Disease-Induced Modification in Nanoparticle-Corona Identity and Toxicity

 描述（由申请人提供）：纳米材料越来越多地用于生物医学应用，作为治疗和药物输送系统。在它们被引入生理环境后，它们迅速地结合各种大分子形成冠。这种电晕改变了纳米材料的尺寸和相互作用界面，导致生物分布、清除、活性和毒性改变。冠的组成取决于纳米材料的物理化学性质以及生理环境。迄今为止，大多数纳米材料毒性的评价是在正常健康条件下进行的。然而，由于我们人口中患有慢性疾病（如肥胖和心血管疾病）的比例巨大且不断增长，这些纳米材料将不会被引入健康的生理环境中。在该提案中，我们假设已知改变血清蛋白和脂质含量的潜在条件，高脂血症，将改变在纳米材料上形成的冠，以及不同的尺寸和治疗表面涂层。此外，我们将研究冠状组成的这些修改如何影响细胞摄取，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，这是目前正在开发的生物医学应用，包括其作为MRI造影剂和银纳米颗粒，这是用于其抗微生物/真菌性能。将在巨噬细胞和内皮细胞中检查细胞相互作用和毒理学效应，以代表将与纳米材料相互作用并在炎症和血管生物学中至关重要的两种关键细胞类型。最终，通过对电晕及其生物学后果的深入了解，我们可以开发出有效的纳米治疗药物，其毒理学影响有限。

 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.