Nanoparticle size monitoring is a central requirement for the development of targeted drug delivery systems, where therapeutic molecules must be transported directly to specific organs or cell types. To achieve this, drugs are frequently packaged inside biocompatible particles, typically composed of fat molecules. The efficiency of this process depends heavily on specific characteristics of the particles, including their internal and external structure as well as the homogeneity of the size distribution within a batch. International quality standards dictate that particle sizes should not vary by more than 30% to be considered safe for application, making the monitoring of size distribution a fundamental step throughout the manufacturing process.
To monitor nanoparticle size, manufacturers commonly rely on a technique called asymmetric-flow field-flow fractionation (AF4). This method separates particles in solution based on their size, with smaller particles moving faster than larger ones. AF4 is typically coupled with methods such as ultraviolet light absorbance or light scattering to measure the amount of particles in each size group. While researchers have previously combined AF4 with small-angle X-ray scattering (SAXS) to investigate magnetic particles, it had never before been combined with neutron-based techniques such as small-angle neutron scattering (SANS).
An international team of scientists from the Leibniz Institute for Polymer Research (Dresden), Stellenbosch University, Max IV, Lund University, and the Institut Laue-Langevin (ILL) recently overcame this challenge. The researchers successfully carried out the world’s first AF4-SANS experiment on the ILL’s D11 instrument. Using nanoparticles designed for drug delivery, the team analyzed them with an AF4 setup coupled simultaneously to Multi-Angle Light scattering and SANS. This powerful combination allowed the researchers to determine not only the dimensions of the particles but also to test the homogeneity of their internal structure and the potential location of drug molecules with great precision.
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According to Prof. Dr. Albena Lederer from the Leibniz Institute of Polymer Research Dresden, this first successful AF4-SANS experiment demonstrates how powerful such combined analytical platforms can be for biomedical research. She noted that her team has pioneered the coupling of advanced field-flow fractionation techniques with scattering methods, including AF4-SANS and thermal FFF-SAXS. These multidetection approaches allow researchers to extract complementary, orthogonal information from very small amounts of sample, which is particularly valuable in biomedical research.
As targeted treatments continue to develop, precise characterization of drug delivery nanoparticles is becoming increasingly important. The experimental framework established in the study described here is an important contribution to tackling this challenge, and opens new possibilities for the use of neutron scattering in biomedical research. The study details the structural profiling of lipid nanoparticles at sub-10 nm resolution via AF4 coupled online to SAXS and SANS.
