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（由申请人提供）：虽然工程纳米颗粒具有作为治疗工具的巨大潜力，但在全身注射后，纳米颗粒与血液蛋白相互作用，导致危及生命的超敏反应。免疫细胞与抗癌毒素的作用会导致严重的免疫抑制和剂量限制性毒性，补体级联的激活是造成工程化药物的许多副作用和免疫摄取的原因。在初步数据中，我们证明补体通过旁路途径的激活是中性粒细胞、单核细胞、淋巴细胞和血小板对氧化铁纳米颗粒的大部分吸收的原因。在许多类型的纳米制剂中，补体激活至关重要，但减轻纳米颗粒旁路途径激活的策略实际上不存在，该提案的新颖贡献是开发基于天然抑制剂的纳米表面缀合的补体抑制剂。这些蛋白质已用于补体相关疾病的治疗，但从未评估过其保护纳米表面免受补体侵害的作用。我们的初步数据有力地支持了我们建立的天然替代途径抑制剂的缀合将显着改善纳米颗粒的血液相容性的假设。具体目标如下： 1) 在计算机中设计替代途径抑制剂，以便随后与纳米表面缀合我们将对纳米颗粒表面的补体因子和抑制剂蛋白进行 3D 计算机建模，以识别候选抑制剂。和缀合策略；2）确定表面缀合抑制剂的补体抑制效率，或者通过化学合成更小的多肽，通过工程化的半胱氨酸基团缀合到各种类型的纳米颗粒上。缀合抑制剂的效率与抑制剂密度、连接类型、纳米颗粒尺寸和表面化学（电荷、靶向抗体和荧光染料的存在）的关系。这些实验将确定最有效的抑制剂和缀合策略；3) 确定抑制剂在改善药物递送纳米平台的血液相容性方面的效率，我们将制备装载化疗药物的纳米平台，并使用来自健康个体的血液和测试其补体激活和免疫细胞摄取。研究结果对于指导抑制剂修饰的纳米平台的未来临床前和临床开发非常有益。