Biodegradable gold nanoparticles as contrast agents for CT

项目总结 在美国，计算机断层扫描每年被用于约8000万次成像研究。碘化对比剂 在这些研究中，大约有一半使用了制剂。计算机断层扫描对于 冠状动脉疾病的诊断，依赖于使用碘化造影剂来可视化 动脉。然而，这些试剂有一些缺点，如循环时间短，导致 过敏反应和造影剂引起的肾病。后一种情况导致更高的发病率、死亡率 和费用，最常见的是肾功能不佳的患者。65岁以上的患者中， 肾脏疾病占26%。这一比例正在迅速上升，因为糖尿病的发病率正在迅速增加。 (预计到2050年将影响美国30%的人口)，肾脏疾病是一种常见的并发症 糖尿病。糖尿病患者患心血管疾病的风险增加了两倍。因此，人口在不断增长 会患心血管疾病，但目前的诊断试剂对他们可能是有害的，造成 迫切需要新的CT造影剂。 其他人和我们已经展示了金纳米颗粒是高效的、生物兼容的CT造影剂 有很长的流通时间。然而，金纳米颗粒通常排出非常缓慢，导致风险 长期毒性，并将排除FDA的批准。 宾夕法尼亚大学教职员工和PolyAurum LLC建议通过开发可生物降解的材料来解决这个问题 金纳米粒子。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。纳米颗粒应该在血液中循环几个小时，然后 逐渐分解成它们的成分以供肾脏排泄。应避免快速排泄，以 防止对肾脏造成负担，但排泄应相当快，以避免潜在的长期 安全问题和令人困惑的后续成像研究。因此，我们将研究如何将退化调整为 发生在48小时以上。我们将在体外确认新制剂的生物相容性。然后我们将确保 新配方提供了出色的体内CT对比度，并确定了体内的生物相容性 和排泄物。 在这些试验后，我们将有条件筹集额外资金，以完成毒理学筛查 允许我们申请研究新药(IND)地位。IND申请的批准将为 用于该配方的临床试验。

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.