Characterization of Non-Specific Uptake and Retention Mechanisms of [177Lu]Lu-PSMA-617 in the Salivary Glands

Abstract

The radionuclide therapy [177Lu]Lu-PSMA-617 was recently FDA-approved for treatment of metastatic castration-resistant prostate cancer. Salivary gland toxicity is currently considered as the main dose-limiting side effect. However, its uptake and retention mechanisms in the salivary glands remain elusive. Therefore, our aim was to elucidate the uptake patterns of [177Lu]Lu-PSMA-617 in salivary gland tissue and cells by conducting cellular binding and autoradiography experiments. Briefly, A-253 and PC3-PIP cells, and mouse kidney and pig salivary gland tissue, were incubated with 5 nM [177Lu]Lu-PSMA-617 to characterize its binding. Additionally, [177Lu]Lu-PSMA-617 was co-incubated with monosodium glutamate, ionotropic or metabotropic glutamate receptor antagonists. Low, non-specific binding was observed in salivary gland cells and tissues. Monosodium glutamate was able to decrease [177Lu]Lu-PSMA-617 in PC3-PIP cells, mouse kidney and pig salivary gland tissue. Kynurenic acid (ionotropic antagonist) decreased the binding of [177Lu]Lu-PSMA-617 to 29.2 ± 20.6% and 63.4 ± 15.4%, respectively, with similar effects observed on tissues. (RS)-MCPG (metabotropic antagonist) was able to decrease the [177Lu]Lu-PSMA-617 binding on A-253 cells to 68.2 ± 16.8% and pig salivary gland tissue to 53.1 ± 36.8%. To conclude, we showed that the non-specific binding on [177Lu]Lu-PSMA-617 could be reduced by monosodium glutamate, kynurenic acid and (RS)-MCPG.

DNA-encoded chemical libraries enable the discovery of potent PSMA-ligands with substantially reduced affinity towards the GCPIII anti-target

“…According to alternative studies, salivary gland accumulation appears to be non-PSMA-related 48 or partly non-specific. 49 It is evident that the underlying mechanism is still under investigation, and additional work is necessary to advance in the field of PSMA radioligand therapeutics.…”

Human ABC and SLC Transporters: The Culprit Responsible for Unspecific PSMA-617 Uptake?

“…Since they are inherently radiosensitive, this uptake critically limits the scope of PSMA-targeted radioligands’ application. Realizing this, a substantial effort has been made to improve the related side-effects and to decrease undesired SG uptake, e.g., through local cooling [ 37 ], injecting botulinum toxin A into affected areas [ 38 ] or co-administering cold PSMA ligands [ 15 , 39 ] and glutamate receptor binders, such as monosodium glutamate [ 40 ] or Tris-POC-2-PMPA [ 41 ], to minimize kidney retention. However, none of these measures have led to a significant reduction in side-effects such as xerostomia, and studies hint at unspecific uptake mechanisms for the respective PSMA moieties.…”

Combining theranostic/particle therapy with immunotherapy for the treatment of GU malignancies

“…Prostate‐specific membrane antigen (PSMA) is a type II transmembrane glycoprotein with a large extracellular portion. Despite its name, PSMA is also expressed on other tissues including salivary glands, duodenal mucosa, RCC and colon carcinoma 71 , 72 albeit 100–1000 fold less than on prostate epithelium. 73 Its overexpression on prostate tumour tissue is positively correlated with Gleason score, metastatic status and hormone resistance.…”