The alternative complement pathway and hemocompatibility of nanosurfaces

补体替代途径和纳米表面的血液相容性

基本信息

批准号：
9274284
负责人：
Dmitri Simberg
金额：
$ 34.39万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9274284
关键词：
3-Dimensional Adverse effects Alternative Complement Pathway Antibodies Artificial nanoparticles Blood Blood Platelets Blood Proteins Cancer Patient Cell membrane Cell surface Cells Charge Chemicals Chemistry Clinical Collaborations Complement Complement 3a Complement 3b Complement 5a Complement Activation Complement Factor H Complement Inactivators Computational Biology Computer Simulation Core Facility Cysteine Data Deposition Development Disease Dose-Limiting Doxorubicin Drug Delivery Systems Drug Targeting Drug usage Engineering Event Fluorescent Dyes Future Generic Drugs Genetic Complementation Test Goals Human Hypersensitivity ImProv Image Immune Immunosuppression Individual Inflammatory Injection of therapeutic agent Lectin Leukocytes Life Lipids Liposomes Lymphocyte Mediating Modeling Organism Pathway interactions Patients Pharmaceutical Preparations Play Proteins Reaction Role Safety Serum Serum Proteins Surface Testing Therapeutic Toxic effect Toxin Work base chemical conjugate chemotherapy clinical development complement system computational chemistry density design docetaxel eosinophil experimental study improved individual patient inhibitor/antagonist innovation iron oxide monocyte nanoformulation nanomaterials nanoparticle neutrophil novel overexpression polypeptide preclinical development prevent public health relevance tool translational pipeline uptake virtual

项目摘要

DESCRIPTION (provided by applicant): While having tremendous potential as a therapeutic tool, clinical use of engineered nanoparticles has also been associated with serious safety concerns. Following systemic injection, nanoparticles interact with blood proteins causing life-threating hypersensitivity. The uptake of nanoformulations loaded with anticancer toxins by immune cells causes' severe immunosuppression and dose-limiting toxicity. Activation of complement cascade is responsible for many side effects and immune uptake of engineered nanomaterials. In the preliminary data, we demonstrate that activation of complement via the alternative pathway is responsible for the majority of uptake of iron oxide nanoparticles by neutrophils, monocytes, lymphocytes, and platelets. Despite the fact that the alternative pathway has been shown to be essential for complement activation in many types of nanoformulations, the strategies to mitigate the alternative pathway activation on nanoparticles are virtually non-existent. The novel contribution of this proposal is to develop nanosurface-conjugated complement inhibitors based on natural inhibitor proteins. These proteins have been used in the therapeutics of complement-related disorders but have never been evaluated for protecting nanosurfaces against complement. Our preliminary data strongly support the hypothesis that conjugation of the natural alternative pathway inhibitors will significantly improv hemocompatibility of nanoparticles. We established the following Specific Aims: 1) Design alternative pathway inhibitors in silico for subsequent conjugation to nanosurfaces. We will perform 3-D computer modeling of the complement factors and the inhibitor proteins on nanoparticle surface to identify candidate inhibitors and conjugation strategies; 2) determine the complement inhibition efficiency of surface conjugated inhibitors. We will overexpress the inhibitor proteins, or chemically synthesize smaller polypeptides. The inhibitors will be conjugated to various types of nanoparticles via an engineered cysteine group. We will determine the efficiency of the conjugated inhibitors as a function of the inhibitor density, linke type, nanoparticle size, and surface chemistry (charge, presence of targeting antibody and fluorescent dye). These experiments will determine the most efficient inhibitors and conjugation strategies; 3) determine the efficiency of the inhibitors in improving hemocompatibility of drug delivery nanoplatforms. We will prepare nanoplatforms loaded with chemotherapy drugs. The nanoparticles will be modified with inhibitors and tested for complement activation and immune cell uptake using blood from healthy individuals and cancer patients. The results will be highly beneficial in guiding future preclinical and clinical development of inhibitor-decorated nanoplatforms.

描述（由适用提供）：在具有治疗工具的巨大潜力的同时，工程纳米颗粒的临床使用也与严重的安全问题有关。全身注射后，纳米颗粒与血液蛋白相互作用，导致威胁生命的超敏反应。免疫细胞中载有抗癌毒素的纳米制剂的摄取会导致严重的免疫抑制和限制剂量的毒性。级联的激活造成了许多副作用和工程纳米材料的免疫。在初步数据中，我们证明，通过替代途径的完成激活是由中性粒细胞，单核细胞，淋巴细胞和血小板造成大部分氧化铁纳米颗粒的吸收。尽管事实证明，替代途径对于在许多类型的纳米形式中的完成至关重要，但减轻纳米颗粒上替代途径激活的策略实际上是不存在的。该建议的新贡献是开发基于天然抑制剂蛋白的纳米表面偶联的补体抑制剂。这些蛋白质已用于治疗与补体相关疾病的治疗，但从未评估过保护纳米表面免受完成的评估。我们的初步数据强烈支持以下假设：自然替代途径抑制剂的结合将显着提高血流相容性，我们确定了以下特定目的：1）设计硅中的替代途径抑制剂，以随后与纳米外缀合。我们将对纳米颗粒表面上的补体因子和抑制剂蛋白进行3-D计算机建模，以鉴定候选抑制剂和共轭策略。 2）确定表面共轭抑制剂的补体抑制剂效应。我们将过表达抑制剂蛋白，或化学合成较小的多肽。抑制剂将通过工程性半胱氨酸组将各种类型的纳米颗粒共轭。我们将确定共轭抑制剂的效率，这是抑制剂密度，链接类型，纳米颗粒大小和表面化学（电荷，靶向抗体和荧光染料的存在）的效率。这些实验将确定最有效的抑制剂和结合策略。 3）确定抑制剂在改善药物输送纳米植物的血液相容性方面的效率。我们将准备装有化学疗法药物的纳米植物。纳米颗粒将通过抑制剂进行修饰，并使用健康个体和癌症患者的血液进行了完成激活和免疫剂摄取。该结果将在指导抑制剂装饰纳米平台的未来临床前和临床发展方面非常有益。