Biodegradable gold nanoparticles as contrast agents for CT

可生物降解的金纳米颗粒作为 CT 造影剂

• 批准号: 9341531
• 负责人: David Peter Cormode
• 金额: $ 22.3万
• 依托单位: POLYAURUM, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2019-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9341531
• 关键词: Acute; Address; Affect; Allergic Reaction; American; Animal Model; Arteries; Biodistribution; Biological Assay; Blood; Blood Circulation; Caliber; Cardiac; Cardiovascular Diseases; Chronic Kidney Failure; Clinic; Clinical Chemistry; Clinical Trials; Complications of Diabetes Mellitus; Contrast Media; Coronary Arteriosclerosis; Coronary artery; Data; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Diagnostic radiologic examination; Dose; Drug Kinetics; Encapsulated; Ensure; Excretory function; Faculty; Formulation; Functional disorder; Funding; Gold; Histologic; Hour; Image; Imaging Techniques; In Vitro; Incidence; Injectable; Investigational Drugs; Investigational New Drug Application; Kidney; Kidney Diseases; Kidney Failure; Laboratories; Lead; Measures; Methods; Molecular Weight; Morbidity - disease rate; Nanotechnology; Patient risk; Patients; Pennsylvania; Phase; Polymers; Population; Positioning Attribute; Property; Renal function; Resources; Risk; Risk Factors; Roentgen Rays; Running; Safety; Series; Small Business Technology Transfer Research; System; Technology; Testing; Time; Tissues; Toxic effect; Toxicology; Translations; United States National Institutes of Health; Universities; Urine; X-Ray Computed Tomography; base; biodegradable polymer; biomaterial compatibility; cardiovascular disorder risk; cardiovascular imaging; comparative; contrast imaging; cost; data acquisition; design; diabetic; experimental study; flexibility; follow-up; imaging study; improved; in vivo; innovative technologies; mortality; mouse model; nanoparticle; non-diabetic; novel; patient population; prevent; public health relevance; safety testing; scale up; screening; small molecule

PROJECT SUMMARY Computed tomography is used in about 80 million imaging studies per year in the USA. Iodinated contrast agents are used in roughly half of these studies. Computed tomography is particularly important for the diagnosis of coronary artery disease, where it depends on the use of iodinated contrast agents to visualize the arteries. However, these agents have a number of shortcomings, such as short circulation times, causing allergic reactions and contrast-induced nephropathy. The latter condition results in higher morbidity, mortality and costs and is most common in patients with poor kidney function. The proportion of patients over 65 with kidney disease is 26%. This percentage is rapidly rising, since the incidence of diabetes is rapidly increasing (projected to affect 30% of the US population by 2050) and kidney disease is a common complication of diabetes. The risk of cardiovascular disease is trebled for diabetics. Therefore there is a growing population that will suffer cardiovascular disease, but for whom the current diagnostic agents can be harmful, creating a pressing need for new CT contrast agents. Others and we have shown gold nanoparticles to be highly effective, biocompatible CT contrast agents that have long circulation times. However, gold nanoparticles are typically very slowly excreted, leading to the risk of long term toxicities and would preclude FDA-approval. Penn faculty, together with PolyAurum LLC, propose to address this issue via development of biodegradable gold nanoparticles. We have chosen a comparatively simple, yet flexible nanoparticle design in order to improve the likelihood of translation. The nanoparticles should circulate in the blood for some hours, before gradually breaking down into their components for renal excretion. Rapid excretion should be avoided to prevent a burden on the kidneys, but excretion should be reasonably fast to avoid the potential for long-term safety issues and confounding follow-up imaging studies. We will therefore study how to tune degradation to occur over 48 hours. We will confirm the biocompatibility of the new formulations in vitro. We will then ensure that the new formulation provides excellent in vivo CT contrast, as well as determining in vivo biocompatibility and excretion. After these experiments, we will be well placed to raise additional funds to complete toxicology screening to allow us to apply for investigational new drug (IND) status. Approval of the IND application would set the stage for clinical trials of the formulation.

项目概要 在美国，计算机断层扫描每年用于约 8000 万次成像研究。碘造影剂 这些研究中大约有一半使用了药物。计算机断层扫描对于 冠状动脉疾病的诊断，依赖于使用碘造影剂来可视化 动脉。然而，这些药剂存在一些缺点，例如流通时间短，导致 过敏反应和造影剂肾病。后一种情况导致较高的发病率和死亡率 且费用高，并且在肾功能较差的患者中最常见。 65岁以上患者比例 肾脏疾病占26%。由于糖尿病的发病率正在迅速增加，这一比例正在迅速上升 （预计到 2050 年将影响 30% 的美国人口），肾脏疾病是常见的并发症 糖尿病。糖尿病患者患心血管疾病的风险增加三倍。因此人口不断增长 将会患有心血管疾病，但目前的诊断药物对他们来说可能是有害的，从而产生了 迫切需要新的 CT 造影剂。 我们和其他人已经证明金纳米粒子是高效、生物相容性 CT 造影剂 流通时间长。然而，金纳米粒子的排泄通常非常缓慢，导致风险 长期毒性，并会妨碍 FDA 的批准。 宾夕法尼亚大学教师与 PolyAurum LLC 一起建议通过开发可生物降解的材料来解决这个问题 金纳米颗粒。我们选择了一种相对简单但灵活的纳米颗粒设计，以便 提高翻译的可能性。纳米粒子应在血液中循环几个小时，然后 逐渐分解成其成分，由肾脏排泄。应避免快速排泄 防止肾脏负担，但排泄应相当快，以避免长期的潜在风险 安全问题和令人困惑的后续影像学研究。因此，我们将研究如何调整退化 发生超过48小时。我们将在体外确认新配方的生物相容性。然后我们将确保 新配方可提供出色的体内 CT 对比度，并确定体内生物相容性 和排泄。 经过这些实验，我们将有能力筹集更多资金来完成毒理学筛选 允许我们申请研究性新药 (IND) 状态。 IND 申请的批准将为我们奠定基础 用于制剂的临床试验。