Viral nanoparticles as platforms for the design of novel targeted therapeutics

描述(由申请人提供)：在避开健康组织的同时，专门针对身体疾病区域的治疗和显像剂是生物医学的一个重要目标。在这个项目中，将利用具有良好特性的植物病毒豌豆花叶病毒(CPMV)作为平台，设计新型的“智能”靶向疗法。CPMV结合了结构、功能、组装和体内特性(如生物利用度)的知识，使其成为此类平台开发的极佳候选者。多价荧光CPMV探针在活体动物血管成像中的应用被证明。这项建议的目标是首先了解体内靶向病毒纳米粒(VNPs)的基本机制。我将研究内皮靶向多肽的多价展示是否允许将CPMV传感器特异性地靶向肿瘤血管系统和/或肿瘤细胞。第二个目标是探索治疗性VNP制剂的潜力。我将评估多柔比星CPMV制剂用于癌症治疗的潜力。第二种策略将使用VNPs作为模板，在衣壳内部限制合成氧化铁纳米晶体，以用于热疗的潜在应用。在第三种方法中，我将评估用于光激活癌症治疗的VNP-富勒烯杂化材料。最后但同样重要的是，为了结合靶向、成像和治疗，我将设计和制造高度组织、可控和可调的VNPs网络，由各种不同的“专门”VNPs组成。这种复杂的配方有望克服单一VNPs的局限性我的长期目标是将VNPs与其他纳米材料或设备相结合来研究体内过程，并利用纳米材料作为开发“智能”靶向疗法的平台。在我的博士前培训期间，我学会了用化学方法量身定做VNPs和制造纳米结构材料。我只有体外和体内技术的基本知识。为了填补这一空白，我加入了斯克里普斯研究所曼彻斯特教授的实验室。有了TSRI的专业知识和一流的设施，我将能够填补这一空白。这将使我处于一个独特的位置，能够创造和设计纳米材料，也能够研究它们的体内特性。 相关性：癌症在世界各地造成大量死亡和残疾。化疗一般没有针对性，因此会出现许多副作用。有针对性的治疗将提高效率，减少副作用，从而改善生活质量。这个项目将有助于理解如何建立一个复杂的网络，将几个特征结合在一个治疗配方中进行治疗，包括靶向和治疗。

DESCRIPTION (provided by applicant): Targeting therapies and imaging agents specifically to areas of disease in the body, while avoiding healthy tissue, is an important goal in biomedicine. In this project the well-characterized plant virus Cowpea mosaic virus (CPMV) will be utilized as a platform for the design of novel "smart" targeted therapeutics. The combined knowledge of structure, function, assembly, and in vivo properties such as bioavailability make CPMV an excellent candidate for such platform development. The utility of multivalent fluorescent CPMV probes for vascular imaging in live animals was demonstrated. The goals of this proposal are first, to understand the fundamental mechanisms for targeting viral nanoparticles (VNPs) in vivo. I will examine whether the multivalent display of endothelial targeting peptides will allow to specifically target CPMV sensors to tumor-vasculature and/or tumor cells. The second goal is to explore the potential of therapeutic VNP formulations. I will evaluate the potential of doxorubicin-loaded CPMV formulations for cancer therapies. A second strategy will use VNPs as a template for the constrained synthesis of iron oxide nanocrystals within the capsid interior for potential applications in hyperthermia treatment. In a third approach I will evaluate VNP-fullerene hybrid materials for photo-activated cancer therapy. Last but not least, to combine targeting, imaging, and therapy, I will design and fabricate highly organized, controllable, and tunable VNPs networks consisting of various different "specialized" VNPs. This complex formulation is expected to overcome limitations of single VNPs My long-term goal is to utilize VNPs in combination with other nanomaterials or devices to study in vivo processes and to utilize nanomaterials as platforms for the development of "smart" targeted therapies. During my pre-doctoral training I have learned to chemically tailor VNPs and to fabricate nanostructured materials. I only have basic knowledge in in vitro and in vivo techniques. To fill this gap I have joined Prof. Manchester's laboratory at The Scripps Research Institute. With the expertise and the great facilities at TSRI, I will be able to fill this gap. This will put me in a unique position of being able to create and design nanomaterials, but also to study their in vivo properties. RELEVANCE: Cancer is causing substantial death and disabilities all over the world. Chemotherapy is generally not targeted and therefore many adverse side effects occur. Specifically targeted therapies would increase efficiency and result in fewer side effects, and thus improve quality of life. This project will help to understand how to build a complex network that combines several features including targeting and therapy in one therapeutic formulation for treatment.