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An Albumin-Binding PSMA Ligand with Higher Tumor Accumulation for PET Imaging of Prostate Cancer

ABSTRACT: Prostate-specific membrane antigen (PSMA) is an ideal target for the diagnosis and treatment of prostate cancer. Due to the short half-life in blood, small molecules/peptides are rapidly cleared by the circulatory system. Prolonging the half-life of PSMA probes has been considered as an effective strategy to improve the tumor detection. Herein, we reported a 64Cu-labeled PSMA tracer conjugating with maleimidopropionic acid (MPA), 64Cu-PSMA-CM, which showed an excellent ability to detect PSMA-overexpressing tumors in delayed time. Cell experiments in PSMA-positive 22Rv1 cells, human serum albumin binding affinity, and micro-PET imaging studies in 22Rv1 model were performed to investigate the albumin binding capacity and PSMA specificity. Comparisons with 64Cu-PSMA-BCH were performed to explore the influence of MPA on the biological properties. 64Cu-PSMA-CM could be quickly prepared within 30 min. The uptake of 64Cu-PSMA-CM in 22Rv1 cells increased over time and it could bind to HSA with a high protein binding ratio (67.8 ± 1.5%). When compared to 64Cu-PSMA-BCH, 64Cu-PSMA-CM demonstrated higher and prolonged accumulation in 22Rv1 tumors, contributing to high tumor-to-organ ratios. These results showed that 64Cu-PSMA-CM was PSMA specific with a higher tumor uptake, which demonstrated that MPA is an optional strategy for improving the radioactivity concentration in PSMA-expressing tumors and for developing the ligands for PSMA radioligand therapy.

SUBMITTER: Ren Y

PROVIDER: S-EPMC9143078 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Project description:PURPOSE:The first aim of this study was to evaluate 68Ga-PSMAHBED-CC conjugate 11 positron emission tomography (PSMA PET) parameters for assessment of response to 177Lu-PSMA-617 radioligand therapy (RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC). The second aim was to investigate factors associated with overall survival (OS). METHODS:We retrospectively assessed mean standardized uptake values (SUVmean) and total tumor volumes (TTV) on PSMA PET in 38 of 55 mCRPC patients before and after RLT. PSA testing and PSMA PET/CT(MRI) imaging were performed during the 8 weeks before and the 6 weeks after RLT. PSMA PET and CT(MRI) images were reviewed separately according to the modified PET Response Criteria in Solid Tumors (mPERCIST) and RECIST1.1. The results were compared with PSA responses. Associations between OS and the RECIST evaluation and changes in SUVmean, TTV, and PSA, CRP, LDH, hemoglobin and ALP levels were determined in a univariable survival analysis. RESULTS:The median PSA level at the time of pretherapy PSMA PET/CT(MRI) was 60.8 ng/ml (IQR 15.4, 264.2 ng/ml). After RLT the median PSA level decreased by 44%, TTV by 45.1%, SUVmean by 25.8% and RECIST by 11.3%. A PSA response was seen in 18 patients (47.4%), stable disease in 12 (31.6%) and progressive disease in 8 (21.1%). Contrary to the changes in SUVmean and the RECIST evaluation, the change in TTV was significantly associated with PSA response (p?=?0.15, p?=?0.58, and p?<?0.001, respectively). After a median follow-up of 17 months (IQR 8.0, 24.2 months), 11 patients (28.9%) had died of their prostate cancer. The changes in both TTV and PSA levels were associated with OS (HR 1.001, 95% CI 1-1.003, p?=?0.04, and HR 1.004, 95% CI 1.001-1.008, p?=?0.01, respectively), while the changes in SUVmean and the RECIST evaluation were not. The pre-therapy CRP level was also associated with OS (HR 1.07, 95% CI 1.009-1.14, p?=?0.02). CONCLUSION:TTV on PSMA PET seems to be a reliable parameter for response assessment in mCRPC patients undergoing RLT and might overcome the limitations of RECIST in prostate cancer. Furthermore, the change in TTV was significantly associated with OS in our cohort.

Project description:BackgroundDelineation of PSMA-positive tumor volume on PET using PSMA-ligands is of highest clinical interest as changes of PSMA-PET/CT-derived whole tumor volume (WTV) have shown to correlate with treatment response in metastatic prostate cancer patients. So far, WTV estimation was performed on PET using 68Ga-labeled ligands; nonetheless, 18F-labeled PET ligands are gaining increasing importance due to advantages over 68Ga-labeled compounds. However, standardized tumor delineation methods for 18F-labeled PET ligands have not been established so far. As correlation of PET-based information and morphological extent in osseous and visceral metastases is hampered by morphological delineation, low contrast in liver tissue and movement artefacts, we correlated CT-based volume of lymph node metastases (LNM) and different PET-based delineation approaches for thresholding on 18F-PSMA-1007 PET.MethodsFifty patients with metastatic prostate cancer, 18F-PSMA-1007 PET/CT and non-bulky LNM (short-axis diameter ≥10mm) were included. Fifty LNM were volumetrically assessed on contrast-enhanced CT (volumetric reference standard). Different approaches for tumor volume delineation were applied and correlated with the reference standard: I) fixed SUV threshold, II) isocontour thresholding relative to SUVmax (SUV%), and thresholds relative to III) liver (SUVliver), IV) parotis (SUVparotis) and V) spleen (SUVspleen).ResultsA fixed SUV of 4.0 (r=0.807, r2 = 0.651, p<0.001) showed the best overall association with the volumetric reference. 55% SUVmax (r=0.627, r2 = 0.393, p<0.001) showed highest association using an isocontour-based threshold. Best background-based approaches were 60% SUVliver (r=0.715, r2 = 0.511, p<0.001), 80% SUVparotis (r=0.762, r2 = 0.581, p<0.001) and 60% SUVspleen (r=0.645, r2 = 0.416, p<0.001). Background tissues SUVliver, SUVparotis & SUVspleen did not correlate (p>0.05 each). Recently reported cut-offs for intraprostatic tumor delineation (isocontour 44% SUVmax, 42% SUVmax and 20% SUVmax) revealed inferior association for LNM delineation.ConclusionsA threshold of SUV 4.0 for tumor delineation showed highest association with volumetric reference standard irrespective of potential changes in PSMA-avidity of background tissues (e. g. parotis). This approach is easily applicable in clinical routine without specific software requirements. Further studies applying this approach for total tumor volume delineation are initiated.

Project description:PurposeSince the introduction of positron emission tomography (PET) imaging with (68)Ga-PSMA-HBED-CC (=(68)Ga-DKFZ-PSMA-11), this method has been regarded as a significant step forward in the diagnosis of recurrent prostate cancer (PCa). However, published data exist for small patient cohorts only. The aim of this evaluation was to analyse the diagnostic value of (68)Ga-PSMA-ligand PET/CT in a large cohort and the influence of several possibly interacting variables.MethodsWe performed a retrospective analysis in 319 patients who underwent (68)Ga-PSMA-ligand PET/CT from 2011 to 2014. Potential influences of several factors such as prostate-specific antigen (PSA) level and doubling time (DT), Gleason score (GSC), androgen deprivation therapy (ADT), age and amount of injected tracer were evaluated. Histological verification was performed in 42 patients after the (68)Ga-PSMA-ligand PET/CT. Tracer uptake was measured in 901 representative tumour lesions.ResultsIn 82.8% of the patients at least one lesion indicative of PCa was detected. Tumor-detection was positively associated with PSA level and ADT. GSC and PSA-DT were not associated with tumor-detection. The average maximum standardized uptake value (SUVmax) of tumour lesions was 13.3 ± 14.6 (0.7-122.5). Amongst lesions investigated by histology, 30 were false-negative in 4 different patients, and all other lesions (n = 416) were true-positive or true-negative. A lesion-based analysis of sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) revealed values of 76.6%, 100%, 91.4% and 100%. A patient-based analysis revealed a sensitivity of 88.1%. Of 116 patients available for follow-up, 50 received local therapy after (68)Ga-PSMA-ligand PET/CT.Conclusion(68)Ga-PSMA-ligand PET/CT can detect recurrent PCa in a high number of patients. In addition, the radiotracer is highly specific for PCa. Tumour detection is positively associated with PSA and ADT. (68)Ga-PSMA-ligand PET/CT can help delay systemic therapy of PCa.

Project description:BACKGROUND:Several scan parameters for PET imaging with 18F-PSMA-11 such as dosage, acquisition time and scan duration were evaluated to determine the most appropriate scan protocol, as well as the effect of furosemide administration on lesion visualization. Forty-four patients were randomly assigned to a dosage group (2.0?±?0.2 or 4.0?±?0.4?MBq/kg 18F-PSMA-11). All patients received a full-body PET/CT 1?h and 3?h after radiotracer injection with a scan duration of 3?min/bed position. For comparison of the scan duration, images were reconstructed for 1.5 and 3?min/bed position. Patients were intravenously administered 0.5?mg/kg furosemide with a maximum dose of 40?mg. To evaluate the furosemide effect, 22 additional patients were recruited and received one full-body PET/CT 1?h after administration of 2.0?±?0.2?MBq/kg 18F-PSMA-11 with a scan duration of 3?min/bed position. To this group, no furosemide was administered. Images were scored on image quality using a 7-point scale and each suspicious lesion was described. To assess interrater reliability, two nuclear physicians scored all scans independently and described all observed suspicious lesions. RESULTS:The 4?MBq/kg group received for all reconstructed images (60?min p.i., 1.5 and 3?min/bed position and 180?min p.i., 1.5 and 3?min/bed position) the highest median image quality score compared to the 2?MBq/kg group (p values <?0.01). When comparing all reconstructed images, the highest image quality score was given to images at 60?min p.i., 3?min/bed position for both dosage groups (score 5 and 6 for 2 and 4?MBq/kg, respectively). The addition of furosemide administration decreased the interference score with one point (p =?0.01106) and facilitated the evaluation of lesions in proximity to the ureters. The interrater reliability for the comparison of each lesion separately after more than 40 18F-PSMA-11 scan readings showed an increasing ? value from 0.78 (95% CI, 0.65-0.92) to 0.94 (95% CI, 0.87-1). CONCLUSION:Although the results indicate an administered activity of 4.0?±?0.4?MBq/kg, preference will be given to 2.0?± 0.2?MBq/kg due to the small difference in absolute score (max 1 point) and the ALARA principle. For evaluation of lesions in proximity to the ureters, the co-administration of a diuretic can be useful. The increase of the ? value from 0.78 to 0.94 suggests a learning curve in the interpretation of 18F-PSMA-11 images. TRIAL REGISTRATION:Clinicaltrials.gov, NCT03573011. Retrospectively registered 28 June 2018.

Project description:Objective:To synthesize 68Ga-Glu-urea-Lys(Ahx)-HBED-CC (68Ga-PSMA-11) with a synthesis module and investigate PET-CT imaging to monitor PSMA expression during prostate cancer (PCa) progression and tumor growth in mice bearing subcutaneous PCa xenografts. Method:The radiochemical purity and stability of 68Ga-PSMA-11 were determined via radio-HPLC. The PCa cell lines of different PSMA expression levels (PC3, VCAP±, CWR22RV1+, and LNCaP++) were selected to mimic the PCa progression. 68Ga-PSMA-11 biodistribution was studied by dissection method and in vivo imaging with micro PET-CT. The expression levels of PSMA in tumor cells and tissues were analyzed by immunofluorescence, flow cytometry, and western blot. The correlation between PSMA expression and radio-uptake was also evaluated. 2-PMPA preadministration served as a block group. Results:The radiochemical purity of 68Ga-PSMA-11 was 99.6 ± 0.1% and stable in vitro for 2 h. The equilibrium binding constant (Kd) of 68Ga-PSMA-11 to LNCaP, CWR22Rv1, PC-3, and VCAP cells was 4.3 ± 0.8 nM, 16.4 ± 1.3 nM, 225.3 ± 20.8 nM, and 125.6 ± 13.1 nM, respectively. Results of tumor uptake (% ID and % ID/g or % ID/cm3) of 68Ga-PSMA-11 in biodistribution and micro PET imaging were LNCaP > CWR22RV1 > PC-3 and VCAP due to different PSMA expression levels. It was confirmed by flow cytometry, western blot, and immunofluorescence. Tumor uptake (% ID/cm3) of 68Ga-PSMA-11 increased with the tumor anatomical volume in quadratic polynomial fashion and reached the peak (when tumor volume was 0.5 cm3) earlier than tumor uptake (% ID). Tumor uptake (% ID/cm3) of 68Ga-PSMA-11 based on functional volume correlated well with the PSMA expression in a linear manner (y = 9.35x + 2.59, R2 = 0.8924, and p < 0.0001); however, low dose 2-PMPA causes rapid renal clearance of increased tumor/kidney uptake of 68Ga-PSMA-11. Conclusions:The 68Ga-PSMA-11 PET-CT imaging could invasively evaluate PSMA expression during PCa progression and tumor growth with % ID/cm3 (based on functional volume) as an important index. Low dose 2-PMPA preadministration might be a choice to decrease kidney uptake of 68Ga-PSMA-11.

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An Albumin-Binding PSMA Ligand with Higher Tumor Accumulation for PET Imaging of Prostate Cancer

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