CAREER: Viral Capsids as Smart Nanocontainers

非技术性：德克萨斯大学达拉斯分校材料研究部生物材料项目的CAREER奖旨在研究基于蛋白质的纳米颗粒，使用非感染性和无毒的病毒衣壳作为可能的药物递送应用的支架材料。基于纳米颗粒的药物递送系统传统上集中于使用来自金属、二氧化硅、聚合物等的纳米颗粒。然而，这些材料中的一些在其应用中遇到了障碍。例如，基于无机和聚合物材料的纳米颗粒通常需要很长时间才能被身体清除，并且可能在不同器官中积累。一个可能的解决方案是使用非感染性和无毒的病毒颗粒作为支架，从蛋白质中制备纳米颗粒。从概念上讲，病毒是药物递送系统的理想选择，因为它们在进化上被赋予了将货物递送到特定细胞所需的所有资源和性质。然而，阻碍基于蛋白质的纳米颗粒用于药物递送的问题之一是缺乏在制备过程中不会引起病毒颗粒蛋白质解折叠或变性的条件下的合成化学物质。该提案的重点之一是开发几种新的反应方法，并为未来的应用建立一个工具包。这些新的反应将使我们能够看到从蛋白质纳米颗粒中释放药物的新方法，包括使用外部触发源，如脉冲激光。为了实现这一目标，该项目将用“光热天线”使蛋白质纳米颗粒功能化，当受到适当波长的光照射时，将导致衣壳破裂并释放其内容物（货物，药物等）。进入细胞。这项研究的一个重要好处是，这项研究是多学科的性质，并随时借给自己创造一个合作的环境，为学生的教学和培训。这些努力将通过为这些学生提供创建基于网络的漫画计划的机会来加以利用，该计划不仅可以教育，而且还可以通过讲述纳米材料如何与身体相互作用的故事来娱乐学龄K-12儿童及其父母，以及它们如何帮助为许多生物医学应用带来未来的药物输送系统。技术支持：该CAREER奖项的主要目标是合成基于热响应蛋白质的纳米级分子药物递送系统，该系统由病毒衍生的纳米颗粒制备，无感染性和无毒。目前许多释放纳米颗粒（大分子或小分子）内容物的方法都依赖于利用细胞环境。该奖项的重要组成部分是扩大可用于从病毒样颗粒QB（VLP QB）官能化蛋白质纳米颗粒的反应的种类和范围。此外，该奖项将研究新的方法，寻求开发一种方法，允许货物释放使用外部辐射源-特别是光学辐射。为此，该项目将重点关注两个目标：1）使用来自QB的病毒样颗粒作为模型，该奖项将开发生物缀合化学，重点关注病毒衣壳表面发现的二硫基，而不会显著破坏病毒颗粒的热稳定性;以及2）引入光热活性受体QB病毒颗粒的蛋白质表面的表面上的（触角），并且当暴露于脉冲激光辐射时这些修饰的病毒颗粒将引起纳米载体的快速加热和冷却从而导致颗粒的破裂，这又将导致存储在VLP内的货物/药物的释放。此外，该项目还将证明双层膜破坏与货物释放同时进行，作为逃避内体捕获的替代方法，这通常会导致货物的降解。在这个项目中工作的学生，它结合了生物化学，物理和合成化学，将获得经验和跨学科的学习，这些学生将从事创造高品质的在线和免费提供的科学导向和基于网络的漫画针对K-12学生。这些漫画将被用来促进科学素养，并鼓励学生和他们的家长参与和讨论当代研究中出现的想法和概念。为此，该项目将利用校园独特的多样性，创作多语言漫画，让来自世界各地的人们参与到通过该奖项资助的研究中来。

Non-technical:This CAREER award by the Biomaterials program in the Division of Materials Research to University of Texas at Dallas is to study protein-based nanoparticles using non-infectious and non-toxic virus capsids as scaffolding materials for possible drug delivery applications. Nanoparticle-based drug delivery systems have traditionally focused on using nanoparticles derived from metals, silica, polymers, etc. However, some of these materials have encountered roadblocks in their applications. For instance, nanoparticles based on inorganic and polymeric materials typically take a long time in clearing by the body, and possible accumulation in different organs. One possible solution is to make nanoparticles from proteins using non-infectious and non-toxic virus particles as a scaffolding. Conceptually, viruses are ideal for drug delivery system as they have been evolutionarily endowed with all the resources and properties needed to deliver a cargo to specific cells. However, one of the issues holding back in the use of protein-based nanoparticles for drug delivery is the lack of synthetic chemistries under conditions that don't cause unfolding or a denaturation of the proteins of the virus particles during their preparation. One of the thrusts of this proposal is in developing several new reaction methods and building a tool kit for future applications. These new reactions would enable to look at new approaches for drug release from protein-based nanoparticles, including the use of external trigger sources like pulsed laser light. To accomplish this, this project will functionalize the protein nanoparticles with 'photo-thermal antennae' that when struck by the appropriate wavelength of light, will result in the rupture of the capsids and release of their contents (cargo, drugs, etc.) into the cell. An important benefit of this research is that this study is multidisciplinary in nature, and readily lends itself to creating a collaborative environment for student teaching and training. These efforts will be harnessed by giving these students opportunities in creating a web-based comics program, which are expected not only to educate, but also entertain school-aged K-12 children and their parents by telling stories on how nanomaterials interact with the body, and how they could help bring about future drug delivery systems for many biomedical applications. Technical: The main objective of this CAREER award is to synthesize thermally responsive protein-based nanoscopic molecular drug delivery system prepared from virus derived nanoparticles that are non-infectious and non-toxic. Many of the current approaches for releasing contents of nanoparticles - either macromolecular or small molecule - depend on exploiting the cellular environment. The significant part of this award is to expand the variety and scope of reactions available for the functionalization of protein-based nanoparticles from virus-like particles QB (VLPs QB). Additionally, this award will study novel approaches in seeking the development of a method to permit cargo release using external sources of radiation - in particular optical radiation. To these ends, this project will focus on two objectives: 1) using a virus-like particles derived from QB as a model, this award will develop bioconjugation chemistries focusing on the disulfide groups found in viral capsid surfaces without significantly undermining the thermal stability of viral particle; and 2) introducing photothermally active receptors (antennae) on the surface of the proteinaceous surface of QB virus particles, and these modified viral particles when exposed to pulsed laser irradiation will cause rapid heating and cooling of the nano carriers resulting in the ruptue of the particles, and this in turn will result in the release of cargo/drug stored inside the VLP. This project, in addition, will demonstrate concurrent bilayer membrane disruption with cargo release as an alternate approach to escape from endosome capture, which in general would result in the degradation of the cargo. The students working in this project, which combines biochemical, physical, and synthetic chemistry, will gain experience and interdisciplinary learning, and these students will be engaging in creating high quality on-line and freely available science oriented and web-based comic strips aimed at K-12 students. These comic strips will be used to promote scientific literacy, and to encourage students and their parents to engage and discuss the ideas and concepts emerging from contemporary research. To that end, the project will take advantage of the unique diversity available at the campus to create multi-lingual comics to engage people from all over the world in the research that is being funded through this award.