Combining Solid‐State NMR with Structural and Biophysical Techniques to Design Challenging Protein‐Drug Conjugates

2023-06-06T13:08:21+00:00June 6th, 2023|Categories: Publications|

Several protein-drug conjugates are currently being used in cancer therapy. These conjugates rely on cytotoxic organic compounds that are covalently attached to the carrier proteins or that interact with them via non-covalent interactions. Human transthyretin (TTR), a physiological protein, has already been identified as a possible carrier protein for the delivery of cytotoxic drugs. Here we show the structure-guided development of a new stable cytotoxic molecule based on a known strong binder of TTR and a well-established anticancer drug. This example is used to demonstrate the importance of the integration of multiple biophysical and structural techniques, encompassing MST, X-ray crystallography and NMR. In particular, we show that solid-state NMR has the ability to reveal effects caused by ligand binding which are more easily relatable to structural and dynamical alterations that impact the stability of macromolecular complexes.

Published in: "Angewandte Chemie International Edition".

The Formation of NaYF4 : Er3+, Yb3+ Nanocrystals Studied by In Situ X‐ray Scattering: Phase Transition and Size Focusing

2023-06-06T13:08:17+00:00June 6th, 2023|Categories: Publications|

The synthesis of β-NaYF4 nanocrystals from α-NaYF4 precursor particles was followed using in situ X-ray scattering. The experiments reveal the kinetics of particle growth (small-angle scattering) and phase transformation (wide-angle scattering). A surprising particle size evolution is observed, where α-phase particles develop a bimodal size distribution before they transform into β-phase. Abstract β-NaYF4 nanocrystals are a popular class of optical materials. They can be doped with optically active lanthanide ions and shaped into core-multi-shell geometries with controlled dopant distributions. Here, we follow the synthesis of β-NaYF4 nanocrystals from α-NaYF4 precursor particles using in situ small-angle and wide-angle X-ray scattering and ex situ electron microscopy. We observe an evolution from a unimodal particle size distribution to bimodal, and eventually back to unimodal. The final size distribution is narrower in absolute numbers than the initial distribution. These peculiar growth dynamics happen in large part before the α-to-β phase transformation. We propose that the splitting of the size distribution is caused by variations in the reactivity of α-NaYF4 precursor particles, potentially due to inter-particle differences in stoichiometry. Rate equation modeling confirms that a continuous distribution of reactivities can result in the observed particle growth dynamics.

Published in: "