach program that provides classroom support for teachers and infuses technology into the curriculum through modern, engaging modules. This program integrates modern technology and interdisciplinary science for young students and teachers in the Brooklyn schools. Additional hands-on, technologically advanced modules will be developed together with undergraduate fellows. For example, they have developed an iPad app "Lewis Dots" that enables the molecular visualization of chemical structures that, together with blog-based learning approaches, has been implemented in the UAI classroom.