Purpose

Ultrasmall silver sulfide nanoparticles (Ag₂S-NP) have been identified as promising contrast agents for a number of modalities and in particular for dual-energy mammography. These Ag₂S-NP have demonstrated marked advantages over clinically available agents with the ability to generate higher contrast with high biocompatibility. However, current synthesis methods for inorganic nanoparticles are low-throughput and highly time-intensive, limiting the possibility of large animal studies or eventual clinical use of this potential imaging agent.

Methods

We herein report the use of a scalable silicon microfluidic system (SSMS) for the large-scale synthesis of Ag₂S-NP. Ag₂S-NP produced using this system were compared to bulk synthesis and a commercially available microfluidic device through characterization, contrast generation, in vivo imaging, and clearance profiles.

Results

Using SSMS chips with 1 channel, 10 parallelized channels, and 256 parallelized channels, we determined that the Ag₂S-NP produced were of similar quality as measured by core size, concentration, UV–visible spectrometry, and in vitro contrast generation. Moreover, by combining parallelized chips with increasing reagent concentration, we were able to increase output by an overall factor of 5,100. We also found that in vivo imaging contrast generation was consistent across synthesis methods and confirmed renal clearance of the ultrasmall nanoparticles. Finally, we found best-in-class clearance of the Ag₂S-NP occurred within 24 h.

Conclusions

These studies have identified a promising method for the large-scale production of Ag₂S-NP, paving the way for eventual clinical translation.

中文翻译：

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硫化银纳米颗粒造影剂的临床转化：使用高度并行化的微流控芯片进行大规模生产

 目的

超小硫化银纳米颗粒 （Ag₂S-NP） 已被确定为多种方式的有前途的造影剂，特别是双能乳腺 X 线摄影。与临床可用的药物相比，这些 Ag₂S-NP 已显示出明显的优势，能够产生更高的对比度和高生物相容性。然而，目前无机纳米颗粒的合成方法通量低且耗时长，限制了这种潜在显像剂进行大型动物研究或最终临床使用的可能性。

 方法

我们在此报告了使用可扩展的硅微流控系统 （SSMS） 大规模合成 Ag₂S-NP。通过表征、造影剂生成、体内成像和清除曲线，将使用该系统产生的 Ag₂S-NP 与批量合成和市售微流控装置进行比较。

 结果

使用具有 1 个通道、10 个并行通道和 256 个并行通道的 SSMS 芯片，我们确定产生的 Ag₂S-NP 具有与通过核心尺寸、浓度、紫外-可见光谱法和体外造影剂生成测量的质量相似。此外，通过将平行芯片与增加的试剂浓度相结合，我们能够将产量提高 5,100 倍。我们还发现，体内成像造影剂的产生在合成方法中是一致的，并证实了超小纳米颗粒的肾脏清除率。最后，我们发现 Ag₂S-NP 的最佳清除率发生在 24 小时内。

 结论

这些研究确定了一种有前途的大规模生产 Ag₂S-NP 的方法，为最终的临床转化铺平了道路。