Characterization/bioinformatics-modeling of nanoparticle:complement interactions

纳米粒子的表征/生物信息学建模：补体相互作用

• 批准号: 8068114
• 负责人: DENNIS EMIL HOURCADE
• 金额: $ 101.16万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-27 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8068114
• 关键词: Address; Adverse effects; Biochemical; Bioinformatics; Biological; Biological Assay; Biological Models; Blood; Cells; Characteristics; Charge; Clinical; Complement; Complement Activation; Complement Inactivators; Devices; Diagnosis; Encapsulated; Future; Goals; Guidelines; Human; Image; In Vitro; Instruction; Lipids; Medical; Membrane; Methods; Modeling; Mus; Nanostructures; Pathway interactions; Pharmaceutical Preparations; Process; Protocols documentation; Regulation; Safety; Series; Structure-Activity Relationship; Surface; Testing; Therapeutic; Tissues; Water; chemical property; complement system; design; human study; human subject; in vivo Model; instrument; models and simulation; nanoparticle; next generation; particle; surfactant; tool

DESCRIPTION (provided by applicant): Nanoparticles are emerging tools that will impact medical diagnosis and therapeutics with their capacity to target cells and tissues with imaging agents and/or drug payloads. The unique physical aspects of nanoparticles present new challenges for guidance and regulation. A wide variety of blood contact interactions may compromise intended nanoparticle activities and/or cause serious side effects. The simulation modeling of these and other critical biological interactions would provide a powerful predictive instrument that would offer a focus for the safety review of product candidates and allow the crafting of specific guidelines to be addressed by future applicants. It is known that certain lipid encapsulated nanoparticles activate the complement system, with the potential of severe tissue damage. We propose to develop a standard series of assays to characterize the interactions of complement with lipid encapsulated nanoparticles. The results will be applied to a bioinformatics-modeling system to design and assess next generation nanoparticles for clinical use. Our proposed specific efforts would provide a proof-of-concept approach to study a broad array of nanostructure:biological interactions that are currently difficult to predict prior to human study. To these ends we submit the following specific aims: (1) Develop standardized protocols using human in vitro and mouse In vivo models to characterize the capacity of lipid encapsulated nanoparticles to activate complement, to identify the activation pathways that facilitate the process, and to assess the impact of endogenous complement inhibitors on nanoparticle-dependent complement activation. (2) Vary lipid encapsulated nanoparticles to understand the influence of particle surface characteristics on complement activation. Manipulate surfactant components by utilizing natural and synthetically modified lipids to create a broad spectrum of biochemical presentations at, above, and below water-membrane interface that impart different charge or surface chemical properties. (3) Develop structure-activity relationships to predict complement activation. PUBLIC HEALTH RELEVANCE: Nanoparticles are emerging tools that will impact medical diagnosis and therapeutics but present new challenges for product safety. The goal of this proposal is to construct a method for predicting likely harmful effects of nanoparticles prior to their testing in human subjects. Such a device would offer a focus for safety review of new candidate nanoparticle products and allow the crafting of specific guidelines to be addressed hv future nannnartinip riPRinns

描述（由申请人提供）：纳米颗粒是新兴工具，将通过其利用显像剂和/或药物有效负载靶向细胞和组织的能力影响医学诊断和治疗。纳米颗粒独特的物理特性给指导和监管带来了新的挑战。各种各样的血液接触相互作用可能会损害预期的纳米颗粒活性和/或导致严重的副作用。这些和其他关键生物相互作用的模拟模型将提供强大的预测工具，为候选产品的安全审查提供重点，并允许制定未来申请人需要解决的具体指南。众所周知，某些脂质封装的纳米颗粒会激活补体系统，可能会造成严重的组织损伤。我们建议开发一系列标准测定法来表征补体与脂质封装纳米颗粒的相互作用。研究结果将应用于生物信息学建模系统，以设计和评估临床使用的下一代纳米颗粒。我们提出的具体努力将提供一种概念验证方法来研究广泛的纳米结构：目前在人类研究之前很难预测的生物相互作用。为此，我们提出以下具体目标：（1）使用人体体外和小鼠体内模型开发标准化方案，以表征脂质封装纳米颗粒激活补体的能力，确定促进该过程的激活途径，并评估内源性补体抑制剂对纳米颗粒依赖性补体激活的影响。 (2) 改变脂质封装的纳米颗粒，以了解颗粒表面特性对补体激活的影响。利用天然和合成改性的脂质来操纵表面活性剂成分，在水膜界面、上方和下方产生广泛的生化表现，赋予不同的电荷或表面化学性质。 (3) 建立结构-活性关系来预测补体激活。 公共健康相关性：纳米颗粒是新兴工具，将影响医学诊断和治疗，但对产品安全提出了新的挑战。该提案的目标是构建一种方法，在对人体进行测试之前预测纳米粒子可能产生的有害影响。这样的设备将为新候选纳米粒子产品的安全审查提供焦点，并允许制定具体指南以解决未来的nannnartinip riPRinns