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Binding site exchange kinetics revealed through efficient spin-spin dephasing of hyperpolarized ¹²⁹Xe.

ABSTRACT: Spin exchange between different chemical environments is an important observable for characterizing chemical exchange kinetics in various contexts, including protein folding, chelation chemistry, and host-guest interactions. Such spins experience effective spin-spin relaxation rate, R _2,eff, that typically shows a dispersive behavior which requires detailed analysis. Here, we describe a class of highly simplified R _2,eff behavior by relying on hyperpolarized ¹²⁹Xe as a freely exchanging ligand reporter. It provides large chemical shift separations that yield reduced expressions of both the Swift-Connick and the Carver-Richards treatment of exchange-induced relaxation. Despite observing a diamagnetic system, R _2,eff is dominated by large Larmor frequency jumps and thus allows detection of otherwise inaccessible analyte concentrations with a single spin echo train (only 0.01% of the overall hyperpolarized spins need to be transiently bound to the molecule). The two Xe hosts cryptophane-A monoacid (CrA-ma) and cucurbit[6]uril (CB6) represent two exemplary families of container molecules (the latter one also serving as drug delivery vehicles) that act as highly efficient phase shifters for which we observed unprecedented exchange-induced relaxivity r ₂ (up to 866 s^-1 mM^-1). By including methods of spatial encoding, multiple data points can be collected simultaneously to isolate the exchange contribution and determine the effective exchange rate in partially occupied binding sites with a single delivery of hyperpolarized nuclei. The relaxivity is directly related to the guest turnover in these systems and temperature-dependent measurements yield an activation energy of E _A = 41 kJ mol^-1 for Xe@CrA-ma from simple relaxometry analysis. The concept is transferable to many applications where Xe is known to exhibit large chemical shifts.

SUBMITTER: Kunth M

PROVIDER: S-EPMC8178811 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeTo present a methodology to use pulmonary gas exchange maps to guide functional avoidance treatment planning in radiation therapy (RT) and evaluate its efficacy compared with ventilation-guided treatment planning.Methods and materialsBefore receiving conventional RT for non-small cell lung cancer, 11 patients underwent hyperpolarized 129Xe gas exchange magnetic resonance imaging to map the distribution of xenon in its gas phase (ventilation) and transiently bound to red blood cells in the alveolar capillaries (gas exchange). Both ventilation and gas exchange maps were independently used to guide development of new functional avoidance treatment plans for every patient, while adhering to institutional dose-volume constraints for normal tissues and target coverage. Furthermore, dose-volume histogram (DVH)-based reoptimizations of the clinical plan, with reductions in mean lung dose (MLD) equal to the functional avoidance plans, were created to serve as the control group. To evaluate each plan (regardless of type), gas exchange maps, representing end-to-end lung function, were used to calculate gas exchange-weighted MLD (fMLD), gas exchange-weighted volume receiving ≥20 Gy (fV20), and mean dose in the highest gas exchanging 33% and 50% volumes of lung (MLD-f33% and MLD-f50%). Using each clinically approved plan as a baseline, the reductions in functional metrics were compared for ventilation-optimization, gas exchange optimization, and DVH-based reoptimization. Statistical significance was determined using the Freidman test, with subsequent subdivision when indicated by P values less than .10 and post hoc testing with Wilcoxon signed rank tests to determine significant differences (P < .05). Toxicity modeling was performed using an established function-based model to estimate clinical significance of the results.ResultsCompared with DVH-based reoptimization of the clinically approved plans, gas exchange-guided functional avoidance planning more effectively reduced the gas exchange-weighted metrics fMLD (average ± SD, -78 ± 79 cGy, compared with -45 ± 34 cGy; P = .03), MLD-f33% (-135 ± 136 cGy, compared with -52 ± 47 cGy; P = .004), and MLD-f50% (-96 ± 95 cGy, compared with -47 ± 40 cGy; P = .01). Comparing the 2 functional planning types, Gas Exchange-Guided planning more effectively reduced MLD-f33% compared with ventilation-guided planning (-64 ± 95; P = .009). For some patients, Gas Exchange-Guided functional avoidance plans demonstrated clinically significant reductions in model-predicted toxicity, more so than the accompanying ventilation-guided plans and DVH-based reoptimizations.ConclusionGas Exchange-Guided planning effectively reduced dose to high gas exchanging regions of lung while maintaining clinically acceptable plan quality. In many patients, ventilation-guided planning incidentally reduced dose to higher gas exchange regions, to a lesser extent. This methodology enables future prospective trials to examine patient outcomes.

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Binding site exchange kinetics revealed through efficient spin-spin dephasing of hyperpolarized ¹²⁹Xe.

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Binding site exchange kinetics revealed through efficient spin-spin dephasing of hyperpolarized 129Xe.

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OmicsDI is part of the ELIXIR infrastructure

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Binding site exchange kinetics revealed through efficient spin-spin dephasing of hyperpolarized ¹²⁹Xe.