Viral nanoparticles as platforms for the design of novel targeted therapeutics

描述（由申请人提供）：靶向治疗和显像剂特异性针对身体疾病区域，同时避免健康组织，是生物医学的一个重要目标。在这个项目中，充分表征的植物病毒豇豆花叶病毒（CPMV）将被用作设计新的“智能”靶向治疗的平台。结构、功能、组装和体内性质（如生物利用度）的综合知识使CPMV成为此类平台开发的优秀候选者。证明了多价荧光CPMV探针用于活体动物血管成像的实用性。 该提案的目标是首先了解体内靶向病毒纳米颗粒（VNPs）的基本机制。我将检查内皮靶向肽的多价展示是否允许将CPMV传感器特异性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。我将评估多柔比星负载的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，用于在衣壳内部约束合成氧化铁纳米晶体，用于高温治疗中的潜在应用。在第三种方法中，我将评估VNP-富勒烯混合材料用于光活化癌症治疗。最后但并非最不重要的是，为了结合联合收割机靶向、成像和治疗，我将设计和制造由各种不同的“专用”VNPs组成的高度组织化、可控和可调谐的VNPs网络。这种复杂的配方有望克服单一VNPs的局限性。我的长期目标是利用VNPs与其他纳米材料或装置的组合来研究体内过程，并利用纳米材料作为开发“智能”靶向治疗的平台。在我的博士前培训期间，我学会了化学剪裁VNPs和制造纳米结构材料。我只知道体外和体内技术的基本知识。为了填补这一空白，我加入了曼彻斯特教授在斯克里普斯研究所的实验室。凭借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，但也可以研究它们的体内特性。 相关性：癌症在全世界造成大量死亡和残疾。化疗通常没有针对性，因此会发生许多不良副作用。具体的靶向治疗将提高效率，减少副作用，从而提高生活质量。该项目将有助于了解如何建立一个复杂的网络，该网络结合了多种功能，包括在一个治疗配方中进行治疗的靶向和治疗。

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.