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Monosodium glutamate reduces 68Ga-PSMA-11 uptake in salivary glands and kidneys in preclinical prostate cancer model

Kevin Yang Kevin Yang ⎜ Sep 21, 2018 ⎜ Industry

INTRODUCTION: Prostate-specific membrane antigen (PSMA) is an excellent prostate cancer target for theranostic applications. Many imaging agents showing high sensitivity/specificity for PSMA-expressing tissues have been developed. Some have been labeled with therapeutic radionuclides (i.e. 177Lu, 225Ac) and have had success in treating castration-resistant metastatic prostate cancer. The activity administered to patients is limited by toxicity to normal organs; high uptake is observed in lacrimal glands, parotids, submandibular glands, and renal cortex. The potential side effects of higher doses include hematotoxicity, xerostomia, and renal dysfunction. In particular, xerostomia with alpha-emitters is so severe that patients have discontinued treatment. A means of decreasing this toxicity without affecting tumor uptake would allow administration of greater activity with presumably greater tumoricidal effect.
Different pharmaceuticals including 2-(phosphonomethyl)pentanedioic acid (PMPA), a PSMA inhibitor, have been explored for nephroprotection. PMPA displaced renal activity of a PSMA radiotherapeutic in cancer models, but this was generally accompanied by a reduction in tumor uptake. Mannitol infusion reduced renal uptake of 68Ga-PSMA-11, but its effect on tumor uptake requires further investigations. Botulinum toxin was administered in the parotid gland of a patient and significantly decreased PSMA-ligand uptake. While this procedure is promising, it is invasive, costly, and may affect salivary gland function for weeks. In this study, we investigated monosodium glutamate (MSG) for reducing uptake of 68Ga-PSMA-11 in salivary glands and kidneys, in LNCaP tumor-bearing mice. MSG is a well-studied food additive and can stimulate salivary flow. While PSMA is expressed in salivary glands and kidneys, part of PSMA-ligand uptake in salivary glands may be due to off-target binding, as uptake is not observed in human studies with the radiolabeled J591 monoclonal antibody. As many PSMA ligands integrate glutamate for binding to PSMA, we hypothesized MSG could reduce non-specific accumulation in non-cancerous tissues.

ABSTRACT: We evaluated the ability of monosodium glutamate (MSG) to reduce salivary and kidney uptake
of a prostate-specific membrane antigen (PSMA) radioligand without affecting tumor uptake.

CONCLUSION: MSG decreased salivary and kidney uptake of 68Ga-PSMA-11 in a dose-dependent manner, while tumor uptake was unaffected.

Etienne Rousseau, Joseph Lau, Hsiou-Ting Kuo1, Zhengxing Zhang, Helen Merkens1, Navjit Hundal-Jabal, Nadine Colpo, Kuo-Shyan Lin, François Bénard

*Contributed equally to this work: Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada; Department of Radiology, University of British Columbia, Vancouver, BC, Canada

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