Unpredictable Nanoparticle Retention in Commonly Used Plastic Syringes Introduces Dosage Uncertainties That May Compromise the Accuracy of Nanomedicine and Nanotoxicology Studies

Abstract

In recent animal experiments with suspensions of radiolabeled TiO2 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 TiO2 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 in vivo 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.

Pre-Drawn Syringes of Comirnaty for an Efficient COVID-19 Mass Vaccination: Demonstration of Stability

“…It was underlined the importance of adopting multiple analytical techniques for product characterization to meet the intrinsic complexity of such nanosystems. However, despite scientific findings on different nanosystems suggesting that their retention in syringes might be a quality issue [ 11 ], the in-use stability of LN and/or their compatibility with administration devices has not been documented yet. To fill this gap, LN were primarily characterized by TEM, DLS, and NTA, as these complementary techniques can provide evidence on variations in morphology, size, and size distribution which can drastically change the formulation features, including the dose-to-dose reproducibility, the fate, and the biodistribution of the particles upon injection [ 3 , 15 , 16 ].…”

“…On the contrary, studies on the physical stability of nanoparticles in disposable syringes are not available in the literature. At the time of writing, only few data were collected on radiolabeled nanosystems and exosomes demonstrating a certain degree of particle retention into plastic insulin-type syringes [ 11 ]. Comirnaty LN from different batches instead were physically stable in disposable syringes, regardless of the device material, storage temperature, and road transportation since no sign of aggregation or adsorption was detected at 2–25 °C over 24 h ( Table 1 and Table 2 ).…”

“…Nevertheless, no data on the environmental factors controlling and limiting vaccine stability in the syringe are publicly available, as of the writing of this manuscript. This lack of information seems particularly critical taking also into consideration that researchers of the European Commission’s Joint Research Centre (JRC) demonstrated that nanosystems’ retention in the syringe might be a critical drawback affecting the reproducibility of dosing of several types of nanosystems (e.g., inorganic nanoparticles, exosomes, protein-based nanoparticles, nanocrystal) in in vivo studies [ 11 ].…”

Characterization, bio-uptake and toxicity of polymer-coated silver nanoparticles and their interaction with human peripheral blood mononuclear cells

“…Furthermore, cysteine and thiol-containing proteins are found in FBS and have a high affinity for Ag ions and NPs. Ag loss to the container wall could be another reason that we did not get full recovery of Ag, as it was discussed in [ 47 ]. This may lead to decreased Ag ion availability and possible NP surface interactions with the aqueous phase, ultimately reducing toxicity [ 10 , 48 ].…”

Time-course Analysis of Pulmonary Inflammation Induced by Intratracheal Instillation of Fine Crystalline Silica Particles

“…An additional limitation of instillation studies has recently been raised. Holzwarth et al (37) reported that some instillation studies are not able to achieve nominal dose amounts because of the unexpected retention of dosing syringes; the authors pointed out that numerous misleading results have been published.…”