Biodegradable polymetal nanoparticle CT contrast agents for vascular imaging

用于血管成像的可生物降解多金属纳米粒子 CT 造影剂

• 批准号: 9242691
• 负责人: David Peter Cormode
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242691
• 关键词: Address; Adult; Affect; American; Ammonia; Atherosclerosis; Attenuated; Biological; Biological Assay; Blood; Blood Circulation; Blood Vessels; Body Weights and Measures; Caliber; Cardiovascular Diseases; Chronic Kidney Failure; Clinic; Clinical; Clinical Chemistry; Clinical Markers; Clinical Trials; Complication; Contrast Media; Coronary Arteriosclerosis; Coronary artery; Diabetes Mellitus; Diagnosis; Diagnostic; Diagnostic radiologic examination; Disease model; Dose; Effectiveness; Elements; Encapsulated; Event; Excretory function; Fluoroscopy; Formulation; Generations; Goals; Gold; Health; Heart; Histology; Hour; Hypersensitivity; Image; Imaging Techniques; In Vitro; Incidence; Injectable; Injection of therapeutic agent; Kidney; Kidney Diseases; Kidney Failure; Lanthanum; Lead; Libraries; Magnetic Resonance Imaging; Metals; Methods; Modeling; Morbidity - disease rate; Mus; Nanosphere; Nanostructures; Organ; Oxidative Stress; Patients; Polyethylene Glycols; Polymers; Population; Prevalence; Property; Proteins; Renal function; Risk; Risk Factors; Roentgen Rays; Solubility; Stenosis; Structure; Surface; Tantalum; Techniques; Testing; Time; Tissues; Toxic effect; Toxicology; Translations; Urine; Vascular blood supply; Wild Type Mouse; X-Ray Computed Tomography; base; behavioral study; biomaterial compatibility; cardiovascular disorder risk; cost; design; diabetic; disorder risk; hydrophilicity; imaging potential; imaging study; in vivo; inorganic phosphate; mortality; nanoparticle; non-diabetic; novel; patient population; polyphosphazene; public health relevance; response; small molecule

 DESCRIPTION (provided by applicant): Currently used X-ray imaging contrast agents are primarily iodinated small molecules. These iodinated small molecule agents are used in the diagnosis and treatment of cardiovascular disease, among other conditions. However, they frequently cause a condition known as contrast-induced nephropathy in patients with poor kidney function. This condition results in higher morbidity, mortality and costs. More than 10% of American adults have poor kidney function, and that proportion is rapidly increasing, due to the rise in prevalence of diabetes, a complication of which is reduced kidney function. In addition, the risk of cardiovascular disease for diabetics is trebled and it is predicted that 30% of the US population will be diabetic by 2050. Therefore there is an increasing number of patients who will suffer from cardiovascular disease, will need to receive current agents for diagnosis and treatment, but will suffer increased morbidity and mortality as a result. Gold nanoparticles are biocompatible, more strongly attenuating, long-circulating alternatives to iodinated agents. However, these nanoparticles suffer from poor excretion and are expensive. To address these issues, we propose to develop novel, small (<5 nm) metal nanoparticles that can be easily excreted, made from lanthanum, tantalum and gold. We have found that combining several elements further increases contrast in CT, compared with gold alone, as the k-edges of the elements are spread over the diagnostic X-ray spectrum. As lanthanum and tantalum are more than tenfold cheaper than gold, this reduces the cost of the agent. In addition, the risk of toxiciy is decreased as the dose of the nanoparticles formed from each element is lowered by a factor of three. We will then encapsulate these small nanoparticles into hydrophilic polyphosphazene nanospheres to create polymetal nanoparticles. These nanospheres are a novel contrast agent delivery platform, are biodegradable and coated with polyethylene glycol to promote long circulation. These larger nanostructures are designed to break down into harmless byproducts and release the small nanoparticles for swift excretion when applied in vivo. We hypothesize that nanoparticles, having a much lower surface to volume to ratio than small molecules, will prove less toxic than iodinated small molecules. Furthermore, encapsulation in a slow-releasing polymer matrix should result in a low dose of agent reaching the kidneys at any time, additionally reducing the potential for toxicity. Both smaller and larger nanoparticles will be characterized, tested for biocompatibility in vitro and selected formulations will be probed for their excretion and effectiveness as contrast agents in blood vessel imaging with CT. We will use a model of kidney disease and compare the novel agents to clinically approved agents. Thorough toxicological assessments will be performed, with the goal of identifying highly biocompatible agents to be moved towards the clinic.

 说明(申请人提供)：目前使用的X射线成像造影剂主要是碘化小分子。这些碘化小分子药物用于心血管疾病的诊断和治疗，以及其他疾病。然而，在肾功能不佳的患者中，它们经常会导致一种称为造影剂诱导的肾病。这种情况会导致更高的发病率、死亡率和成本。超过10%的美国成年人肾功能不佳，由于糖尿病患病率的上升，这一比例正在迅速上升，糖尿病的一个并发症是肾功能下降。此外，糖尿病患者患心血管疾病的风险增加了两倍，预计到2050年，美国将有30%的人口患有糖尿病。因此，越来越多的患者将患有心血管疾病，需要接受目前的药物进行诊断和治疗，但结果将增加发病率和死亡率。金纳米粒子是一种生物相容的、更强的衰减性、长期循环的碘化剂替代品。然而，这些纳米颗粒排泄能力差，价格昂贵。为了解决这些问题，我们建议开发新型的、小的(&lt；5 nm)金属纳米颗粒，这些纳米颗粒可以很容易地排出，由镧、钽和金制成。我们发现，与单独使用金相比，几种元素的组合进一步增加了CT的对比度，因为这些元素的k边分布在诊断X射线光谱上。由于镧和钽的价格比黄金便宜十倍以上，这降低了试剂的成本。此外，由于每种元素形成的纳米颗粒的剂量降低了三倍，中毒的风险也降低了。然后，我们将这些小纳米颗粒封装到亲水性聚磷腈纳米球中，以创建多金属纳米颗粒。这些纳米球是一种新型的造影剂输送平台，可生物降解，并被聚乙二醇包覆以促进长循环。这些较大的纳米结构被设计成分解成无害的副产品，并在体内应用时释放出快速排泄的小纳米颗粒。我们假设，纳米颗粒比小分子的表面积体积比小得多，其毒性将被证明比加碘的小分子小。此外，在缓释聚合物基质中的包裹应该导致低剂量的试剂在任何时候到达肾脏，另外还减少了潜在的毒性。将对较小和较大的纳米颗粒进行表征，并在体外测试其生物兼容性，并将探索选定的配方，以确定它们作为CT血管成像造影剂的排泄和有效性。我们将使用肾脏疾病的模型，并将新药物与临床批准的药物进行比较。将进行彻底的毒理学评估，目标是确定将用于临床的高度生物相容的药物。