Name: synthesis of 68ga core-doped iron oxide nanoparticles for dual positron emission tomography /(t1)magnetic resonance imaging
Uploaded: 2018-11-20T13:00:00
Description: Watch this Scientific Journal Video about Synthesis of 68Ga Core-doped Iron Oxide Nanoparticles for Dual Positron Emission Tomography /T1Magnetic Resonance Imaging at JoVE.com

这项研究得到了西班牙经济和竞争力部 (赠款编号: saf2016-79993-p) 和卡洛斯三世健康研究所 (赠款编号: dts16/00059) 的赠款支持。该中心由新闻中心和专业大学基金会提供支助, 是 severo ochoa 英才中心 (meic 奖 sev-2015-0505)。

1. 试剂制备
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0.05 m hcl
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<li>将0.08μl 的 37% hcl 添加到50毫升的蒸馏水中, 制备 0.05 m hcl。</li>
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高效液相色谱洗脱液
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<li>通过溶解6.9 克一水二氢钠、7.1 克磷酸氢二钠、8.7 克氯化钠和0.7 克氮化钠, 制备高效液相色谱 (hplc) 洗脱液。混合好, 检查 ph 值。使用前, 通过0.1μm 的切断无菌过滤器和除气。验收范围: ph 6.2-7.0 (如果不是, 请与 naoh [1 m] 或 hcl [5m] 调...

<ol>
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氧化铁纳米颗粒是一种成熟的 t型加权 mri 造影剂。然而, 由于这种类型的对比度的缺点, 诊断某些疾病, t1 加权或明亮的对比度是许多倍的首选。这里介绍的纳米粒子不仅克服了这些限制, 在 mri 提供了积极的对比, 而且还提供了一个信号, 在功能成像技术, 如 pet, 通过68ga 纳入其核心。微波技术增强了这种可复制的纳米粒子合成, 将反应时间大大缩短到总共约 20分钟 (?...

医疗成像技术的结合引发了对合成多模态探针1、2、3的不同方法的探索。由于正电子发射断层扫描 (pet) 扫描仪的灵敏度和 mri 的空间分辨率, pet/mri 组合似乎是最吸引人的可能性之一, 同时提供解剖和功能信息 4。在 mri 中, 可以使用 t2 加权序列, 使它们积累的组织变暗。t1加权序列也可以使用, 产生特定聚集位置5的亮化。其中, 正对比往往是最充分的选择, 因为负对比使信号更难以与内源性低指区域区分开来, 包括那些经常由肺等器官呈现的区域.传统上, 基于 gd 的分子探针被用来获得正对比。然而, 基于 gd 的造影剂存在一个主要的缺点, 即其毒性, 这在肾病患者7,8,9中至关重要。这促使了在合成生物相容性材料作为 t1 造影剂的研究方面取得了积极的努力。一个有趣的方法是使用氧化铁纳米粒子 (ionps), 具有非常小的核心尺寸, 提供积极的对比10。由于这个非常小的核心 (~ 2 纳米), 大多数的 fe3 +离子都在表面, 每个都有5个未配对的电子。这增加了纵向松弛时间 (r1) 值, 并产生更低的横向比 (r2/r1) 相比, 传统的 ionps, 产生所需的正对比11。
要将 nanoparticle 与 pet 的正电子发射器结合, 需要考虑两个关键问题: 放射性同位素选择和纳米粒子放射性标记。关于第一个问题, 68ga 是一个诱人的选择。它的半衰期相对较短 (67.8 分)。它的半衰期适合于肽标记, 因为它与普通肽生物分布时间相匹配。此外,在发电机中生产 68 ga, 使其能够在工作台模块中进行合成, 并避免了在 12、13、14附近使用回旋加速器。为了使纳米颗粒的放射性, 表面标记放射性同位素的结合是目前流行的策略。这可以使用螯合 68 ga 的配体或利用与纳米粒子表面的辐射相互关系来完成。文献中有关 ionps 的大多数例子都使用螯合剂。有使用杂环配体的例子, 如 1, 4, 7, 10-四氮唑二钠-1, 4, 7, 10-四乙酸 (dota)15, 1, 4, 7-三氮环酮-1, 4, 7-三乙酸 (nota)16,17, 和 1, 4, 7-三氮环酮烯 1-谷氨酸 4-7-乙酸 (nodaga)18, 并使用 2, 3-二羧基丙酸-1-二膦酸 (dpd), 四聚体脂质 19. madru等人20在2014年制定了一项无螯合剂战略, 使用另一个集团在第21后使用的无螯合剂方法给 ionps 贴上标签.
然而, 这种方法的主要缺点包括体内转金属的高风险、低放射性标记的产量以及不适合寿命短的同位素22、23、24 的冗长协议。为此, wong等人.25开发了第一个掺杂核纳米粒子的例子, 在使用微波技术进行的5分钟合成中, 成功地将64铜纳入了 nanoparticles 的核心。
在这里, 我们描述了一个快速和有效的程序, 以纳入纳米粒子的核心, 阐明了传统方法提出的许多缺点。为此, 我们建议使用微波驱动合成 (mws), 它大大缩短了反应时间, 提高了产量, 并增强了可重复性, 这在 ionp 合成中至关重要。mws 的精细化性能是由于介电加热: 快速样品加热, 因为分子偶极子试图与交变电场对齐, 是极性溶剂和试剂更有效地用于这种合成。此外, 使用柠檬酸作为表面活性剂, 加上微波技术, 产生了非常小的纳米粒子, 产生了双 t1 加权 micet 26 信号, 这里表示为68ga 核掺杂氧化铁纳米粒子 (68ga-c-ionp)。
该协议结合了微波技术, 68gocl3作为正电子发射器, 氯化铁, 柠檬酸钠, 水合氨, 导致双 t 1 加权 mri\ pet 纳米颗粒材料在几乎20分钟。此外, 它在68ga 活性 (37 mbq、111 mbq、370 mbq 和 1110 mbq) 范围内产生一致的结果, 对纳米粒子的主要物理化学特性没有显著影响。该方法使用高68ga 活性的重现性扩展了可能的应用领域, 包括大型动物模型或人类研究。此外, 该方法中还包含一个单一的纯化步骤。在此过程中, 任何过量的游离镓、氯化铁、柠檬酸钠和水合氨都通过凝胶过滤去除。完全自由的同位素消除和样品的纯度确保无毒性, 并提高成像分辨率。在过去, 我们已经证明了这种方法在有针对性的分子成像27,28的有用性。

<table>
	<tbody>
		<tr>
			<td>Iron (III) chloride hexahydrate</td>
			<td>POCH</td>
			<td>2317294</td>
			<td></td>
		</tr>
		<tr>
			<td>Citric acid, trisodium salt dihydrate 99%</td>
			<td>Acros organics</td>
			<td>227130010</td>
			<td></td>
		</tr>
		<tr>
			<td>Hydrazine hydrate</td>
			<td>Aldrich</td>
			<td>225819</td>
			<td></td>
		</tr>
		<tr>
			<td>Hydrochloric acid 37%</td>
			<td>Fisher Scientific</td>
			<td>10000180</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium dihydrogen phosphate monohydrate</td>
			<td>Aldrich</td>
			<td>S9638</td>
			<td></td>
		</tr>
		<tr>
			<td>Disodium phosphate dibasic</td>
			<td>Aldrich</td>
			<td>S7907</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium chloride</td>
			<td>Aldrich</td>
			<td>746398</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium Azide</td>
			<td>Aldrich</td>
			<td>S2002</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium dihydrogen phosphate anhydrous</td>
			<td>POCH</td>
			<td>799200119</td>
			<td></td>
		</tr>
		<tr>
			<td>68Ga Chloride</td>
			<td>&#160;ITG Isotope Technologies Garching GmbH, Germany</td>
			<td>68Ge/68Ga generator system</td>
			<td></td>
		</tr>
		<tr>
			<td>Microwave</td>
			<td>Anton Paar</td>
			<td>Monowave 300</td>
			<td></td>
		</tr>
		<tr>
			<td>Centrifuge</td>
			<td>Hettich</td>
			<td>Universal 320</td>
			<td></td>
		</tr>
		<tr>
			<td>Size Exclusion columns</td>
			<td>GE Healthcare</td>
			<td>PD-10</td>
			<td></td>
		</tr>
	</tbody>
</table>

synthesis of 68ga core-doped iron oxide nanoparticles for dual positron emission tomography /(t1)magnetic resonance imaging

在这里, 我们描述了微波合成, 以获得氧化铁纳米粒子掺杂与 68 ga. 微波技术实现快速和可重复的合成过程。在这种情况下, 从 ficl3和柠檬酸三钠开始, 在10分钟内在微波中获得涂有柠檬酸的氧化铁纳米颗粒。这些纳米粒子的核心尺寸为 4.2±1.1 nm, 流体动力尺寸为 7.5±2.1 nm。此外, 它们具有 11.9 mm-1·s-1 的高纵向松弛性 (r1) 值和 22.9 mm-1-1的适度横向松弛度值 (r2), 从而导致较低的 r2 /r1 比率为1.9。这些值可在磁共振成像 (mri) 中产生正对比度, 而不是用于氧化铁纳米粒子的负对比度。此外, 如果在起始材料中加入68ge-68 ga 发生器中的68gal3 洗脱,则可获得掺杂 68 ga 的纳米辐射仪.无论使用何种初始活性, 该产品都具有较高的放射性标记产率 (& gt; 90%)。此外, 一个单一的纯化步骤使纳米辐射材料准备在体内使用。

68将 ficl3、 68gocl 3、柠檬酸、水和水合氨合成了 ga-c-ionp。这种混合物在120°c 和控制压力下被引入微波炉10分钟。一旦样品冷却到室温, 纳米颗粒通过凝胶过滤进行纯化, 以消除未反应的物种 (fecl 3, 柠檬酸,水合氨) 和游离68ga (图 1)。
利用动态光散射 (dls) 测?...

Watch this Scientific Journal Video about Synthesis of 68Ga Core-doped Iron Oxide Nanoparticles for Dual Positron Emission Tomography /T1Magnetic Resonance Imaging at JoVE.com

Synthesis of 68Ga Core-doped Iron Oxide Nanoparticles for Dual Positron Emission Tomography /T1Magnetic Resonance Imaging

在这里, 我们提出了一个协议,以获得68ga 掺杂氧化铁纳米粒子通过快速微波驱动合成。该方法使 pet/i 1) mri 纳米颗粒在20分钟的合成中具有90% 以上的放射性标记效率和99% 的放射化学纯度。

双正电子发射层析成像用 68 ga 芯掺杂氧化铁纳米粒子的合成/(t1) 磁共振成像

Here, we describe a microwave synthesis to obtain iron oxide nanoparticles core-doped with 68Ga. Microwave technology enables fast and reproducible ...

该方法为混合PET/MR分子成像提供了一些引人入胜的合成氦-68核心掺杂纳米粒子。该技术的主要优点是，由于微波技术的使用，合成是快速的，更重要的是，完全可重复。首先，在9毫升水中溶解75毫克氯化铁六水合物和80毫克柠檬酸三钠盐二水合物。将混合物转移到微波适应的烧瓶中。接下来，在微波中加载动态协议。将温度设置为 120 摄氏度，时间设置为 10 分钟，压力设置为 250 psi，功率设置为 240 瓦。在反应混合物中加入一毫升水合物。然后启动微波协议。同时，用20毫升蒸馏水冲洗凝胶过滤脱盐柱。一旦协议完成，烧瓶冷却到室温，移液器2.5毫升的最终混合物到列上，并丢弃流。之后，在柱子中加入三毫升蒸馏水，并将纳米颗粒收集到塑料管中。将75毫克氯化铁六水合物和80毫克柠檬酸三钠盐二水合物加入小瓶。根据供应商的说法，使用推荐的盐酸体积和浓度来洗脱氦-68发生器。在自屏蔽发生器中注射盐酸后，获得四毫升氯化铀，无需进一步处理即可使用。在微波适应的烧瓶中加入四毫升的氯化铀。然后移液器将五毫升蒸馏水放入烧瓶中，混合好。现在，在微波中加载动态协议。将温度设置为 120 摄氏度，时间设置为 10 分钟，压力设置为 250 psi，功率设置为 240 瓦。在反应混合物中加入一毫升水合物。然后启动微波协议。同时，用20毫升蒸馏水冲洗凝胶过滤脱盐柱。一旦协议完成，烧瓶冷却到室温，移液器2.5毫升的最终混合物到柱上，并丢弃流。然后将三毫升蒸馏水加入柱中，将纳米颗粒收集在玻璃瓶中。为了测量氦-68纳米粒子的流体动力学大小，移液器将样品的60微升放入一个花盘中，并每个样品进行三次动态光散射测量。为了评估高-68纳米粒子的胶体稳定性，在37摄氏度的不同时间，从零到24小时，在不同的缓冲液中孵育500微升样品。在选定的时间，将 60 微升等分转移到库维特，并测量其流体动力学大小。为了获得凝胶过滤放射性光瘤图，在凝胶过滤纯化步骤中，将洗脱从大小排除柱切成 500 微升等分。然后使用活性计测量每个等分中存在的放射性。为了确定放射化学的稳定性，在37摄氏度下在小鼠血清中孵育30分钟。孵育后，通过超滤净化纳米粒子。然后测量纳米粒子和滤物中的放射性。68纳米粒子的流体动力学尺寸数据显示，其大小分布较窄，平均水动力尺寸为7.9纳米。五种不同合成的测量证明了方法的可重复性。从零到24小时在不同介质中孵育的68纳米粒子的流体动力学尺寸没有显著变化，这意味着样品在不同的缓冲液和血清中保持稳定。由于使用微波技术实现的快速加热，纳米粒子的超小核心尺寸约为四纳米。电子显微镜图像显示均匀的核心大小和缺乏聚合。68纳米粒子凝胶过滤色谱显示与纳米粒子对应的主要放射性峰值和与自由铀-68相对应的降低峰。无线电标记产量为 92%，与每毫微米 7.1 千兆克勒相比，这转化为特定活动。在5个高-68纳米粒子合成中，获得了11.9的极佳纵向值和22.9的适度松弛值，平均比为1.9，这意味着高-68纳米粒子是T1加权MRI的优异。不同氦-68纳米粒子浓度的 MR 幻象图像显示铁浓度增加和正对比度。铁浓度的增加意味着铀-68浓度的增加，PET信号越来越强烈。微波技术的使用允许可重复和快速合成氧化铁纳米粒子，用于多模态成像。按照这个程序，我们产生了一个示踪剂，可用于靶向分子成像与PET，T1MRI，或混合方法。该技术开发后，为研究人员探索混合分子成像在肿瘤学和心血管疾病等领域的应用铺平了道路。不要忘记，使用放射性化合物可能极其危险，执行此过程时应始终采取放射性保护预防措施。

Research

JoVE Journal

Biology

Synthesis of 68Ga Core-doped Iron Oxide Nanoparticles for Dual Positron Emission Tomography /(T1)Magnetic Resonance Imaging

Labeling hESCs and hMSCs with Iron Oxide Nanoparticles for Non-Invasive in vivo Tracking with MR Imaging

氧化铁标记的胚胎干细胞和的hMSCs纳米粒子在体内的跟踪与非侵入性磁共振成像

In recent years, stem cell research has led to a better understanding of developmental biology, various diseases and its potential impact on regenerative ...

科研

生物学

In vitro Labeling of Human Embryonic Stem Cells for Magnetic Resonance Imaging

在人类胚胎干细胞体外培养的标签用于磁共振成像

Human embryonic stem cells (hESC) have demonstrated the ability to restore the injured myocardium. Magnetic resonance imaging (MRI) has emerged as one of ...

Born Normalization for Fluorescence Optical Projection Tomography for Whole Heart Imaging

生于正常化荧光整个心脏成像的光学投影层析成像

Optical projection tomography is a three-dimensional imaging technique that has been recently introduced as an imaging tool primarily in developmental ...

Mesoscopic Fluorescence Tomography for In-vivo Imaging of Developing Drosophila

Mesoscopic Fluorescence Tomography for In-vivo Imaging of Developing Drosophila

为介观荧光体层摄影术在体内成像的发展果蝇</em

Visualizing  developing organ formation as well as progession and treatment of disease often  heavily relies on the ability to optically interrogate ...

Electron Spin Resonance Micro-imaging of Live Species for Oxygen Mapping

电子自旋共振氧测绘活体物种显微成像

This protocol describes an electron spin resonance (ESR) micro-imaging method for three-dimensional mapping of oxygen levels in the immediate environment ...

Preparation, Purification, and Characterization of Lanthanide Complexes for Use as Contrast Agents for Magnetic Resonance Imaging

制备，纯化和磁共振成像造影剂的使用稀土配合物的表征

Polyaminopolycarboxylate-based ligands are commonly used to chelate lanthanide ions, and the resulting complexes are 
useful as contrast agents for ...

Quantifying Mixing using Magnetic Resonance Imaging

量化混合使用磁共振成像

Mixing is a unit operation that combines two or more components into a homogeneous mixture.  This work involves mixing two viscous liquid streams using an ...

Strategies for Optimization of Cryogenic Electron Tomography Data Acquisition

优化低温电子断层扫描数据采集策略

Cryogenic electron tomography (cryoET) is a powerful method to study the 3D structure of biological samples in a close-to-native state. Current ...

Imaging Replicative Domains in Ultrastructurally Preserved Chromatin by Electron Tomography

通过电子断层扫描对超构造保存的染色质中的复制结构域进行成像

Principles of DNA folding in the cell nucleus and its dynamic transformations that occur during the fulfillment of basic genetic functions (transcription, ...

Quantitating Iron Transport Across the Mouse Placenta In Vivo Using Nonradioactive Iron Isotopes

Quantitating Iron Transport Across the Mouse Placenta In Vivo Using Nonradioactive Iron Isotopes

使用非放射性铁同位素定量体内通过小鼠胎盘的铁转运

Iron is essential for maternal and fetal health during pregnancy, with approximately 1 g of iron needed in humans to sustain a healthy pregnancy. Fetal ...