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.

 描述（由适用提供）：当前使用的X射线成像对比剂主要是碘化的小分子。这些碘化的小分子剂用于心血管疾病的诊断和治疗等。但是，它们经常引起肾功能较差的患者的称为对比度诱导的肾病的疾病。这种情况会导致发病率更高，死亡率和成本。超过10％的美国成年人的肾功能较差，并且由于糖尿病患病率的升高，该比例正在迅速增加，其并发症的并发症会降低肾脏功能。此外，糖尿病患者患心血管疾病的风险是三倍，并且预测，到2050年，美国30％的人口将是糖尿病。因此，越来越多的患者将需要患有心血管疾病的患者，需要接受当前的诊断和治疗患者，但会遭受诊断和治疗的症状，结果会增加。金纳米颗粒具有生物相容性，更强烈的衰减，长期循环的碘化剂。但是，这些纳米颗粒的排泄量很差，而且昂贵。为了解决这些问题，我们建议开发可容易超过灯笼，坦塔尔和黄金制成的新颖的小（<5 nm）金属纳米颗粒。我们发现，与单独使用黄金相比，将几个元素组合进一步增加了CT的对比度，因为元素的K-Edges分布在诊断X射线频谱上。由于灯笼和塔塔勒姆（Lanthanum）和塔塔勒姆（Tantalum）比黄金（Gold）便宜十倍，因此降低了代理商的成本。另外，随着由每个元素形成的纳米颗粒的剂量降低了三倍，毒性的风险会降低。然后，我们将将这些小纳米颗粒封装到亲水的聚磷酸纳米球中，以产生多头纳米颗粒。这些纳米球是一个新型的对比剂递送平台，可生物降解，并用聚乙烯乙二醇覆盖以促进长循环。这些较大的纳米结构旨在分解成无害的副产品，并在体内应用时释放小纳米颗粒以迅速排泄。我们假设比小分子的表面与体积比的比率低得多，纳米颗粒的毒性比碘化的小分子更小。此外，在缓慢释放的聚合物基质中的封装应导致剂量低剂量，随时到达儿童，并降低了毒性的潜力。将对较小和较大的纳米颗粒进行表征，在体外测试生物相容性，并将选定的配方探测出它们的极端和有效性，作为用CT进行血管成像的对比剂。我们将使用一种肾脏疾病模型，并将新型药物与临床认可的药物进行比较。将进行彻底的毒理学评估，目的是确定要转向诊所的高度生物相容性药物。