Engineering 'Grapevine Virus A' filaments for nanomedical applications

工程“葡萄病毒 A”细丝用于纳米医学应用

• 批准号: 9144385
• 负责人: Nicole Franziska Steinmetz
• 金额: $ 7.93万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-14 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144385
• 关键词: Advanced Malignant Neoplasm; Applications Grants; Area; Behavior; Binding; Biochemical; Biocompatible Materials; Biodistribution; Blood; Blood Circulation; CD47 gene; Capsid Proteins; Cardiovascular Diseases; Cells; Chemical Engineering; Chemistry; Communicable Diseases; Contrast Media; Data; Dependence; Development; Drug Delivery Systems; Drug Kinetics; Engineering; Evaluation; Filament; Foundations; Gene Transduction Agent; Genes; Genetic Engineering; Goals; Gold; Health; Human; Image; Immune; Label; Ligands; Liposomes; Liver; Malignant Neoplasms; Mammals; Medical; Medicine; Modification; Mononuclear; Nanotechnology; Nature; Organ; Peptides; Pharmaceutical Preparations; Plant Viruses; Plants; Production; Property; Protocols documentation; Research; Research Project Grants; Role; Shapes; Specificity; Spleen; Structure; Surface; System; Technology; Testing; Therapeutic; Tissues; Toxic effect; Viral; Virus; base; biophysical properties; cell motility; chemotherapy; flexibility; fluorophore; imaging agent; immunogenic; immunogenicity; in vivo; insight; interest; large scale production; malignant breast neoplasm; mouse model; nanofilament; nanomaterials; nanomedicine; nanoparticle; nanorod; nanoscale; neutralizing antibody; new technology; novel; oncolytic virotherapy; particle; physical property; pre-clinical; scale up; technology development; tumor; uptake; vaccine development; vector vaccine; viral nanoparticle

 DESCRIPTION: The goal of this small research grant proposal (R03) is to develop and evaluate a flexible, filamentous bionanomaterial for applications in cancer nanotechnology. A growing body of data suggests advantageous pharmacokinetic and tumor accumulation properties of long, elongated, filamentous nanomaterials compared to their spherical counterparts. Tailoring materials at the nanoscale to create such high aspect ratio materials remains challenging. Therefore, we have turned toward a bio-inspired approach: we will make use of nature's nanomaterials and adapt the filamentous plant virus grapevine virus A (GVA) as a novel carrier for delivery of therapeutics and contrast agents. The use of virus-based nanoparticles in medicine has been recognized and gene therapy vectors, vaccines, and oncolytic virotherapies are under development. The use of plant-derived materials, such as GVA, is considered safe from a human health perspective, because plant viruses are not pathogenic in mammals. Plant viruses can be engineered with therapeutic payloads, contrast agents, and targeting ligands to create tissue-specific drug delivery systems and imaging agents. Most (viral) nanoparticle systems under evaluation are spherical (i.e. icosahedral). It is becoming increasingly clear that filamentous (bio)nanomaterials are of broad biomedical interest. GVA presents a novel biomaterial; its highly flexible structure may offer advantages over hard or low aspect ratio materials currently in the development pipeline. GVA is a highly flexible, 800 x 12 nm filament formed by approximately 4,200 identical copies of a coat protein. In addition to its soft and flexible structure, GVA offers a high aspect ratio and large surface area allowing to deliver high payloads of drugs or imaging agents. The goals of this proposal are to (1) establish large-scale production of GVA and develop bioconjugate chemistry protocols enabling functionalization of the nanofilaments with imaging moieties, stealth and/or camouflage, and targeting ligands, and (2) to gain an understanding of the pharmacokinetics, immunogenicity, and biodistribution properties, specifically its tumor accumulation properties. We hypothesize that GVA will show favorable in vivo behavior and enhanced partitioning to tumors (tumor uptake>>liver uptake) based on its biophysical properties. Data gained will lay the foundation for the further development of GVA for nanomedical applications. The PI has a track record of developing virus-based materials for medical applications and is thus uniquely suited to develop and oversee the proposed research. The data gained from the proposed study is a critical stepping-stone for the GVA technology development and will lay a foundation for application GVA-based materials in medicine. We envision broad applications of GVA, which include its application as a gene, drug, or contrast agent delivery vehicle. GVA could find applications in cancer medicine, cardiovascular disease as well as infectious disease. This is a self-contained research project focused on the development of a new technology; the proposal is thus well aligned with the R03 mechanism.

 描述：这项小型研究赠款提案（R03）的目的是开发和评估用于癌症纳米技术应用的灵活的丝状生物植物材料。越来越多的数据表明，与球形对应物相比，长，细长，丝状纳米材料的有利的药代动力学和肿瘤积累特性。在纳米级的剪裁材料以创建如此高的纵横比材料仍然受到挑战。因此，我们已经转向了一种受生物启发的方法：我们将利用大自然的纳米材料，并适应丝状植物病毒葡萄病毒A（GVA）作为治疗和对比剂的新型载体。已经认识到基于病毒的纳米颗粒在医学中的使用，并且正在开发基因治疗载体，疫苗和溶瘤病毒疗法。从人类健康的角度来看，使用植物来源的材料（例如GVA）被认为是安全的，因为植物病毒在哺乳动物中不是致病性。可以通过治疗有效载荷，对比剂和靶向配体来设计植物病毒，以创建组织特异性药物输送系统和成像剂。评估中的大多数（病毒）纳米颗粒系统是球形的（即二十面体）。越来越清楚的是，丝状（生物）纳米材料具有广泛的生物医学兴趣。 GVA提出了一种新颖的生物材料；其高度灵活的结构可能比目前开发管道中的硬宽高比或低纵横比的材料具有优势。 GVA是一种高度柔韧的800 x 12 nm丝，由大约4,200张外套蛋白质副本形成。除了其柔软而柔韧的结构外，GVA还提供了高纵横比和较大的表面积，可提供高效的药物或成像剂。该提案的目标是（1）建立GVA的大规模生产并开发生物偶联化学方案，以实现具有成像，隐身和/或伪装的纳米丝的功能化，并靶向配体，以及（2）以了解药物的构成属性，并累积了构成物质，并累积了特性，并累积了属性。我们假设GVA会根据其生物物理特性表现出有利的体内行为，并增强对肿瘤的分配（肿瘤摄取>>肝脏摄取）。获得的数据将为纳米医学应用的进一步开发GVA奠定基础。 PI具有开发用于医疗应用的病毒材料的记录，因此非常适合在拟议的研究中开发和开发和开发。从拟议的研究中获得的数据是GVA技术开发的关键垫脚石，并将为基于GVA的医学材料奠定基础。我们设想了GVA的广泛应用，其中包括其作为基因，药物或造影剂输送工具的应用。 GVA可以在癌症医学，心血管疾病以及感染疾病中找到应用。这是一个专注于开发新技术的独立研究项目。因此，该提案与R03机制很好地对齐。