Utrecht University

Biological Solid-State NMR

Utrecht University

Drug Delivery

Many drugs need to enter the cell interior to be active. However, to their large size or high net charge, many drugs can not cross biological cell membranes by themselves. To get into the cell nevertheless, many drugs hence have to rely on supramolecular drug delivery systems. Such nano-scale drug delivery systems need to be smart and tunable materials, since many hurdles have to be overcome to get a drug into cell. Once in the cell interior smart drug carriers need to be sensitive to a stimulus that triggers the release of the drug. It is for example imaginable to design a drug vector that only releases its cargo once it feels the acidic environment of a tumor cell. Such smart drug vectors can be self-assembled from peptides, which feature an excellent biocompatibility and, in particular, are straightforward to tune and optimize by changing the amino acid sequence. However, to precisely steer and program the biophysical and pharmaceutical profile of peptide-based drug vectors, a precise knowledge of their supramolecular code is mandatory. Yet, peptide assemblies are often not amenable to most high-resolution methods and hence poorly understood at the molecular level. 


In collaboration with Enrico Mastrobattista (Utrecht University, Pharmacy Department), we have recently reported (Rad Malekshahi et al., JACS 2015) the local and global organization of the multi-megadalton SA2 peptide-based nanocarrier at unprecedented detail and at close-to physiological conditions. By integrating a multitude of experimental techniques (solid-state NMR, AFM, SLS, DLS, FT-IR, CD) with large- and multi-scale MD simulations, we could show that SA2 peptide nanocarriers are built of interdigitated antiparallel β-sheets, which bear little resemblance to phospholipid liposomes. Our high-resolution study provides a number of potential leads to improve and tune the biophysical properties of the nanocarrier and our approach may be of general utility to investigate peptide-based nanomaterials at high-resolution and at physiological conditions.