Characterization/bioinformatics-modeling of nanoparticle:complement interactions

描述（由申请人提供）：纳米颗粒是一种新兴工具，将影响医学诊断和治疗，因为它们具有利用显像剂和/或药物载荷靶向细胞和组织的能力。纳米颗粒独特的物理特性给指导和调控带来了新的挑战。各种各样的血液接触相互作用可能会损害纳米颗粒的预期活性和/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，将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导方针。众所周知，某些脂质包裹的纳米颗粒激活补体系统，具有严重组织损伤的潜力。我们建议开发一系列标准的测定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，用于设计和评估用于临床的下一代纳米颗粒。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：生物相互作用，目前在人类研究之前很难预测。为此，我们提出了以下具体目标：(1)使用人体外和小鼠体内模型制定标准化方案，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)改变脂质包裹纳米颗粒，了解颗粒表面特性对补体活化的影响。通过利用天然和合成改性脂质来操纵表面活性剂成分，在水膜界面上、上面和下面产生广谱的生化表现，赋予不同的电荷或表面化学性质。(3)建立结构-活性关系，预测补体活化。

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