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.

 产品说明：这项小型研究资助提案（R 03）的目标是开发和评估一种灵活的丝状生物纳米材料，用于癌症纳米技术的应用。越来越多的数据表明，与球形纳米材料相比，细长的丝状纳米材料具有有利的药代动力学和肿瘤蓄积特性。在纳米尺度上定制材料以产生如此高的纵横比材料仍然具有挑战性。因此，我们转向了一种生物启发的方法：我们将利用自然界的纳米材料，并将丝状植物病毒葡萄藤病毒A（GVA）作为一种新型载体，用于输送治疗剂和造影剂。基于病毒的纳米颗粒在医学中的应用已经得到认可，基因治疗载体、疫苗和溶瘤病毒疗法正在开发中。从人类健康的角度来看，使用植物来源的材料（如GVA）被认为是安全的，因为植物病毒在哺乳动物中不具有致病性。植物病毒可以与治疗有效载荷、造影剂和靶向配体一起工程化以产生组织特异性药物递送系统和成像剂。大多数（病毒）纳米颗粒系统的评价是球形（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意义。GVA提出了一种新型生物材料;其高度灵活的结构可能比目前正在开发的硬或低纵横比材料具有优势。GVA是一种高度柔性的800 × 12 nm细丝，由大约4，200个相同的外壳蛋白拷贝形成。除了其柔软和灵活的结构外，GVA还提供了高纵横比和大表面积，允许输送高有效载荷的药物或成像剂。该提案的目标是（1）建立GVA的大规模生产并开发生物缀合物化学方案，使纳米丝能够用成像部分、隐形和/或伪装以及靶向配体官能化，以及（2）了解药代动力学、免疫原性和生物分布特性，特别是其肿瘤蓄积特性。基于其生物物理性质，我们假设GVA将显示有利的体内行为和增强的肿瘤分配（肿瘤摄取>>肝脏摄取）。所获得的数据将为GVA在纳米医学应用中的进一步发展奠定基础。PI拥有开发用于医疗应用的病毒材料的记录，因此非常适合开发和监督拟议的研究。从拟议的研究中获得的数据是GVA技术发展的关键垫脚石，并将为GVA基材料在医学上的应用奠定基础。我们设想了GVA的广泛应用，包括其作为基因、药物或造影剂递送载体的应用。GVA可以在癌症医学、心血管疾病以及传染病中找到应用。这是一个独立的研究项目，专注于新技术的开发;因此，该提案与R 03机制保持一致。