Determination of pharmacokinetics and tissue distribution of a novel lutetium-labeled PSMA-targeted ligand, 177Lu-DOTA-PSMA-GUL, in rats by using LC–MS/MS
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SUBMITTER: Song C
PROVIDER: S-EPMC9474474 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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Project description:Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [177Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that 177Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from 177Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [177Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis.
| S-EPMC10317889 | biostudies-literature
Project description:PurposeTo develop a prostate-specific membrane antigen (PSMA)-targeted radiotherapeutic for metastatic castration-resistant prostate cancer (mCRPC) with optimized efficacy and minimized toxicity employing the β-particle radiation of 177Lu.MethodsWe synthesized 14 new PSMA-targeted, 177Lu-labeled radioligands (177Lu-L1-177Lu-L14) using different chelating agents and linkers. We evaluated them in vitro using human prostate cancer PSMA(+) PC3 PIP and PSMA(-) PC3 flu cells and in corresponding flank tumor models. Efficacy and toxicity after 8 weeks were evaluated at a single administration of 111 MBq for 177Lu-L1, 177Lu-L3, 177Lu-L5 and 177Lu-PSMA-617. Efficacy of 177Lu-L1 was further investigated using different doses, and long-term toxicity was determined in healthy immunocompetent mice.ResultsRadioligands were produced in high radiochemical yield and purity. Cell uptake and internalization indicated specific uptake only in PSMA(+) PC3 cells. 177Lu-L1, 177Lu-L3 and 177Lu-L5 demonstrated comparable uptake to 177Lu-PSMA-617 and 177Lu-PSMA-I&T in PSMA-expressing tumors up to 72 h post-injection. 177Lu-L1, 177Lu-L3 and 177Lu-L5 also demonstrated efficient tumor regression at 8 weeks. 177Lu-L1 enabled the highest survival rate. Necropsy studies of the treated group at 8 weeks revealed subacute damage to lacrimal glands and testes. No radiation nephropathy was observed 1 year post-treatment in healthy mice receiving 111 MBq of 177Lu-L1, most likely related to the fast renal clearance of this agent.Conclusions177Lu-L1 is a viable clinical candidate for radionuclide therapy of PSMA-expressing malignancies because of its high tumor-targeting ability and low off-target radiotoxic effects.
| S-EPMC8068522 | biostudies-literature
Project description:BackgroundThe AAZTA chelator and in particular its bifunctional derivative AAZTA5 was recently investigated to demonstrate unique capabilities to complex diagnostic and therapeutic trivalent radiometals under mild conditions. This study presents a comparison of 68Ga, 44Sc and 177Lu-labeled AAZTA5-PSMA-617 with DOTA-PSMA-617 analogues. We evaluated the radiolabeling characteristics, in vitro stability of the radiolabeled compounds and evaluated their binding affinity and internalization behavior on LNCaP tumor cells in direct comparison to the radiolabeled DOTA-conjugated PSMA-617 analogs.ResultsAAZTA5 was synthesized in a five-step synthesis and coupled to the PSMA-617 backbone on solid phase. Radiochemical evaluation of AAZTA5-PSMA-617 with 68Ga, 44Sc and 177Lu achieved quantitative radiolabeling of > 99% after less than 5 min at room temperature. Stabilities against human serum, PBS buffer and EDTA and DTPA solutions were analyzed. While there was a small degradation of the 68Ga complex over 2 h in human serum, PBS and EDTA/DTPA, the 44Sc and 177Lu complexes were stable at 2 h and remained stable over 8 h and 1 day. For all three compounds, i.e. [natGa]Ga-AAZTA5-PSMA-617, [natSc]Sc-AAZTA5-PSMA-617 and [natLu]Lu-AAZTA5-PSMA-617, in vitro studies on PSMA-positive LNCaP cells were performed in direct comparison to radiolabeled DOTA-PSMA-617 yielding the corresponding inhibition constants (Ki). Ki values were in the range of 8-31 nM values which correspond with those of [natGa]Ga-DOTA-PSMA-617, [natSc]Sc-DOTA-PSMA-617 and [natLu]Lu-DOTA-PSMA-617, i.e. 5-7 nM, respectively. Internalization studies demonstrated cellular membrane to internalization ratios for the radiolabeled 68Ga, 44Sc and 177Lu-AAZTA5-PSMA-617 tracers (13-20%IA/106 cells) in the same range as the ones of the three radiolabeled DOTA-PSMA-617 tracers (17-20%IA/106 cells) in the same assay.ConclusionsThe AAZTA5-PSMA-617 structure proved fast and quantitative radiolabeling with all three radiometal complexes at room temperature, excellent stability with 44Sc, very high stability with 177Lu and medium stability with 68Ga in human serum, PBS and EDTA/DTPA solutions. All three AAZTA5-PSMA-617 tracers showed binding affinities and internalization ratios in LNCaP cells comparable with that of radiolabeled DOTA-PSMA-617 analogues. Therefore, the exchange of the chelator DOTA with AAZTA5 within the PSMA-617 binding motif has no negative influence on in vitro LNCaP cell binding characteristics. In combination with the faster and milder radiolabeling features, AAZTA5-PSMA-617 thus demonstrates promising potential for in vivo application for theranostics of prostate cancer.
| S-EPMC7691401 | biostudies-literature
Project description:PurposeGastroenteropancreatic -neuroendocrine tumours (GEP-NETs) are commonly treated with surgical resection or long-term therapies for tumour growth control. Lutetium [177Lu]-DOTA-TATE was approved for the treatment of GEP-NETs after the phase III NETTER 1trial demonstrated improved progression free survival, objective response rates and health-related quality of life (HRQoL) compared to high-dose somatostatin analogues. No real-world data exist on prescribing habits and clinically significant endpoints for [177Lu]Lu-DOTA-TATE treatment in Italy. REAL-LU is a multicentre, long-term observational study in patients with unresectable/metastatic GEP-NETs progressing on standard therapies in Italian clinical practice. A pre-specified interim analysis was performed at the end of the enrolment period, data from which are described herein.MethodsOverall duration of REAL-LU will be approximately 48 months, with 12- and 36-month recruitment and follow-up periods, respectively. The primary objective is to evaluate [177Lu]Lu-DOTA-TATE effectiveness in terms of progression-free survival. Secondary objectives include safety, impact on HRQoL, and identification of prognostic factors. This pre-specified interim analysis describes patient profiles, at the end of enrollment, of those prescribed [177Lu]Lu-DOTA-TATE for GEP-NETs in Italy.ResultsAmong 161 evaluable patients, mean age was 64.7 ± 10.3 years at study entry, 83.8% presented with no clinical signs of disease at physical examination, and most had minor disease symptoms. All patients had metastatic disease, most commonly in the liver (83.9%) with a median of two metastatic sites. In 90.7% of patients, the disease was stage IV, and 68.3% had ≥ 1 target lesion. [177Lu]Lu-DOTA-TATE was prescribed mainly as second-line therapy (61.6%) and following surgery (58.4%). HRQoL assessments revealed high levels of functioning and low levels of symptoms at baseline; 50.0% of patients were symptom-free at study entry.ConclusionThe characteristics of patients who received [177Lu]Lu-DOTA-TATE in Italy are similar to those of the GEP-NET population of NETTER 1 with trial but with a higher proportion of patients with a grade 2 (71%). With regard to the tumor grade profile, our study cohort appears to be closer to that of NETTER-2 study population which included patients with G2 or G3 advanced GEP-NETs (i.e. Ki-67 ≥ 10% and ≤ 55%). Further analysis of effectiveness and safety can be anticipated as REAL-LU data mature.Study registrationClinicalTrials.gov, NCT04727723; Study Registration Date: 25 January, 2021; https://clinicaltrials.gov/study/NCT04727723?cond=NCT04727723&rank=1.
| S-EPMC11368969 | biostudies-literature
Project description:BackgroundPeptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-TATE has shown efficacy in patients with metastatic neuroendocrine tumours (NETs). Personalised dosimetry is crucial to optimise treatment outcomes and minimise adverse events. In this study, we investigated the correlation between the tumour-absorbed dose (TAD) estimated from [177Lu]Lu-DOTA-TATE SPECT/CT and the therapeutic response.MethodA retrospective analysis was conducted on patients with advanced well-differentiated NETs grades 1-3 who underwent PRRT and exhibited greater uptake than liver on pre-therapeutic [68Ga]Ga-DOTA-TOC PET/CT. Target lesions were selected based on the RECIST 1.1 and PERCIST 1.0 criteria using [177Lu]Lu-DOTA-TATE SPECT/CT and pre-therapeutic contrast-enhanced CT scans. For anatomical image analysis, the sum of the longest diameter (SLD) of the target lesions was measured using the RECIST 1.1 criteria for patient-based analysis and the longest diameter (LD) of the target lesion using the RECIST-L criteria for lesion-based analysis. Standardised uptake values (SUVs) were measured on SPECT/CT images, and TADs were calculated based on the SUVs. Dosimetry was performed using a single SPECT/CT imaging time point at day 4-5 post-therapy. Statistical analyses were conducted to investigate correlations and determine the target lesion responses.ResultsTwenty patients with primary tumour sites and hepatic metastases were included. Fifty-five target lesions, predominantly located in the pancreas and liver, were analysed. The cumulative TAD (lesion-based analysis: r = 0.299-0.301, p = 0.025-0.027), but not the cycle 1 SUV (lesion-based analysis: r = 0.198-0.206, p = 0.131-0.147) or cycle 1 TAD (lesion-based analysis: r = 0.209-0.217, p = 0.112-0.126), exhibited a significant correlation with the change in LD of the target lesion. Binary logistic regression analysis identified the significance of the cumulative TAD in predicting disease control according to the RECIST-L criteria (odds ratio = 1.031-1.051, p = 0.024-0.026).ConclusionsThe cumulative TAD estimated from [177Lu]Lu-DOTA-TATE SPECT/CT revealed a significant correlation with change in LD, which was significantly higher for the cumulative TAD than for the cycle 1 SUV or TAD. A higher cumulative TAD was associated with disease control in the target lesion. However, considering the limitations inherent to a confined sample size, careful interpretation of these findings is required. Estimation of the cumulative TAD of [177Lu]Lu-DOTA-TATE therapy could guide the platform towards personalised therapy.
| S-EPMC10844176 | biostudies-literature
Project description:BackgroundTargeted radionuclide therapy with [177Lu]Lu-PSMA I&T (zadavotide guraxetan) has proven high efficacy and safety in treating patients with advanced prostate cancer worldwide. Several methods to determine the radiochemical purity have been reported but also limitations in the HPLC analysis due to retention of the sample and tailing effects when using standard gradients containing trifluoroacetic acid (TFA). We here report on the validation of a method for quality control of [177Lu]Lu-PSMA I&T including determination of radiochemical purity, identity testing and limit test for PSMA I&T by HPLC using a Phosphate buffer /Acetonitrile gradient system, complemented with a TLC system with 0.1N Citrate buffer pH 5 as mobile phase including validation of the methods, batch and stability data as well as identification of the main radiochemical impurity by mass spectrometry.ResultsThe described HPLC method met the defined acceptance criteria in terms of accuracy, specificity, robustness, linearity, range and LOQ. HPLC analysis revealed symmetrical peaks and quantitative recovery from the column. Batch data showed a radiochemical purity > 95% as determined by HPLC, stability data a pronounced degradation due to radiolysis, which could be limited by addition of ascorbic acid, dilution and storage at low temperatures. The main radiochemical impurity was found to be the de-iodinated form of [177Lu]Lu-PSMA I&T. TLC analysis allowed to determine the amount of free Lu-177 even in the presence of DTPA in the final formulation.ConclusionOverall the described combination of HPLC and TLC provides a reliable tool for quality control of [177Lu]Lu-PSMA I&T.
| S-EPMC10043144 | biostudies-literature
Project description:BackgroundIndividualized dosimetry is recommended for [177Lu]Lu-PSMA radioligand therapy (RLT) which is resource-intensive and protocols are often not optimized. Therefore, a simulation study was performed focusing on the determination of efficient optimal sampling schedules (OSS) for renal and tumour dosimetry by investigating different numbers of time points (TPs).MethodsSampling schedules with 1-4 TPs were investigated. Time-activity curves of the kidneys and two tumour lesions were generated based on a physiologically based pharmacokinetic (PBPK) model and biokinetic data of 13 patients who have undergone [177Lu]Lu-PSMA I&T therapy. Systematic and stochastic noise of different ratios was considered when modelling time-activity data sets. Time-integrated activity coefficients (TIACs) were estimated by simulating the hybrid planar/SPECT method for schedules comprising at least two TPs. TIACs based on one single SPECT/CT measurement were estimated using an approximation for reducing the number of fitted parameters. For each sampling schedule, the root-mean-squared error (RMSE) of the deviations of the simulated TIACs from the ground truths for 1000 replications was used as a measure for accuracy and precision.ResultsAll determined OSS included a late measurement at 192 h p.i., which was necessary for accurate and precise tumour TIACs. OSS with three TPs were identified to be 3-4, 96-100 and 192 h with an additional SPECT/CT measurement at the penultimate TP. Kidney and tumour RMSE of 6.4 to 7.7% and 6.3 to 7.8% were obtained, respectively. Shortening the total time for dosimetry to e.g. 96 h resulted in kidney and tumour RMSE of 6.8 to 8.3% and 9.1 to 11%, respectively. OSS with four TPs showed similar results as with three TPs. Planar images at 4 and 68 h and a SPECT/CT shortly after the 68 h measurement led to kidney and tumour RMSE of 8.4 to 12% and 12 to 16%, respectively. One single SPECT/CT measurement at 52 h yielded good approximations for the kidney TIACs (RMSE of 7.0%), but led to biased tumour TIACs.ConclusionOSS allow improvements in accuracy and precision of renal and tumour dosimetry for [177Lu]Lu-PSMA therapy with potentially less effort. A late TP is important regarding accurate tumour TIACs.
| S-EPMC7300169 | biostudies-literature
Project description:PurposePSMA-targeted radioligand therapy (PRLT) is a promising treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, a high uptake of the radiopharmaceutical in the salivary glands (SG) can lead to xerostomia and becomes dose-limiting for 225Ac-PSMA-617. This study investigated the sialotoxicity of 177Lu-PSMA-I&T/-617 monotherapy and co-administered 225Ac-PSMA-617 and 177Lu-PSMA-617 (Tandem-PPRLT).MethodsThree patient cohorts, that had undergone 177Lu-PSMA-I&T/-617 monotherapy or Tandem-PRLT, were retrospectively analyzed. In a short-term cohort (91 patients), a xerostomia assessment (CTCAE v.5.0), a standardized questionnaire (sXI), salivary gland scintigraphy (SGS), and SG SUVmax and the metabolic volume (MV) on 68Ga-PSMA-11-PET/CT were obtained before and after two cycles of 177Lu-PSMA-I&T/-617. In a long-term cohort, 40 patients were similarly examined. In a Tandem cohort, the same protocol was applied to 18 patients after one cycle of Tandem-PRLT.ResultsGrade 1 xerostomia in the short-term follow-up was observed in 22 (24.2%) patients with a worsening of sXI from 7 to 8 at (p < 0.05). In the long-term cohort, xerostomia grades 1 to 2 occurred in 16 (40%) patients. SGS showed no significant changes, but there was a decline of the MV of all SGs. After Tandem-PRLT, 12/18 (66.7%) patients reported xerostomia grades 1 to 2, and the sXI significantly worsened from 9.5 to 14.0 (p = 0.005), with a significant reduction in the excretion fraction (EF) and MV of all SGs.Conclusion177Lu-PSMA-I&T/-617 causes only minor SG toxicity, while one cycle of Tandem-PRLT results in a significant SG impairment. This standardized protocol may help to objectify and quantify SG dysfunction.
| S-EPMC9406477 | biostudies-literature
Project description:Background177Lu-radiopharmaceuticals are routinely used for the treatment of various tumor entities. The productions of radiopharmaceuticals follow strict good-manufacturing practice guidelines and synthesis optimizations thereof have a strong impact on e.g. the quality of the product, radiation safety and costs. The purpose of this study is to optimize the precursor load of three radiopharmaceuticals. For that, different precursor loads were evaluated and compared to previously reported findings.ResultsAll three radiopharmaceuticals were successfully synthesized in high radiochemical purities and yields on the ML Eazy. The precursor load was optimized for [177Lu]Lu-FAPI-46 from 27.0 to 9.7 µg/GBq, for [177Lu]Lu-DOTATOC from 11 to 10 µg/GBq and for [177Lu]Lu-PSMA-I&T from 16.3 to 11.6 µg/GBq.ConclusionsWe successfully reduced the precursor load for all three radiopharmaceuticals while maintaining their quality.
| S-EPMC10219910 | biostudies-literature
Project description:Clinical trials have shown the significant efficacy of [177Lu]Lu-PSMA-617 for treating prostate cancer. However, the pharmacokinetic characteristics and therapeutic performance of [177Lu]Lu-PSMA-617 still need further improvement to meet clinical expectations. The aim of this study was to evaluate the feasibility and therapeutic potential of three novel 177Lu-labeled ligands for the treatment of prostate cancer. The novel ligands were efficiently synthesized and radiolabeled with non-carrier added 177Lu; the radiochemical purity of the final products was determined by Radio-HPLC. The specific cell-binding affinity to PSMA was evaluated in vitro using prostate cancer cell lines 22Rv1and PC-3. Blood pharmacokinetic analysis, biodistribution experiments, small animal SPCET imaging and treatment experiments were performed on normal and tumor-bearing mice. Among all the novel ligands developed in this study, [177Lu]Lu-PSMA-Q showed the highest uptake in 22Rv1 cells, while there was almost no uptake in PC-3 cells. As the SPECT imaging tracer, [177Lu]Lu-PSMA-Q is highly specific in delineating PSMA-positive tumors, with a shorter clearance half-life and higher tumor-to-background ratio than [177Lu]Lu-PSMA-617. Biodistribution studies verified the SPECT imaging results. Furthermore, [177Lu]Lu-PSMA-Q serves well as an effective therapeutic ligand to suppress tumor growth and improve the survival rate of tumor-bearing mice. All the results strongly demonstrate that [177Lu]Lu-PSMA-Q is a PSMA-specific ligand with significant anti-tumor effect in preclinical models, and further clinical evaluation is worth conducting.
| S-EPMC9782218 | biostudies-literature