Genetic and Chemically Programmed Nanoparticles for Prodrug Therapy
用于前药治疗的遗传和化学编程纳米颗粒
基本信息
- 批准号:8439586
- 负责人:
- 金额:$ 36.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-30 至 2017-07-31
- 项目状态:已结题
- 来源:
- 关键词:AntibodiesBacteriophagesBenignBindingBiodistributionBiologyBiomedical ResearchBlood CirculationCaliberCapsidCapsid ProteinsCellsChemicalsChemistryCrystallographyCytotoxic agentDevelopmentDiseaseEffectivenessEnzymatic BiochemistryEnzymesEscherichia coliGeneticGenomeGoalsHeatingHybridsImmune responseImmunizationIn VitroLearningMalignant NeoplasmsMammalian CellMethodsModificationNanostructuresOrganic solvent productPathway interactionsPeptide HydrolasesPeptidesProdrugsProductionPropertyProteinsRNASiteStructureSurfaceSurveysTechnologyTertiary Protein StructureTestingTherapeuticTimeTissuesVirusVirus-like particlebasecancer cellcell typechemical geneticsclinical applicationdesignfunctional groupimmunogenicityin vivomouse modelnanomedicinenanoparticleparticlepolypeptidepreclinical evaluationprogramspublic health relevancereceptortumorigenic
项目摘要
DESCRIPTION (provided by applicant): Virus-like particles (VLPs) represent the best-characterized and most easily tailored nanostructures for the targeting of disease. They are the largest assemblies to be routinely analyzed by x-ray crystallography, and the smallest entities to possess a genome, and thus they occupy a unique place between the worlds of chemistry and biology. Our recent efforts have focused on the 28 nm diameter icosahedral particle derived from the coat protein of bacteriophage Q¿. This structure, produced recombinantly in E. coli in high yield and purity, is very stable toward heat, variable pH, organic solvents, and conditions of
chemical modification. It is also recognized by no specific receptor on mammalian cells, and therefore may be imbued with desired properties by installing functional groups on the outside surface and inside compartment of the capsid. We have developed methods to genetically encode polypeptides on the exterior of Q¿ VLPs while at the same time packaging multiple copies of active enzymes on the inside. The outside groups serve to bind to chosen receptors for the targeting of specific cell types or to display antibodies for the same purpose. The enzymes on the inside can convert benign prodrugs to cytotoxic agents with high catalytic efficiency, while being protected from protease attack and denaturation. We will further develop and enhance the technology to produce these particles, with the goal of more precisely controlling their composition and using more functional components. We will also apply them to proof-of-concept tests of prodrug activation both in vitro and in vivo to determine the scope and limitations of this therapeutic approach. For their eventual clinical application, the consequences
of the anti-particle immune response must also be determined. We will therefore conduct the first quantitative assessment of the effects of pre-immunization on the circulation lifetime and biodistribution of this type of nanoparticle, and test sophisticated methods to diminish their immunogenicity and opsonization in the context of these goals. The result of these efforts will be new capabilities in protein nanoparticle design and production, an exciting preclinical evaluation of the merits of prodrug therapy using targeted VLP-packaged enzymes, and a major contribution to the fundamental understanding of nanoparticle targeting and avoidance of opsonization and immunological pathways.
描述(由申请人提供):病毒样颗粒(VLP)代表了用于靶向疾病的最佳表征和最容易定制的纳米结构。它们是X射线晶体学常规分析的最大组件,也是拥有基因组的最小实体,因此它们在化学和生物学世界之间占据了独特的位置。我们最近的努力集中在28 nm直径的二十面体颗粒来自噬菌体Q的外壳蛋白。该结构在E.大肠杆菌中的高产率和纯度,是非常稳定的热,可变的pH值,有机溶剂,和条件,
化学修饰。它也不被哺乳动物细胞上的特异性受体识别,因此可以通过在衣壳的外表面和内部隔室上安装官能团来赋予所需的性质。我们已经开发出在Q?VLP外部对多肽进行遗传编码的方法,同时在内部包装多个活性酶拷贝。外部基团用于结合选定的受体以靶向特定的细胞类型或出于相同目的展示抗体。内部的酶可以将良性前药转化为具有高催化效率的细胞毒性剂,同时受到保护免受蛋白酶攻击和变性。我们将进一步开发和提高生产这些颗粒的技术,目标是更精确地控制其成分,并使用更多的功能成分。我们还将它们应用于体外和体内前药活化的概念验证测试,以确定这种治疗方法的范围和局限性。对于它们最终的临床应用,
还必须确定抗粒子免疫反应的强度。因此,我们将进行第一次定量评估预免疫对这种类型的纳米颗粒的循环寿命和生物分布的影响,并测试复杂的方法,以减少其免疫原性和调理作用在这些目标的背景下。这些努力的结果将是蛋白质纳米颗粒设计和生产的新能力,使用靶向VLP包装酶的前药治疗优点的令人兴奋的临床前评估,以及对纳米颗粒靶向和避免调理作用和免疫途径的基本理解的重大贡献。
项目成果
期刊论文数量(0)
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M.G. Finn其他文献
M.G. Finn的其他文献
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