Andrea Bertarello

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H-1 Detected Relayed Dynamic Nuclear Polarization

Pierrick Berruyer, Andrea Bertarello, David Lyndon Emsley

Recently, it has been shown that methods based on the dynamics of 1 H nuclear hyperpolarization in magic angle spinning (MAS) NMR experiments can be used to determine mesoscale structures in complex materials. However, these methods suffer from low sensitivity, especially since they have so far only been feasible with indirect detection of 1 H polarization through dilute heteronuclei such as 13C or 29Si. Here we combine relayed-DNP (R-DNP) with fast MAS using 0.7 mm diameter rotors at 21.2 T. Fast MAS enables direct 1 H detection to follow hyperpolarization dynamics, leading to an acceleration in experiment times by a factor 16. Furthermore, we show that by varying the MAS rate, and consequently modulating the 1 H spin diffusion rate, we can record a series of independent R-DNP curves that can be analyzed jointly to provide an accurate determination of domain sizes. This is confirmed here with measurements on microcrystalline L-histidinemiddotHClmiddotH2O at MAS frequencies up to 60 kHz, where we determine a Weibull distribution of particle sizes centered on a radius of 440 +/- 20 nm with an order parameter of k = 2.2.

AMER CHEMICAL SOC2022

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In-Cell Quantification of Drugs by Magic-Angle Spinning Dynamic Nuclear Polarization NMR

Pierrick Berruyer, Andrea Bertarello, David Lyndon Emsley

The determination of intracellular drug concentrations can provide a better understanding of the drug function and efficacy. Ideally, this should be performed nondestructively, with no modification of either the drug or the target, and with the capability to detect low amounts of the molecule of interest, in many cases in the mu M to nM range (pmol to fmol per million cells). Unfortunately, it is currently challenging to have an experimental technique that provides direct quantitative measurements of intracellular drug concentrations that simultaneously satisfies these requirements. Here, we show that magic-angle spinning dynamic nuclear polarization (MAS DNP) can be used to fulfill these requirements. We apply a quantitative N-15 MAS DNP approach in combination with N-15 labeling to quantify the intracellular amount of the drug [N-15]CHIR-98014, an activator of the Wingless and hit-1 signaling pathway, determining intracellular drug amounts in the range of tens to hundreds of picomoles per million cells. This is, to our knowledge, the first time that MAS DNP has been used to successfully estimate intracellular drug amounts.

AMER CHEMICAL SOC2022

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Dynamic nuclear polarization (DNP) allows to dramatically enhance the sensitivity of magic angle spinning nuclear magnetic resonance (MAS NMR). DNP experiments usually rely on the detection of low-γ nuclei hyperpolarized from 1H with the use of cross polarization (CP), which assures more efficient signal enhancement. However, CP is usually not quantitative. Here we determine the quantification performance of three different approaches used in MAS NMR, (conventional CP, variable contact time CP, and multiple-contact CP) under DNP conditions, and we show that absolute quantification in MAS DNP NMR is possible, with errors below 10%.

2021

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