Holzwarth Uwe, Cossío Unai, Llop Jordi, Kreyling Wolfgang G
Joint Research Centre (JRC), European Commission, Ispra, Italy.
Radiochemistry and Nuclear Imaging, CIC biomaGUNE, San Sebastian, Spain.
Front Pharmacol. 2019 Nov 6;10:1293. doi: 10.3389/fphar.2019.01293. eCollection 2019.
In recent animal experiments with suspensions of radiolabeled TiO nanoparticles large and highly variable radioactivity fractions were retained in disposable plastic syringes. After unloading between 10% and up to 70% of the loaded dose were still present in the syringes. As a consequence the effectively delivered nanoparticle dose to the animals was frequently much smaller than the nominal dose of the nanoparticles loaded into the syringe. The high variability of this nanoparticle retention challenges the application of a precise, predefined dose and creates a major error source when normalizing organ and tissue contents to the dose loaded into the syringe, which is usually set as the applied dose. A control study was performed employing six commonly used syringe types with seven types of radiolabeled oxide and metallic nanoparticles. For this purpose the syringes were loaded with a given volume of nanoparticle suspension, the radioactivity was measured, the syringe was unloaded and the activity measurement was repeated with the empty syringe. The highest retention values were found when using TiO nanoparticle suspensions with Tuberkulin type syringes. In the worst case between 6.6% and 79.1% of the nanoparticles were retained in the syringe. When using the same nanoparticle suspension with an insulin-type syringe the retention was reduced to 1.4% to 20.6%. For amorphous silica nanoparticles the maximum observed retention was 8% and for Au nanoparticles it was 5.1%. Further data gathered from animal imaging studies show that nanoparticle retention in syringes also affects experiments with nanoparticles such as exosomes, polymersomes, and protein-based nanoparticles investigated for possible applications in nanomedicine. Since the retention is highly variable the effectively applied dose cannot be determined by applying a simple syringe retention factor. The present work shall alert to the problem and illustrate its possible magnitude and unpredictable variability. As mitigation strategy adequate checks with different syringe types are proposed in order to find out whether a given combination of syringe type and nanoparticle suspension is affected by nanoparticle retention and, if necessary, to select a different syringe type that minimizes retention.
在最近使用放射性标记的二氧化钛纳米颗粒悬浮液进行的动物实验中，一次性塑料注射器中保留了大量且高度可变的放射性部分。在卸载后，注射器中仍存在10%至高达70%的加载剂量。因此，实际输送到动物体内的纳米颗粒剂量通常比装入注射器的纳米颗粒标称剂量小得多。这种纳米颗粒保留的高度变异性对精确预定义剂量的应用提出了挑战，并在将器官和组织含量归一化为装入注射器的剂量（通常设定为应用剂量）时产生了一个主要误差源。进行了一项对照研究，使用了六种常用注射器类型和七种放射性标记的氧化物及金属纳米颗粒。为此，向注射器中装入给定体积的纳米颗粒悬浮液，测量放射性，卸载注射器，然后用空注射器重复活性测量。使用结核菌素型注射器与二氧化钛纳米颗粒悬浮液时发现保留值最高。在最坏的情况下，6.6%至79.1%的纳米颗粒保留在注射器中。当使用胰岛素型注射器与相同的纳米颗粒悬浮液时，保留率降至1.4%至20.6%。对于无定形二氧化硅纳米颗粒，观察到的最大保留率为8%，对于金纳米颗粒为5.1%。从动物成像研究中收集的进一步数据表明，注射器中纳米颗粒的保留也会影响纳米颗粒的实验，如对外泌体、聚合物囊泡和基于蛋白质的纳米颗粒的研究，这些纳米颗粒有望应用于纳米医学。由于保留率高度可变，不能通过应用简单的注射器保留因子来确定实际应用剂量。本研究旨在提醒人们注意这个问题，并说明其可能的严重程度和不可预测的变异性。作为缓解策略，建议对不同注射器类型进行充分检查，以确定给定的注射器类型和纳米颗粒悬浮液组合是否受纳米颗粒保留的影响，如有必要，选择保留率最小的不同注射器类型。
