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剂，这些碘化小分子剂用于诊断和治疗心血管疾病等。然而，它们经常引起一种称为“碘化小分子”的疾病。肾功能较差的患者会出现造影剂肾病，这种情况导致较高的发病率、死亡率和费用。超过 10% 的美国成年人肾功能较差，而且由于患病率上升，这一比例正在迅速增加。糖尿病的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三倍，预计到 2050 年，美国将有 30% 的人口患有糖尿病。因此，患有糖尿病的患者数量不断增加。患有心血管疾病，需要接受当前的药物进行诊断和治疗，但因此发病率和死亡率将大大增加，金纳米粒子是生物相容性更强、毒性更强、循环时间更长的替代品。然而，这些纳米颗粒的排泄性较差且价格昂贵，为了解决这些问题，我们建议开发由镧、钽和金制成的易于排泄的新型小型（<5 nm）金属纳米颗粒。发现与单独的金相比，多种元素的组合进一步增加了 CT 的对比度，因为元素的 k 边分布在诊断 X 射线光谱上，而镧和钽的价格要便宜十倍以上。与金相比，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，因此我们将这些小纳米颗粒封装到亲水性聚磷腈纳米球中。这些纳米球是一种新型造影剂输送平台，可生物降解，并涂有聚乙二醇以促进长时间循环。分解成无害的副产物并释放小纳米颗粒，以便在体内应用时快速排泄。我们追求的纳米颗粒比小分子具有低得多的表面积与体积比，并且比碘化小分子的毒性更低。缓慢释放的聚合物基质应导致低剂量的药物随时到达肾脏，另外还降低了潜在的毒性，将对较小和较大的纳米颗粒进行表征，测试体外生物相容性和选定的配方。我们将使用肾脏疾病模型来探究它们的排泄和作为造影剂的有效性，并将对新药物与临床批准的药物进行比较，以期确定高度生物相容性。代理人将被转移到诊所。