Controlling the size distribution of polymer-based nanoparticles is a challenging task due to their flexible core and surface structures. To accomplish such as task requires a very precise control at the molecular level. Here, we demonstrate a new approach whereby uniform-sized supramolecular nanoparticles (SNPs) can be reliably generated using a digital microfluidic droplet generator (DMDG) chip. A microfluidic environment enabled precise control over the processing parameters and, therefore, high batch-to-batch reproducibility and robust production of SNPs with a very narrow size distribution could be realized. Digitally adjusting the mixing ratios of the building blocks on the DMDG chip allowed us to rapidly scan a variety of synthesis conditions without consuming significant amounts of reagents. Nearly uniform SNPs with sizes ranging from 35 to 350 nm were obtained and characterized by transmission electron microscopy and dynamic light scattering. In addition, we could fine-tune the surface chemistry of the SNPs by incorporating an additional building block functionalized with specific ligands for targeting cells. The sizes and surface properties of these SNPs correlated strongly with their cell uptake efficiencies. This study showed a feasible microfluidic-assisted SNP production and provided a great means for preparing size-controlled SNP with desired surface ligand coverage.

In this manuscript, we review the latest advancement of microfluidics in molecular imaging probe development. Due to increasing needs for medical imaging, high demand for many types of molecular imaging probes will have to be met by exploiting novel chemistry/radiochemistry and engineering technologies to improve the production and development of suitable probes. The microfluidic-based probe synthesis is currently attracting a great deal of interest because of their potential to deliver many advantages over conventional systems. Numerous chemical reactions have been successfully performed in micro-reactors and the results convincingly demonstrate with great benefits to aid synthetic procedures, such as purer products, higher yields, shorter reaction times compared to the corresponding batch/macroscale reactions, and more benign reaction conditions. Several ‘proof-of-principle’ examples of molecular imaging probe syntheses using microfluidics, along with basics of device architecture and operation, and their potential limitations are discussed here.

Biomolecules, including peptides, 1-9 proteins,