Department of Chemical Engineering, University College London, London, WC1E 7JE, UK.
Institut de Physique et Chimie des Matériaux de Strasbourg, BP 43, 67034, Strasbourg, France.
Nanoscale. 2021 May 20;13(19):8795-8805. doi: 10.1039/d1nr00877c.
Small iron oxide nanoparticles (IONPs) were synthesised in water via co-precipitation by quenching particle growth after the desired magnetic iron oxide phase formed. This was achieved in a millifluidic multistage flow reactor by precisely timed addition of an acidic solution. IONPs (≤5 nm), a suitable size for positive T1 magnetic resonance imaging (MRI) contrast agents, were obtained and stabilised continuously. This novel flow chemistry approach facilitates a reproducible and scalable production, which is a crucial paradigm shift to utilise IONPs as contrast agents and replace currently used Gd complexes. Acid addition had to be timed carefully, as the inverse spinel structure formed within seconds after initiating the co-precipitation. Late quenching allowed IONPs to grow larger than 5 nm, whereas premature acid addition yielded undesired oxide phases. Use of a flow reactor was not only essential for scalability, but also to synthesise monodisperse and non-agglomerated small IONPs as (i) co-precipitation and acid addition occurred at homogenous environment due to accurate temperature control and rapid mixing and (ii) quenching of particle growth was possible at the optimum time, i.e., a few seconds after initiating co-precipitation. In addition to the timing of growth quenching, the effect of temperature and dextran present during co-precipitation on the final particle size was investigated. This approach differs from small IONP syntheses in batch utilising either growth inhibitors (which likely leads to impurities) or high temperature methods in organic solvents. Furthermore, this continuous synthesis enables the low-cost (<£10 per g) and large-scale production of highly stable small IONPs without the use of toxic reagents. The flow-synthesised small IONPs showed high T1 contrast enhancement, with transversal relaxivity (r2) reduced to 20.5 mM-1 s-1 and longitudinal relaxivity (r1) higher than 10 mM-1 s-1, which is among the highest values reported for water-based IONP synthesis.
小氧化铁纳米粒子 (IONPs) 通过在所需的磁性氧化铁相形成后猝灭颗粒生长，在水中通过共沉淀合成。这是通过在精确计时添加酸性溶液的微流控多阶段流反应器中实现的。获得了适合正 T1 磁共振成像 (MRI) 对比剂的小 IONPs（≤5nm），并连续稳定。这种新颖的流动化学方法促进了可重复和可扩展的生产，这是将 IONPs 用作对比剂并取代目前使用的 Gd 配合物的关键范式转变。必须小心控制酸的添加时间，因为反尖晶石结构在引发共沉淀后的几秒钟内形成。迟淬可使 IONPs 生长到 5nm 以上，而过早添加酸则会产生不理想的氧化物相。使用流动反应器不仅对于可扩展性至关重要，而且还可以合成单分散且不团聚的小 IONPs，因为 (i) 由于精确的温度控制和快速混合，共沉淀和酸添加在均匀的环境中进行，以及 (ii) 在最佳时间（即引发共沉淀后几秒钟）进行颗粒生长猝灭。除了生长猝灭的时间外，还研究了共沉淀过程中温度和葡聚糖对最终颗粒尺寸的影响。与使用生长抑制剂（可能导致杂质）或有机溶剂中的高温方法的分批小 IONP 合成相比，这种方法有所不同。此外，这种连续合成能够以低成本（每克<£10）和大规模生产高度稳定的小 IONPs，而无需使用有毒试剂。流动合成的小 IONPs 表现出高 T1 对比增强，横向弛豫率 (r2) 降低至 20.5mM-1s-1，纵向弛豫率 (r1) 高于 10mM-1s-1，这是报道的基于水的 IONP 合成中最高值之一。
