Nanoparticles have shown promise in several biomedical applications, including drug delivery and medical imaging; however, quantitative prediction of nanoparticle formation processes that scale from laboratory to commercial production has been lacking. Flash NanoPrecipitation (FNP) is a scalable technique to form highly loaded, block copolymer protected nanoparticles. Here, the FNP process is shown to strictly obey diffusion-limited aggregation assembly kinetics, and the parameters that control the nanoparticle size and the polymer brush density on the nanoparticle surface are shown. The particle size, ranging from 40 to 200 nm, is insensitive to the molecular weight and chemical composition of the hydrophobic encapsulated material, which is shown to be a consequence of the diffusion-limited growth kinetics. In a simple model derived from these kinetics, a single constant describes the 46 unique nanoparticle formulations produced here. The polymer brush densities on the nanoparticle surface are weakly dependent on the process parameters and are among the densest reported in the literature. Though modest differences in brush densities are observed, there is no measurable difference in the amount of protein adsorbed within this range. This work highlights the material-independent and universal nature of the Flash NanoPrecipitation process, allowing for the rapid translation of formulations to different stabilizing polymers and therapeutic loads.

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The formulation of a therapeutic compound into nanoparticles (NPs) can impart unique properties. For poorly water-soluble drugs, NP formulations can improve bioavailability and modify drug distribution within the body. For hydrophilic drugs like peptides or proteins, encapsulation within NPs can also provide protection from natural clearance mechanisms. There are few techniques for the production of polymeric NPs that are scalable. Flash NanoPrecipitation (FNP) is a process that uses engineered mixing geometries to produce NPs with narrow size distributions and tunable sizes between 30 and 400 nm. This protocol provides instructions on the laboratory-scale production of core-shell polymeric nanoparticles of a target size using FNP. The protocol can be implemented to encapsulate either hydrophilic or hydrophobic compounds with only minor modifications. The technique can be readily employed in the laboratory at milligram scale to screen formulations. Lead hits can directly be scaled up to gram-and kilogram-scale. As a continuous process, scale-up involves longer mixing process run time rather than translation to new process vessels. NPs produced by FNP are highly loaded with therapeutic, feature a dense stabilizing polymer brush, and have a size reproducibility of ± 6%. Video Link The video component of this article can be found at https://www.jove.com/video/58757/ 13. Nucleation occurs uniformly in the mixing chamber and particle growth proceeds until halted by the assembly of the BCP onto the surface 9,14. The mixed stream containing stable particles may then be diluted with additional antisolvent to suppress Ostwald ripening of the particles 15,16,17 .

MRI and NIR-active, multi-modal Composite NanoCarriers (CNCs) are prepared using a simple, one-step process, Flash NanoPrecipitation (FNP). The FNP process allows for the independent control of the hydrodynamic diameter, co-core excipient and NIR dye loading, and iron oxide-based nanocrystal (IONC) content of the CNCs. In the controlled precipitation process, 10 nm IONCs are encapsulated into poly(ethylene glycol) stabilized CNCs to make biocompatible T2 contrast agents. By adjusting the formulation, CNC size is tuned between 80 and 360 nm. Holding the CNC size constant at an intensity weighted average diameter of 99 ± 3 nm (PDI width 28 nm), the particle relaxivity varies linearly with encapsulated IONC content ranging from 66 to 533 mM-1s-1 for CNCs formulated with 4 to 16 wt% IONC. To demonstrate the use of CNCs as in vivo MRI contrast agents, CNCs are surface functionalized with liver targeting hydroxyl groups. The CNCs enable the detection of 0.8 mm3 non-small cell lung cancer metastases in mice livers via MRI. Incorporating the hydrophobic, NIR dye PZn3 into CNCs enables complementary visualization with long-wavelength fluorescence at 800 nm. In vivo imaging demonstrates the ability of CNCs to act both as MRI and fluorescent imaging agents.

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