Nuclear spin hyperpolarization of pyruvate enables longitudinal monitoring of treatment response in intestinal tumor organoids

Abstract

Purpose

Colorectal cancer, a leading cause of death in the Western world, is increasingly affecting younger populations. The Warburg effect, characterized by enhanced lactate production, is a hallmark of this cancer type. Although ¹⁸F-FDG PET-CT is commonly used for diagnosis, MRI offers higher spatial and chemical resolution without the drawbacks of radiation. However, MRI's low sensitivity has been a barrier to real-time metabolic imaging, and hence its implementation in clinical practice. Hyperpolarization has significantly boosted NMR sensitivity, enabling detailed metabolic studies in vivo.

Methods

This study uses hyperpolarized [1-¹³C]pyruvate with dissolution dynamic nuclear polarization to noninvasively monitor metabolic changes in intestinal organoids from a genetically defined mouse model of spontaneous carcinogenesis (Rnaseh2b/Xbp1^ΔIEC) with a previously established targeted therapeutic intervention (mTOR inhibition by rapamycin).

Results

Hyperpolarized NMR revealed a 6.6-fold reduction (p < 0.05) in lactate production in rapamycin-treated organoids, indicating suppressed metabolic activity. This method also detected alanine and bicarbonate metabolism, highlighting its sensitivity. Unlike traditional methods that destroy cellular integrity, hyperpolarization enabled repetitive, noninvasive metabolic assessments.

Conclusion

Hyperpolarized [1-13C]pyruvate combined with NMR enables noninvasive, longitudinal monitoring of tumor metabolism in intestinal organoids while preserving cell viability and recultivation potential, bridging preclinical and clinical applications and affirming the method's potential for targeted metabolic imaging as a novel diagnostic and treatment control approach in cancer medicine.