Successful delivery: how drug molecules behave within tiny carriers

Neutrons reveal molecular diffusion mechanisms inside drug-releasing hydrogels

Biologics: powerful therapies, difficult to deliver

The development of novel therapeutics is advancing at a remarkable pace. In recent years, so-called biologics - therapies based on large, complex molecules produced by living organisms, such as proteins or antibodies - have emerged and are increasingly used against a large variety of diseases, offering hope to many chronically ill patients.

The particularly versatile group of biologics comprises, amongst others, protein-based molecules. The long list of their advantages is overshadowed by their pronounced instability with respect to environmental conditions, such as the strong acidity of the stomach and being broken down by digestive enzymes. Administration via pills or tablets therefore often renders them dysfunctional.

Alternatives include delivery by injection, which comes with its own limitations: it often leads to a rapid increase in drug concentration in the bloodstream, an inconvenient side effect of this technique. These challenges therefore raise the quest for drug delivery systems that enable sustained and controlled release.

Hydrogels: a promising solution for delivering biologics

Many drug-releasing systems have been developed over the past years, mostly relying on different types of gels. On a molecular level, these arrange into tiny sieves, thereby allowing for continuous diffusion of the drug particles into the surroundings of the carrier.

Hydrogels are formed from liquids by adding larger molecules (the so-called gelators) which typically make up less than 1% of the total mass, but nevertheless transform the liquid solution into a jelly-like semisolid material. The geometrical model is that of a ‘mesh’-like network formed from these molecules. A very wide variety of gelators is being investigated regarding their possible use in pharmaceutical gels.

So far, many studies of drug release profiles have focused on the size ratio between the drug and the mesh. Interestingly, it has emerged that mesh size is likely not the only parameter governing drug release. In order to optimise release profiles, it is therefore crucial to understand, in as much detail as possible, the motions of drug molecules within the carriers and the molecular interactions that affect their diffusion within and out of the carrier.

Probing molecular motion with neutrons

The typical length and time scales of interest for such studies can be probed using various methods. One particularly precise technique is quasielastic neutron scattering (QENS), which provides detailed information on the motion of individual drug molecules, as well as their interactions with the solvent and the releasing carrier.

Using QENS, scientists from academia and the pharmaceutical industry, including AstraZeneca, investigated how drug molecules behave inside a hydrogel carrier. Using three well-known molecules of different sizes (ibuprofen, insulin and lysozyme), the team was able to deduce detailed insights into the molecules’ behaviour within a hydrogel carrier.

Surprisingly, all drug molecules studied share a common feature: on an extremely short time scale of a few picoseconds (one trillionth of a second), their motion slowed down by about 30% within the hydrogels. At these timescales, such a slow-down is unexpected.

One possible explanation of this observation is that the drug molecules indirectly interact with the hydrogel fibres (e.g., via electrostatic or hydrodynamic effects), which slows their motion. In the case of the larger drug molecules, the components of the carrier may also induce a so-called apparent crowding effect, pushing them closer together and thereby reducing their mobility.

From molecular motion to drug release: a complex picture

In additional experiments monitoring drug release on very long time scales of approximately 12 hours, the team observed no effect of the carrier’s mesh size on release rates in this system. This finding further indicates that various and intricate effects including the solvent, the solute and the carrier are at play in determining drug release profiles.

Towards better drug delivery systems

This study highlights the importance of molecular-level investigations for understanding the mechanisms of sustained drug release and demonstrates the unique capability of neutron scattering to directly probe molecular motion across the relevant time and length scales. These results show that molecular motion at very short time scales does not directly translate into drug release behaviour over longer time scales.

“The work addresses a very fundamental level of understanding and illustrates, in combination with previous studies, that the drug diffusion is very specific not only to the type of drug molecule, but also to the type of hydogel and gelator”, emphasises Riccardo Morbidini, whose PhD project focused on the study described here.

Future studies will help extend this understanding to a wider variety of drug delivery systems, ultimately guiding the design of more effective therapeutics.

Reference:
R. Morbidini, R.M. Edkins, J. Carrascosa-Tejedor, O. Czakkel, B.I. Hanafy, D.R. Kalaria, T. Seydel, K. Edkins. Comparing microscopic and macroscopic diffusion in drug delivery: A study of small drug and protein dynamics in a supramolecular peptide hydrogel. Journal of Colloid And Interface Science (2026). https://doi.org/10.1016/j.jcis.2025.139633

ILL Instrument: IN16B and IN15

ILL Contact Person: Tilo Seydel

Institutions involved in the research: AstraZeneca, University of Manchester, Unversity of Strathclyde