Characterization/bioinformatics-modeling of nanoparticle:complement interactions

描述（由申请人提供）：纳米颗粒是新兴的工具，其将影响医学诊断和治疗，其具有用成像剂和/或药物有效载荷靶向细胞和组织的能力。纳米颗粒独特的物理特性为指导和监管提出了新的挑战。各种各样的血液接触相互作用可能损害预期的纳米颗粒活性和/或引起严重的副作用。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，并允许未来申请人制定具体的指南。已知某些脂质包封的纳米颗粒激活补体系统，具有严重组织损伤的可能性。我们建议开发一个标准的一系列的测定来表征补体与脂质包裹的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，以设计和评估下一代临床使用的纳米颗粒。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难以预测的生物相互作用。为了这些目的，我们提出了以下具体目标：（1）使用人体外和小鼠体内模型开发标准化方案，以表征脂质包封的纳米颗粒激活补体的能力，鉴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)改变脂质包封的纳米颗粒，以了解颗粒表面特征对补体激活的影响。通过利用天然和合成改性脂质来操纵表面活性剂组分，以在水膜界面处、上方和下方产生广泛的生物化学呈现，从而赋予不同的电荷或表面化学性质。(3)开发结构-活性关系以预测补体激活。 公共卫生相关性：纳米颗粒是新兴的工具，将影响医疗诊断和治疗，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，用于在人类受试者中进行测试之前预测纳米颗粒可能的有害影响。这种装置将为新的候选纳米颗粒产品的安全性审查提供焦点，并允许制定特定的指南，以在未来的纳米颗粒产品中解决。

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