scholarly journals The Future of PSMA-Targeted Radionuclide Therapy: An Overview of Recent Preclinical Research

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 560 ◽  
Author(s):  
Eline A.M. Ruigrok ◽  
Wytske M. van Weerden ◽  
Julie Nonnekens ◽  
Marion de Jong
Keyword(s):  
Radionuclide Therapy ◽  
Therapeutic Strategies ◽  
Prostate Specific Membrane Antigen ◽  
Targeted Radionuclide Therapy ◽  
Tumor Uptake ◽  
Research Projects ◽  
Major Focus ◽  
Preclinical Research ◽  
Specific Membrane ◽  
Focus Point

Prostate specific membrane antigen (PSMA) has become a major focus point in the research and development of prostate cancer (PCa) imaging and therapeutic strategies using radiolabeled tracers. PSMA has shown to be an excellent target for PCa theranostics because of its high expression on the membrane of PCa cells and the increase in expression during disease progression. Therefore, numerous PSMA-targeting tracers have been developed and (pre)clinically studied with promising results. However, many of these PSMA-targeting tracers show uptake in healthy organs such as the salivary glands, causing radiotoxicity. Furthermore, not all patients respond to PSMA-targeted radionuclide therapy (TRT). This created the necessity of additional preclinical research studies in which existing tracers are reevaluated and new tracers are developed in order to improve PSMA-TRT by protecting the (PSMA-expressing) healthy organs and improving tumor uptake. In this review we will give an overview of the recent preclinical research projects regarding PCa-TRT using PSMA-specific radiotracers, which will give an indication of where the PSMA-TRT research movement is going and what we can expect in future clinical trials.

scholarly journals Dosimetric Analysis of the Short-Ranged Particle Emitter 161Tb for Radionuclide Therapy of Metastatic Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2011
Author(s):  
Peter Bernhardt ◽  
Johanna Svensson ◽  
Jens Hemmingsson ◽  
Nicholas P. van der Meulen ◽  
Jan Rijn Zeevaart ◽  
...  
Keyword(s):  
Radionuclide Therapy ◽  
Formation Rate ◽  
Prostate Specific Membrane Antigen ◽  
Targeted Radionuclide Therapy ◽  
Absorbed Doses ◽  
Iodine 131 ◽  
Low Energy Electron ◽  
Dosimetric Analysis ◽  
Specific Membrane ◽  
Yttrium 90

The aim of this study was to analyze the required absorbed doses to detectable metastases (Dreq) when using radionuclides with prostate specific membrane antigen (PSMA)-targeting radioligands to achieve a high probability for metastatic control. The Monte Carlo based analysis was performed for the clinically-used radionuclides yttrium-90, iodine-131, lutetium-177, and actinium-225, and the newly-proposed low-energy electron emitter terbium-161. It was demonstrated that metastatic formation rate highly influenced the metastatic distribution. Lower values generated few large detectable metastases, as in the case with oligo metastases, while high values generated a distribution of multiple small detectable metastases, as observed in patients with diffused visualized metastases. With equal number of detectable metastases, the total metastatic volume burden was 4–6 times higher in the oligo metastatic scenario compared to the diffusely visualized scenario. The Dreq was around 30% higher for the situations with 20 detectable metastases compared to one detectable metastasis. The Dreq for iodine-131 and yttrium-90 was high (920–3300 Gy). The Dreq for lutetium-177 was between 560 and 780 Gy and considerably lower Dreq were obtained for actinium-225 and terbium-161, with 240–330 Gy and 210–280 Gy, respectively. In conclusion, the simulations demonstrated that terbium-161 has the potential for being a more effective targeted radionuclide therapy for metastases using PSMA ligands.

scholarly journals Spotlight on PSMA as a new theranostic biomarker for bladder cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria Maddalena Tumedei ◽  
Sara Ravaioli ◽  
Federica Matteucci ◽  
Monica Celli ◽  
Ugo De Giorgi ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Diagnostic Tests ◽  
Radionuclide Therapy ◽  
Tumor Type ◽  
Prostate Specific Membrane Antigen ◽  
Bladder Tissue ◽  
Tissue Samples ◽  
Specific Membrane ◽  
Psma Expression ◽  
Degree Of Extension

AbstractBladder cancer (BCa) patients are diagnosed by cytology and cystoscopy. However, these diagnostic tests bear some limitations. We sought for reliable biomarkers to better determine BCa extension. Prostate-specific membrane antigen (PSMA) appears to fulfill this requirement in prostate cancer but its role in BCa has not been established yet. We then analyzed 87 bladder tissue samples from 74 patients assessing PSMA expression by immunohistochemistry. The median PSMA expression, exclusively found in tumor neovasculature, in terms of H-score significantly differed between non-tumor samples and tumor samples (p = 0.00288) showing a higher neovasculature-related PSMA expression. No differences were observed in relation to tumor type, grade and stage. BCa neovasculature-related PSMA overexpression may be useful in defining the degree of extension of the neoplasm. In addition, testing PSMA expression by immunohistochemistry may hold theranostic implications both considering anti-angiogenesis agents and radio-labelled PSMA ligands for intracavitary radionuclide therapy. In our opinion, BCa neovasculature-related PSMA overexpression may be considered an apt target for anti-angiogenesis and radionuclide treatment in BCa, once the evaluation of tumor-retention time for the appropriateness of long half-life therapeutic PSMA ligands as radionuclide treatment will be performed.

scholarly journals A Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper‐64 with High Tumor Uptake and Retention

2019 ◽  
Vol 58 (42) ◽  
pp. 14991-14994 ◽  
Author(s):  
Nicholas A. Zia ◽  
Carleen Cullinane ◽  
Jessica K. Van Zuylekom ◽  
Kelly Waldeck ◽  
Lachlan E. McInnes ◽  
...  
Keyword(s):  
Prostate Specific Membrane Antigen ◽  
Tumor Uptake ◽  
High Tumor Uptake ◽  
Specific Membrane

scholarly journals A Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper‐64 with High Tumor Uptake and Retention

2019 ◽  
Vol 131 (42) ◽  
pp. 15133-15136
Author(s):  
Nicholas A. Zia ◽  
Carleen Cullinane ◽  
Jessica K. Van Zuylekom ◽  
Kelly Waldeck ◽  
Lachlan E. McInnes ◽  
...  
Keyword(s):  
Prostate Specific Membrane Antigen ◽  
Tumor Uptake ◽  
High Tumor Uptake ◽  
Specific Membrane

scholarly journals Synthesis and Evaluation of 99mTc-Tricabonyl Labeled Isonitrile Conjugates for Prostate-Specific Membrane Antigen (PSMA) Image

Inorganics ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 5 ◽  
Author(s):  
Nadeem Ahmed Lodhi ◽  
Ji Yong Park ◽  
Kyuwan Kim ◽  
Mi Kyung Hong ◽  
Young Joo Kim ◽  
...  
Keyword(s):  
Single Photon ◽  
Ex Vivo ◽  
Photon Emission ◽  
Whole Body ◽  
Emission Computed Tomography ◽  
Prostate Specific Membrane Antigen ◽  
Post Injection ◽  
Tumor Uptake ◽  
Specific Membrane

Prostate-specific membrane antigen (PSMA) is a biomarker expressed on the surface of prostate cancer (PCa). In an effort to improve the detection and treatment of PCa, small urea-based PSMA inhibitors have been studied extensively. In the present study, we aimed to develop 99mTc-tricabonyl labeled urea-based PSMA conjugates containing isonitrile (CN-R)-coordinating ligands ([99mTc]Tc-15 and [99mTc]Tc-16). Both the PSMA conjugates were obtained at high radiochemical efficiency (≥98.5%). High in vitro binding affinity was observed for [99mTc]Tc-15 and [99mTc]Tc-16 (Kd = 5.5 and 0.2 nM, respectively) in PSMA-expressing 22Rv1 cells. Tumor xenografts were conducted using 22Rv1 cells and rapid accumulation of [99mTc]Tc-16 (1.87 ± 0.11% ID/g) was observed at 1 h post-injection, which subsequently increased to (2.83 ± 0.26% ID/g) at 4 h post-injection. However, [99mTc]Tc-15 showed moderate tumor uptake (1.48 ± 0.18% ID/g), which decreased at 4 h post-injection (0.81 ± 0.09% ID/g). [99mTc]Tc-16 was excreted from non-targeted tissues with high tumor-to-blood (17:1) and tumor-to-muscle ratio (41:1) at 4 h post-injection at approximately 4 times higher levels than [99mTc]Tc-15. Uptakes of [99mTc]Tc-15 and [99mTc]Tc-16 to PSMA-expressing tumor and tissues were significantly blocked by co-injection of 2-(Phosphonomethyl)-pentandioic acid (2-PMPA), suggesting that their uptakes are mediated by PSMA specifically. Whole-body single photon emission computed tomography imaging of [99mTc]Tc-16 verified the ex vivo biodistribution results and demonstrated clear visualization of tumors and tissues expressing PSMA compared to [99mTc]Tc-15. In conclusion, using [99mTc]Tc-16 rather than [99mTc]Tc-15 may be the preferable because of its relatively high tumor uptake and retention.

scholarly journals JHU-2545 Selectively Shields Salivary Glands and Kidneys during PSMA-Targeted Radiotherapy

2018 ◽  
Author(s):  
Michael T. Nedelcovych ◽  
Ranjeet P. Dash ◽  
Ying Wu ◽  
Eun Yong Choi ◽  
Rena S. Lapidus ◽  
...  
Keyword(s):  
Salivary Glands ◽  
Prostate Specific Membrane Antigen ◽  
Tumor Uptake ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Psma Pet ◽  
Promising Treatment ◽  
Specific Membrane ◽  
Psma Inhibitor ◽  
Efficacy Profile

ABSTRACTPURPOSEProstate-specific membrane antigen (PSMA) radiotherapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC) with several beta or alpha particle-emitting radionuclide-conjugated small molecules showing efficacy in late stage patients. However, PSMA is also expressed in kidneys and salivary glands where specific uptake causes dose-limiting xerostomia and potential for nephrotoxicity. The PSMA inhibitor 2- (phosphonomethyl)pentanedioic acid (2-PMPA) can prevent kidney uptake in mice, but also blocks tumor uptake, precluding its clinical utility. Selective delivery of 2-PMPA to non-malignant tissues could improve the therapeutic window of PSMA radiotherapy.EXPERIMENTAL DESIGNA tri-alkoxycarbonyloxy alkyl (TrisPOC) prodrug of 2-PMPA, JHU-2545, was synthesized to enhance 2-PMPA delivery to non-malignant tissues. Preclinical pharmacokinetic and imaging experiments were conducted prior to assessment in 3 mCRPC patients receiving PSMA PET and radiotherapy.RESULTSJHU-2545 resulted in 3- and 53-fold greater exposure of 2-PMPA in rodent salivary glands (18.0 ± 0.97 h*nmol/g) and kidneys (359 ± 4.16 h*nmol/g) versus prostate tumor xenograft (6.79 ± 0.19 h*nmol/g). JHU-2545 also blocked rodent kidneys and salivary glands uptake of the PSMA PET tracers 68Ga-PSMA-11 and 18F-DCFPyL by up to 85% without effect on tumor. In a mCRPC patient, JHU-2545 treatment prior to 68Ga-PSMA-617 administration reduced kidney SUVmax by 76% without effect on metastatic lesions. When administered prior to injection of the beta emitter 177Lu-PSMA-617, JHU-2545 shielded both the salivary glands (72% Gy reduction) and kidneys (45% Gy reduction) without effect on metastases’ dose.CONCLUSIONSJHU-2545 pre-treatment raises the cumulative dose limit and improves the safety and efficacy profile of PSMA radiotherapy.STATEMENT OF TRANSLATIONAL RELEVANCEProstate Specific Membrane Antigen (PSMA) molecular radiotherapy has emerged as a promising treatment for metastatic castration-resistant prostate cancer (mCRPC), but endogenous expression of PSMA in kidneys and salivary glands causes uptake into these organs resulting in dose-limiting toxicities. We describe the discovery of JHU-2545, a PSMA inhibitor prodrug that selectively blocks kidney and salivary gland uptake of PSMA theranostics without altering tumor uptake in both preclinical models and in mCRPC patients. Pretreatment of JHU-2545 thereby improves the safety and efficacy profile of the multiple PSMA radiotherapies in development.

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