Abstract
PurposeVarious radiolabeled prostate-specific membrane antigen (PSMA)–targeting tracers are clinically applied for prostate cancer (PCa) imaging and targeted radionuclide therapy. The PSMA binding affinities, biodistribution, and DNA-damaging capacities of these radiotracers have not yet been compared in detail. A major concern of PSMA-targeting radiotracers is the toxicity in other PSMA-expressing organs, such as the salivary glands, thus demanding careful evaluation of the most optimal and safest radiotracer. In this extensive preclinical study, we evaluated the clinically applied PSMA-targeting small molecule inhibitors DOTA-PSMA-617 (PSMA-617) and DOTAGA-PSMA-I&T (PSMA-I&T) and the PSMA nanobody DOTA-JVZ-007 (JVZ-007) using PSMA-expressing cell lines, a unique set of PCa patient-derived xenografts (PDX) and healthy human tissues.Methods and resultsIn vitro displacement studies on PSMA-expressing cells and cryosections of a PSMA-positive PDX revealed high and specific binding affinity for all three tracers labeled with lutetium-177 with IC50 values in the nanomolar range. Interestingly, [177Lu]Lu-JVZ-007 could not be displaced by PSMA-617 or PSMA-I&T, suggesting that this tracer targets an alternative binding site. Autoradiography assays on cryosections of human salivary and renal tissues revealed [177Lu]Lu-PSMA-617 to have the lowest binding to these healthy organs compared with [177Lu]Lu-PSMA-I&T. In vivo biodistribution assays confirmed the in vitro results with comparable tumor uptake of [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T at all timepoints, resulting in induction of similar levels of DNA double-strand breaks in the tumors. However, [177Lu]Lu-PSMA-I&T demonstrated approximately 40× higher renal uptake at 4 and 8 h post injection resulting in an unfavorable tumor-to-kidney ratio.Conclusion[177Lu]Lu-PSMA-617 has the most favorable biodistribution in mice as well as more favorable binding characteristics in vitro in PSMA-positive cells and human kidney and salivary gland specimens compared with [177Lu]Lu-PSMA-I&T and [177Lu]Lu-JVZ-007. Based on our preclinical evaluation, [177Lu]Lu-PSMA-617 is the best performing tracer to be taken further into clinical evaluation for PSMA-targeted radiotherapeutic development although with careful evaluation of the tracer binding to PSMA-expressing organs.
Highlights
Prostate cancer (PCa) is a major public health problem
Prostate-specific membrane antigen (PSMA)-positron emitting tomography scans have shown PCametastases that were untraceable with conventional methods which logically led to the development of PSMAspecific tracers suitable for targeted radionuclide therapy (TRT)
In vitro uptake and autoradiography studies were performed to assess the binding of lutetium-177-labeled PSMA-617, PSMA-I&T, and JVZ-007
Summary
Prostate cancer (PCa) is a major public health problem. In 2018, prostate cancer (PCa) was diagnosed approximately 450,000 times in Europe and had caused an estimated 107,000 deaths [1, 2]. High PSMA expression levels are found in hormone-resistant tumors and metastases indicating that PSMA expression is correlated to disease progression [4,5,6]. This makes PSMA an ideal target for theranostics. The expression of PSMA in healthy organs, such as the small intestine, central nervous system, proximal renal tubules, prostate, and especially the salivary and lacrimal glands, can lead to serious side effects, which may strongly affect the quality of life of the treated patients [10,11,12]. Salivary gland toxicity has been reported as dose-limiting, causing a significant decrease in the quality of life of PSMA-TRT-treated patients [13]
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