Comparing microscopic and macroscopic diffusion in drug delivery: A study of small drug and protein dynamics in a supramolecular peptide hydrogel

Over recent decades, medicine development has increasingly turned to biologics for their higher efficacy and reduced side effects compared to small molecule drugs. However, the necessity for parenteral administration of these labile compounds poses significant challenges, requiring frequent injections and highlighting the need for sustained release systems to improve patient adherence. Drug delivery vehicles are currently regarded as acting as a diffusion barrier and, particularly supramolecular gels, offer a promising solution to this challenge due to their tunable properties and biocompatibility. This study focuses on diffusion within a peptide supramolecular hydrogel based on the ultra-short Fmoc-diphenylalanine (FmocFF) moiety, exploring its potential as a drug delivery carrier. By examining dynamics at different timescales, we aim to decouple steric and non-steric effects of the fibre network on solute diffusion. Using Quasi-Elastic Neutron Scattering (QENS), we investigate solvent and gel network dynamics, and the picosecond self-diffusion behavior of various drugs to focus solely on hydrodynamic interactions. We further assess bulk diffusion over 12 hours by in vitro release studies using the Subcutaneous Injection Site Simulator (SCISSOR), mimicking possible interactions occurring during drug release. Our results demonstrate that from molecular-level to bulk diffusion, hydrodynamic interactions are mitigated and masked by factors such as steric confinement and surface erosion. This work highlights the necessity for more systematic data to bridge short-time to long-time scale bulk diffusion mechanisms to rationally tune drug release and ultimately design better drug delivery vehicles.