Characterization/bioinformatics-modeling of nanoparticle:complement interactions

描述(由申请人提供)：纳米粒子是一种新兴的工具，它能够通过成像剂和/或药物有效载荷来靶向细胞和组织，从而影响医学诊断和治疗。纳米粒子独特的物理方面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。对这些和其他关键生物相互作用的模拟建模将提供一个强大的预测工具，为候选产品的安全性审查提供重点，并允许制定具体的指南，供未来的申请者解决。众所周知，某些脂质包裹的纳米颗粒激活补体系统，有可能造成严重的组织损伤。我们建议开发一系列标准的检测方法来表征补体与脂质包裹的纳米颗粒之间的相互作用。研究结果将应用于生物信息学建模系统，以设计和评估下一代临床使用的纳米粒子。我们提议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难以预测的生物相互作用。为此，我们提出了以下具体目标：(1)利用人类体外和小鼠体内模型建立标准化的方案，以表征脂质包裹的纳米颗粒激活补体的能力，识别促进这一过程的激活途径，并评估内源性补体抑制物对纳米颗粒依赖的补体激活的影响。(2)不同脂质包埋纳米粒，了解颗粒表面特性对补体活化的影响。通过利用天然和人工修饰的脂类来操纵表面活性成分，以在水-膜界面上、之上和之下产生广泛的生化呈现，从而赋予不同的电荷或表面化学性质。(3)建立结构-活性关系以预测补体激活。 与公共卫生相关：纳米颗粒是新兴的工具，将影响医学诊断和治疗，但对产品安全提出了新的挑战。这项提议的目标是构建一种方法，在人体试验之前预测纳米颗粒可能产生的有害影响。这种装置将为新的候选纳米颗粒产品的安全审查提供一个焦点，并允许在未来的Nannnartinip RiPRInn中制定具体的指南

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