PSMA-D4 Radioligand for Targeted Therapy of Prostate Cancer: Synthesis, Characteristics and Preliminary Assessment of Biological Properties

Garnuszek, Piotr; Karczmarczyk, Urszula; Maurin, Michał; Sikora, A; Zaborniak, Jolanta; Pijarowska-Kruszyna, Justyna; Jaroń, Antoni; Wyczółkowska, Monika; Wojdowska, Wioletta; Pawlak, Dariusz; Lipiński, Piotr F. J.; Mikołajczak, Renata

doi:10.37247/pamol2ed.2.2021.23

Cited by 3 publications

(2 citation statements)

References 30 publications

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“…Initially, we have attempted the synthesis of TPP-DOTAGA-PSMA based on a solid-phase approach by reacting compound 6 with a Boc-protected PSMA-617 precursor supported in a Wang resin obtained commercially from Pepmic, using procedures similar to those reported by other authors for the synthesis of PSMA-617 and related compounds. 27,39 However, in our hands, this solid-phase coupling reaction did not work in all the tested conditions (e.g., reagent concentrations, reaction time, or temperature). After reacting the resin with compound 6, its treatment with an appropriate cleavage cocktail always afforded the intact PSMA-617 precursor (data not shown).…”

Section: Synthesis Of Tpp-containing Chelatorsmentioning

confidence: 60%

“…Nevertheless, the metal complexation and the presence of the Gly-Gly-Gly linker showed some influence on the binding affinity of the compounds. To better understand these effects, in silico approaches based on molecular docking and molecular dynamics simulations are a good option, as previously reported by other authors for different families of PSMA inhibitors, 39,50,51 taking advantage of the availability of the X-ray structure of the PSMA protein. 52 However, these in silico studies were outside the scope of the present work.…”

Section: Discussionmentioning

confidence: 99%

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Synthesis and Preclinical Evaluation of PSMA-Targeted ¹¹¹In-Radioconjugates Containing a Mitochondria-Tropic Triphenylphosphonium Carrier

Santos,

Braz,

Raposinho

et al. 2023

Mol. Pharmaceutics

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Nuclear DNA is the canonical target for biological damage induced by Auger electrons (AE) in the context of targeted radionuclide therapy (TRT) of cancer, but other subcellular components might also be relevant for this purpose, such as the energized mitochondria of tumor cells. Having this in mind, we have synthesized novel DOTA-based chelators carrying a prostate-specific membrane antigen (PSMA) inhibitor and a triphenyl phosphonium (TPP) group that were used to obtain dual-targeted 111 In-radioconjugates ([ 111 In]In-TPP-DOTAGA-PSMA and [ 111 In]In-TPP-DOTAGA-G 3 -PSMA), aiming to promote a selective uptake of an AE-emitter radiometal ( 111 In) by PSMA+ prostate cancer (PCa) cells and an enhanced accumulation in the mitochondria. These dual-targeted 111 In-radiocomplexes are highly stable under physiological conditions and in cell culture media. The complexes showed relatively similar binding affinities toward the PSMA compared to the reference tracer [ 111 In]In-PSMA-617, in line with their high cellular uptake and internalization in PSMA+ PCa cells. The complexes compromised cell survival in a dose-dependent manner and in the case of [ 111 In]In-TPP-DOTAGA-G 3 -PSMA to a higher extent than observed for the single-targeted congener [ 111 In]In-PSMA-617. μSPECT imaging studies in PSMA+ PCa xenografts showed that the TPP pharmacophore did not interfere with the excellent in vivo tumor uptake of the "golden standard" [ 111 In]In-PSMA-617, although it led to a higher kidney retention. Such kidney retention does not necessarily compromise their usefulness as radiotherapeutics due to the short tissue range of the Auger/conversion electrons emitted by 111 In. Overall, our results provide valuable insights into the potential use of mitochondrial targeting by PSMA-based radiocomplexes for efficient use of AE-emitting radionuclides in TRT, giving impetus to extend the studies to other AE-emitting trivalent radiometals (e.g., 161 Tb or 165 Er) and to further optimize the designed dual-targeting constructs.

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Section: Synthesis Of Tpp-containing Chelatorsmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Synthesis and Preclinical Evaluation of PSMA-Targeted ¹¹¹In-Radioconjugates Containing a Mitochondria-Tropic Triphenylphosphonium Carrier

Santos,

Braz,

Raposinho

et al. 2023

Mol. Pharmaceutics

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More Than Meets the Eye: Scientific Rationale behind Molecular Imaging and Therapeutic Targeting of Prostate-Specific Membrane Antigen (PSMA) in Metastatic Prostate Cancer and Beyond

Hyväkkä

Virtanen

Kemppainen

et al. 2021

Cancers

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Prostate cancer is the second most common cancer type in men globally. Although the prognosis for localized prostate cancer is good, no curative treatments are available for metastatic disease. Better diagnostic methods could help target therapies and improve the outcome. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed on malignant prostate tumor cells and correlates with the aggressiveness of the disease. PSMA is a clinically validated target for positron emission tomography (PET) imaging-based diagnostics in prostate cancer, and during recent years several therapeutics have been developed based on PSMA expression and activity. The expression of PSMA in prostate cancer can be very heterogeneous and some metastases are negative for PSMA. Determinants that dictate clinical responses to PSMA-targeting therapeutics are not well known. Moreover, it is not clear how to manipulate PSMA expression for therapeutic purposes and develop rational treatment combinations. A deeper understanding of the biology behind the use of PSMA would help the development of theranostics with radiolabeled compounds and other PSMA-based therapeutic approaches. Along with PSMA several other targets have also been evaluated or are currently under investigation in preclinical or clinical settings in prostate cancer. Here we critically elaborate the biology and scientific rationale behind the use of PSMA and other targets in the detection and therapeutic targeting of metastatic prostate cancer.

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[99mTc]Tc-PSMA-T4—Novel SPECT Tracer for Metastatic PCa: From Bench to Clinic

et al. 2022

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Despite significant advances in nuclear medicine for diagnosing and treating prostate cancer (PCa), research into new ligands with increasingly better biological properties is still ongoing. Prostate-specific membrane antigen (PSMA) ligands show great potential as radioisotope carriers for the diagnosis and therapy of patients with metastatic PCa. PSMA is expressed in most types of prostate cancer, and its expression is increased in poorly differentiated, metastatic, and hormone-refractory cancers; therefore, it may be a valuable target for the development of radiopharmaceuticals and radioligands, such as urea PSMA inhibitors, for the precise diagnosis, staging, and treatment of prostate cancer. Four developed PSMA-HYNIC inhibitors for technetium-99m labeling and subsequent diagnosis were subjected to preclinical in vitro and in vivo studies to evaluate and compare their diagnostic properties. Among the studied compounds, the PSMA-T4 (Glu-CO-Lys-L-Trp-4-Amc-HYNIC) inhibitor showed the best biological properties for the diagnosis of PCa metastases. [99mTc]Tc-PSMA-T4 also showed effectiveness in single-photon emission computed tomography (SPECT) studies in humans, and soon, its usefulness will be extensively evaluated in phase 2/3 clinical trials.

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PSMA-D4 Radioligand for Targeted Therapy of Prostate Cancer: Synthesis, Characteristics and Preliminary Assessment of Biological Properties

Cited by 3 publications

References 30 publications

Synthesis and Preclinical Evaluation of PSMA-Targeted ¹¹¹In-Radioconjugates Containing a Mitochondria-Tropic Triphenylphosphonium Carrier

Synthesis and Preclinical Evaluation of PSMA-Targeted ¹¹¹In-Radioconjugates Containing a Mitochondria-Tropic Triphenylphosphonium Carrier

More Than Meets the Eye: Scientific Rationale behind Molecular Imaging and Therapeutic Targeting of Prostate-Specific Membrane Antigen (PSMA) in Metastatic Prostate Cancer and Beyond

[99mTc]Tc-PSMA-T4—Novel SPECT Tracer for Metastatic PCa: From Bench to Clinic

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PSMA-D4 Radioligand for Targeted Therapy of Prostate Cancer: Synthesis, Characteristics and Preliminary Assessment of Biological Properties

Cited by 3 publications

References 30 publications

Synthesis and Preclinical Evaluation of PSMA-Targeted 111In-Radioconjugates Containing a Mitochondria-Tropic Triphenylphosphonium Carrier

Synthesis and Preclinical Evaluation of PSMA-Targeted 111In-Radioconjugates Containing a Mitochondria-Tropic Triphenylphosphonium Carrier

More Than Meets the Eye: Scientific Rationale behind Molecular Imaging and Therapeutic Targeting of Prostate-Specific Membrane Antigen (PSMA) in Metastatic Prostate Cancer and Beyond

[99mTc]Tc-PSMA-T4—Novel SPECT Tracer for Metastatic PCa: From Bench to Clinic

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Product

Resources

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Synthesis and Preclinical Evaluation of PSMA-Targeted ¹¹¹In-Radioconjugates Containing a Mitochondria-Tropic Triphenylphosphonium Carrier

Synthesis and Preclinical Evaluation of PSMA-Targeted ¹¹¹In-Radioconjugates Containing a Mitochondria-Tropic Triphenylphosphonium Carrier