Disease-Induced Modification in Nanoparticle-Corona Identity and Toxicity

 描述(申请人提供)：纳米材料越来越多地被用作治疗和药物输送系统的生物医学应用。在它们被引入生理环境后，它们会迅速将各种大分子结合在一起，形成电晕。这种电晕改变了纳米材料的大小和交互界面，导致生物分布、清除、活性和毒性的改变。电晕的组成取决于纳米材料的物理化学性质以及生理环境。到目前为止，大多数纳米材料毒性的评估都是在正常、健康的条件下进行的。然而，由于我们人口中患有肥胖症和心血管疾病等慢性疾病的比例越来越大，这些纳米材料将不会被引入健康的生理环境。在这项提议中，我们假设一种已知会改变血清蛋白质和脂肪含量的潜在疾病--高脂血症--将改变形成在纳米材料上的日冕，不同的尺寸和治疗性表面涂层也会改变。进一步，我们将研究这些冠状成分的改变如何影响细胞摄取、体内生物分布、亚细胞定位、细胞内命运和毒性。为了验证这一假设，我们将利用氧化铁纳米颗粒，它们目前正在开发用于生物医学应用，包括用作MRI造影剂和银纳米颗粒，它们被用于抗菌/真菌特性。将在巨噬细胞和内皮细胞中研究细胞相互作用和毒理学效应，以代表两种关键细胞类型，这两种细胞类型将与纳米材料相互作用，在炎症和血管生物学中至关重要。最终，通过彻底了解日冕及其从这一提议中获得的生物学后果，我们可以开发出具有有限毒理学影响的有效纳米疗法。

 DESCRIPTION (provided by applicant): Nanomaterials are increasingly being utilized for biomedical applications as therapeutics and drug delivery systems. Following their introduction into a physiological environment they rapidly associate a variety of macromolecules forming a corona. This corona modifies the size and interactive interface of the nanomaterial resulting in altered bio distribution, clearance, activity, and toxicity. The composition of the corona is dependent on the physicochemical properties of the nanomaterial, as well as, the physiological environment. To date most evaluation of nanomaterial toxicity is performed under normal, healthy conditions. However, due to the vast and growing portion of our population that suffer from chronic conditions such as obesity and cardiovascular diseases these nanomaterials will not be introduced into healthy physiological environments. In this proposal we hypothesize that an underlying condition known to alter serum protein and lipid content, hyperlipidemia, will modify the corona that forms on nanomaterials as will different sizes and therapeutic surface coatings. Further we will examine how these modifications in coronal composition influence cellular uptake, in vivo bio distribution, subcellular localization, intracellular fate, and toxiciy. To test this hypothesis we will utilize iron oxide nanoparticles, which are currently in development for biomedical applications including their use as MRI contrast agents and silver nanoparticles, which are being used for their antimicrobial/fungal properties. Cellular interactions and toxicological effects will be examined in macrophages and endothelial cells to represent two key cell types that will interact with nanomaterials and are critical in inflammation and vascular biology. Ultimately, through a thorough understanding of the corona and its biological consequences gained from this proposal, we can develop effective nanotherapeutics with limited toxicological implications.