Dataset Information

Synthesis and preliminary evaluation of ²¹¹At-labeled inhibitors of prostate-specific membrane antigen for targeted alpha particle therapy of prostate cancer.

ABSTRACT:

Introduction

The high potency and short tissue range of α-particles are attractive features for targeted radionuclide therapy, particularly for cancers with micro-metastases. In the current study, we describe the synthesis of a series of ²¹¹At-labeled prostate-specific membrane antigen (PSMA) inhibitors and their preliminary evaluation as potential agents for metastatic prostate cancer treatment.

Methods

Four novel Glu-urea based PSMA ligands containing a trialkyl stannyl group were synthesized and labeled with ²¹¹At, and for comparative purposes, ¹³¹I, via halodestannylation reactions with N-chlorosuccinimide as the oxidant. A PSMA inhibitory assay was performed to evaluate PSMA binding of the unlabeled, iodinated compounds. A series of paired-label biodistribution experiments were performed to compare each ²¹¹At-labeled PSMA ligand to its ¹³¹I-labeled counterpart in mice bearing subcutaneous PC3 PSMA+ PIP xenografts.

Results

Radiochemical yields ranged from 32% to 65% for the ²¹¹At-labeled PSMA inhibitors and were consistently lower than those obtained with the corresponding ¹³¹I-labeled analogue. Good localization in PC3 PSMA+ PIP but not control xenografts was observed for all labeled molecules studied, which exhibited a variable degree of in vivo dehalogenation as reflected by thyroid and stomach activity levels. Normal tissue uptake and in vivo stability for several of the compounds was markedly improved compared with the previously evaluated compounds, [²¹¹At]DCABzL and [*I]DCIBzL.

Conclusions and implications for patient care

Compared with the first generation compound [²¹¹At]DCABzL, several of the novel ²¹¹At-labeled PSMA ligands exhibited markedly improved stability in vivo and higher tumor-to-normal tissue ratios. [²¹¹At]GV-620 has the most promising characteristics and warrants further evaluation as a targeted radiotherapeutic for prostate cancer.

SUBMITTER: Vaidyanathan G

PROVIDER: S-EPMC7987787 | biostudies-literature | 2021 Mar-Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synthesis and preliminary evaluation of <sup>211</sup>At-labeled inhibitors of prostate-specific membrane antigen for targeted alpha particle therapy of prostate cancer.

Vaidyanathan Ganesan G Mease Ronnie C RC Minn Il I Choi Jaeyeon J Chen Ying Y Shallal Hassan H Kang Choong Mo CM McDougald Darryl D Kumar Vivek V Pomper Martin G MG Zalutsky Michael R MR

Nuclear medicine and biology 20210123

<h4>Introduction</h4>The high potency and short tissue range of α-particles are attractive features for targeted radionuclide therapy, particularly for cancers with micro-metastases. In the current study, we describe the synthesis of a series of <sup>211</sup>At-labeled prostate-specific membrane antigen (PSMA) inhibitors and their preliminary evaluation as potential agents for metastatic prostate cancer treatment.<h4>Methods</h4>Four novel Glu-urea based PSMA ligands containing a trialkyl stann ...[more]

PMID: 33601187

Similar Datasets

Project description:PURPOSE:Targeted alpha therapy (TAT) is a promising treatment for micrometastatic and minimal residual cancer. We evaluated systemic α-radioimmunotherapy (α-RIT) of metastatic castration-resistant prostate cancer (mCRPC) using the α-particle emitter 211At-labeled to the anti-PSCA A11 minibody. A11 is specific for prostate stem cell antigen (PSCA), a cell surface glycoprotein which is overexpressed in more than 90% of both localized prostate cancer and bone metastases. METHODS:PC3-PSCA cells were implanted subcutaneously (s.c.) and intratibially (i.t) in nude mice. Efficacy of α-RIT (two fractions-14-day interval) was studied on s.c. macrotumors (0, 1.5 and 1.9 MBq) and on i.t. microtumors (~100-200 μm; 0, 0.8 or 1.5 MBq) by tumor-volume measurements. The injected activities for therapies were estimated from separate biodistribution and myelotoxicity studies. RESULTS:Tumor targeting of 211At-A11 was efficient and the effect on s.c. macrotumors was strong and dose-dependent. At 6 weeks, the mean tumor volumes for the treated groups, compared with controls, were reduced by approximately 85%. The separate myelotoxicity study following one single fraction showed reduced white blood cells (WBC) for all treated groups on day 6 after treatment. For the 0.8 and 1.5 MBq, the WBC reductions were transient and followed by recovery at day 13. For 2.4 MBq, a clear toxicity was observed and the mice were sacrificed on day 7. In the long-term follow-up of the 0.8 and 1.5 MBq-groups, blood counts on day 252 were normal and no signs of radiotoxicity observed. Efficacy on i.t. microtumors was evaluated in two experiments. In experiment 1, the tumor-free fraction (TFF) was 95% for both treated groups and significantly different (p < 0.05) from the controls at a TFF of 66%). In experiment 2, the difference in TFF was smaller, 32% for the treated group versus 20% for the controls. However, the difference in microtumor volume in experiment 2 was highly significant, 0.010 ± 0.003 mm3 versus 3.79 ± 1.24 mm3 (treated versus controls, respectively), i.e., a 99.7% reduction (p < 0.001). The different outcome in experiment 1 and 2 is most likely due to differences in microtumor sizes at therapy, or higher tumor-take in experiment 2 (where more cells were implanted). CONCLUSION:Evaluating fractionated α-RIT with 211At-labeled anti-PSCA A11 minibody, we found clear growth inhibition on both macrotumors and intratibial microtumors. For mice treated with multiple fractions, we also observed radiotoxicity manifested by progressive loss in body weight at 30 to 90 days after treatment. Our findings are conceptually promising for a systemic TAT of mCRPC and warrant further investigations of 211At-labeled PSCA-directed vectors. Such studies should include methods to improve the therapeutic window, e.g., by implementing a pretargeted regimen of α-RIT or by altering the size of the targeting vector.

Project description:Radioligand therapy is a type of internal radiotherapy combining a short-range radioisotope labeled to a carrier with a high affinity for a specific receptor expressed on tumor cells. Targeted alpha therapy (TAT) combines a high-linear energy transfer (LET) emitter (225Ac) with a prostate-specific membrane antigen (PSMA) carrier, specifically binding tumor cells in patients with metastatic castration-resistant prostate cancer. Although the antitumor activity of 225Ac-PSMA is well-documented, this treatment is nowadays only used as salvage therapy because the high incidence of xerostomia limits the therapeutic window. Thus, methods to reduce salivary toxicity and models able to describe xerostomia incidence are needed. We recently studied the efficacy of salivary gland protectors administered in combination with 177Lu-PSMA therapy. Starting from these data, we performed a predictive dosimetric evaluation of 225Ac-PSMA to assess the impact of salivary gland protectors in TAT. 225Ac-PSMA predictive dosimetry was performed in 13 patients treated with 177Lu-PSMA. Sequential whole-body planar images were acquired 0.5-1, 16-24, 36-48, and 120 h post-injection. 177Lu time-activity curves were corrected for 225Ac physical decay and assumed in equilibrium for all daughters. The OLINDA/EXM spherical model was used for dose estimation of the parotid and submandibular glands. The dose for each daughter was calculated and summed for the total dose estimation. The biologically effective dose formalism was extended to high-LET emitters. For the total biologically effective dose formalism extended to high-LET emitters, including the contribution of all daughter isotopes, the brachytherapy formalism for a mixture of radionuclides was implemented. Equivalent doses in 2 Gy/fraction (EQD2) were then calculated and compared with the normal tissue complication probability model derived from external beam radiotherapy for grade ≥2 xerostomia induction. Median predictive doses were 0.86 BdRBE5/MBq for parotid glands and 1.05 BdRBE5/MBq for submandibular glands, with a 53% reduction compared with previously published data. The results show that the radiobiological model implemented is conservative, as it overestimates the complication rate with respect to the clinical data. Our data shows the possibility of reducing salivary gland uptake in TAT with the coadministration of organ protectors, but these results should be confirmed for TAT with 225Ac-PSMA by carrying out prospective trials with defined toxicity endpoints and dosimetry procedures.

Dataset Information

Synthesis and preliminary evaluation of ²¹¹At-labeled inhibitors of prostate-specific membrane antigen for targeted alpha particle therapy of prostate cancer.

Introduction

Methods

Results

Conclusions and implications for patient care

Publications

Synthesis and preliminary evaluation of <sup>211</sup>At-labeled inhibitors of prostate-specific membrane antigen for targeted alpha particle therapy of prostate cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Synthesis and preliminary evaluation of 211At-labeled inhibitors of prostate-specific membrane antigen for targeted alpha particle therapy of prostate cancer.

Introduction

Methods

Results

Conclusions and implications for patient care

Publications

Synthesis and preliminary evaluation of <sup>211</sup>At-labeled inhibitors of prostate-specific membrane antigen for targeted alpha particle therapy of prostate cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Synthesis and preliminary evaluation of ²¹¹At-labeled inhibitors of prostate-specific membrane antigen for targeted alpha particle therapy of prostate cancer.