90Y/177Lu-DOTATOC: From Preclinical Studies to Application in Humans.
Ontology highlight
ABSTRACT:
SUBMITTER: Uccelli L
PROVIDER: S-EPMC8469896 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Pretherapy PET with 86Y-DOTATOC is considered the ideal dosimetry protocol for 90Y-DOTATOC therapy; however, its cost, limited availability, and need for infusion of amino acids to mimic the therapy administration limit its use in the clinical setting. The goal of this study was to develop a dosimetric method for 90Y-DOTATOC using 90Y-DOTATOC PET/CT and bremsstrahlung SPECT/CT and to determine whether dosimetry-based administered activities differ significantly from standard administered activities. Methods: This was a prospective phase 2 trial of 90Y-DOTATOC therapy in patients with somatostatin receptor-positive tumors. 90Y-DOTATOC was given in 3 cycles 6-8 wk apart. In the first cycle of therapy, adults received 4.4 GBq and children received 1.85 GBq/m2; the subsequent administered activities were adjusted according to the dosimetry of the preceding cycle so as not to exceed a total kidney dose of 23 Gy and bone marrow dose of 2 Gy. The radiation dose to the kidneys was determined from serial imaging sessions consisting of time-of-flight 90Y-DOTATOC PET/CT at 5 h after therapy and 90Y-DOTATOC bremsstrahlung SPECT/CT at 6, 24, 48, and 72 h. The PET/CT data were used to measure the absolute concentration of 90Y-DOTATOC and to calibrate the bremsstrahlung SPECT kidney clearance data. The radiation dose to the kidneys was determined by multiplying the time-integrated activity (from the fitted biexponential curve of renal clearance of 90Y-DOTATOC) with the energy emitted per decay, divided by the mass of the kidneys. Results: The radiation dose to the kidneys per cycle of 90Y-DOTATOC therapy was highly variable among patients, ranging from 0.32 to 3.0 mGy/MBq. In 17 (85%) of the 20 adult patients who received the second and the third treatment cycles of 90Y-DOTATOC, the administered activity was modified by at least 20% from the starting administered activity. Conclusion: Renal dosimetry of 90Y-DOTATOC is feasible using 90Y-DOTATOC time-of-flight PET/CT and bremsstrahlung SPECT/CT and has a significant impact on the administered activity in treatment cycles.
| S-EPMC6225542 | biostudies-literature
Project description:We report a practical and high-yield synthesis of a bimodal bifunctional ligand 3p-C-NETA-NCS containing the isothiocyanate group for conjugation to a tumor targeting antibody. 3p-C-NETA-NCS was conjugated to a tumor-targeting antibody, trastuzumab, and the corresponding 3p-C-NETA-trastuzumab conjugate was evaluated and compared to trastuzumab conjugates of the known bifunctional ligands C-DOTA, C-DTPA, and 3p-C-DEPA for radiolabeling kinetics with (90)Y and (177)Lu. 3p-C-NETA-trastuzumab conjugate exhibited extremely rapid complexation kinetics with (90)Y and (177)Lu. (90)Y-3p-C-NETA-trastuzumab and (177)Lu-3p-C-NETA-trastuzumab conjugates were stable in human serum for 2 weeks. A pilot biodistribution study was conducted to evaluate in vivo stability and tumor targeting of (177)Lu-radiolabeled trastuzumab conjugate using nude mice bearing ZR-75-1 human breast cancer. (177)Lu-3p-C-NETA-trastuzumab conjugate displayed low radioactivity level at blood (1.6%), low organ uptake (<2.2%), and high tumor-to-blood ratio (6.4) at 120 h. 3p-C-NETA possesses favorable in vitro and in vivo profiles and is an excellent bifunctional chelator that can be used for targeted RIT applications using (90)Y and (177)Lu and has the potential to replace DOTA and DTPA analogues in current clinical use.
| S-EPMC3447103 | biostudies-literature
Project description:Diabetes is a complex metabolic disorder triggered by the deficient secretion of insulin by the pancreatic β-cell or the resistance of peripheral tissues to the action of the hormone. Chronic hyperglycemia is the major consequence of this failure, and also the main cause of diabetic problems. Indeed, several clinical trials have agreed in that tight glycemic control is the best way to stop progression of the disease. Many anti-diabetic drugs for treatment of type 2 diabetes are commercially available, but no ideal normoglycemic agent has been developed yet. Moreover, weight gain is the most common side effect of many oral anti-diabetic agents and insulin, and increased weight has been shown to worsen glycemic control and increase the risk of diabetes progression. In this sense, the inorganic salt sodium tungstate (NaW) has been studied in different animal models of metabolic syndrome and diabetes, proving to have a potent effect on normalizing blood glucose levels and reducing body weight, without any hypoglycemic action. Although the liver has been studied as the main site of NaW action, positive effects have been also addressed in muscle, pancreas, brain, adipose tissue and intestine, explaining the effective anti-diabetic action of this salt. Here, we review NaW research to date in these different target organs. We believe that NaW deserves more attention, since all available anti-diabetic treatments remain suboptimal and new therapeutics are urgently needed.
| S-EPMC4435618 | biostudies-literature
Project description:Despite impressive results, almost 30% of NET do not respond to PRRT and no well-established criteria are suitable to predict response. Therefore, we assessed the predictive value of radiomics [68Ga]DOTATOC PET/CT images pre-PRRT in metastatic GEP NET. We retrospectively analyzed the predictive value of radiomics in 324 SSTR-2-positive lesions from 38 metastatic GEP-NET patients (nine G1, 27 G2, and two G3) who underwent restaging [68Ga]DOTATOC PET/CT before complete PRRT with [177Lu]DOTATOC. Clinical, laboratory, and radiological follow-up data were collected for at least six months after the last cycle. Through LifeX, we extracted 65 PET features for each lesion. Grading, PRRT number of cycles, and cumulative activity, pre- and post-PRRT CgA values were also considered as additional clinical features. [68Ga]DOTATOC PET/CT follow-up with the same scanner for each patient determined the disease status (progression vs. response in terms of stability/reduction/disappearance) for each lesion. All features (PET and clinical) were also correlated with follow-up data in a per-site analysis (liver, lymph nodes, and bone), and for features significantly associated with response, the Δradiomics for each lesion was assessed on follow-up [68Ga]DOTATOC PET/CT performed until nine months post-PRRT. A statistical system based on the point-biserial correlation and logistic regression analysis was used for the reduction and selection of the features. Discriminant analysis was used, instead, to obtain the predictive model using the k-fold strategy to split data into training and validation sets. From the reduction and selection process, HISTO_Skewness and HISTO_Kurtosis were able to predict response with an area under the receiver operating characteristics curve (AUC ROC), sensitivity, and specificity of 0.745, 80.6%, 67.2% and 0.722, 61.2%, 75.9%, respectively. Moreover, a combination of three features (HISTO_Skewness; HISTO_Kurtosis, and Grading) did not improve the AUC significantly with 0.744. SUVmax, however, could not predict the response to PRRT (p = 0.49, AUC 0.523). The presented preliminary "theragnomics" model proved to be superior to conventional quantitative parameters to predict the response of GEP-NET lesions in patients treated with complete [177Lu]DOTATOC PRRT, regardless of the lesion site.
| S-EPMC8870649 | biostudies-literature
Project description:PurposePretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice.MethodsParallel experiments evaluating the biodistribution, imaging, dosimetry, therapeutic efficacy, and toxicity were performed in female athymic nude mice bearing either Ramos (Burkitt lymphoma) or Granta (mantle cell lymphoma) xenografts, utilizing an anti-CD20 antibody-streptavidin conjugate (1F5-SA) and an 90Y- or 177Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin second step reagent.ResultsThe two radionuclides displayed comparable biodistributions in tumors and normal organs; however, the absorbed radiation dose delivered to tumor was more than twice as high for 90Y (1.3 Gy/MBq) as for 177Lu (0.6 Gy/MBq). More importantly, therapy with 90Y-DOTA-biotin was dramatically more effective than with 177Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq 90Y, whereas 0% were cured using identical amounts of 177Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with 90Y-PRIT and 0% cured with 177Lu-PRIT. Toxicities were comparable with both isotopes.Conclusion90Y was therapeutically superior to 177Lu for streptavidin-biotin PRIT approaches in these human lymphoma xenograft models.
| S-EPMC4364776 | biostudies-literature
Project description:INTRODUCTION:One of the concepts of theranostics in nuclear medicine is peptide receptor radionuclide therapy (PRRT), whereby labeled somatostatin analogs are used for imaging and treating inoperable or disseminated neuroendocrine tumors (NET). AIM:The aim of the study was to determine the therapeutic efficacy and toxicity of tandem 90Y /177Lu-DOTATATE in patients with disseminated NET in a multicenter trial. MATERIALS AND METHODS:103 patients with NET G1/G2 treated with 90Y/177Lu-DOTATATE (1:1) with amino-acid infusion for nephroprotection were included in the study. RESULTS:Overall survival from the disease diagnosis (OS-D) was 127.4 months and from the time of PRRT (OS-T) was 89.5 months. Progression-free survival (PFS) was 29.9 months. An analysis based on the proliferation index revealed a statistically significant impact on PFS and OS-T (PFS G1 vs G2, 59.3 vs 24.3 months; OS-T G1 vs G2, not reached vs 79.9 months). The effect of the primary disease site was also analyzed. For pancreatic vs small bowel vs large bowel, the PFS was 30.8 vs 30.3 vs 40.6 months, the OS-T was 94 vs 61.9 vs 131.2 months and OS-D was 130.4 vs 89.2 vs not reached months, respectively. The 2-year risk of progression was 42%. The probability of 2-year and 5-year overall survival was 89% and 62%, respectively. PRRT was well tolerated by all patients. One patient (1%) developed myelodysplastic syndrome. No other grade 3 and 4 hematological or renal toxicity was observed. CONCLUSIONS:This multicenter trial showed that tandem 90Y/177Lu-DOTATATE is highly effective and safe therapy for patients with disseminated NET.
| S-EPMC7075861 | biostudies-literature
Project description:We aimed to explore the effects of (90)Y-DOTATOC and (90)Y-DOTATOC plus (177)Lu-DOTATOC on survival of patients with metastasized gastrinoma. Patients with progressive metastasized gastrinoma were treated with repeated cycles of (90)Y-DOTATOC or with cycles alternating between (90)Y-DOTATOC and (177)Lu-DOTATOC until tumor progression or permanent toxicity. Multivariable Cox regression analyses were used to study predictors of survival. A total of 36 patients were enrolled; 30 patients received (90)Y-DOTATOC (median activity per patient 11.8GBq; range: 6.1-62.2GBq) and 6 patients received (90)Y-DOTATOC plus (177)Lu-DOTATOC (median activity per patient: 14.8GBq; range: 7.4-14.8GBq). Response was found in 26 patients (72.2%), including morphological (n=12, 33.3%), biochemical (n=14, 38.9%) and/or clinical response (n=6, 16.2%). A total of 21 patients (58.3%) experienced hematotoxicity grade 1/2, while 1 patient (2.8%) experienced hematotoxicity grade 3; no grade 4 hematotoxicity occurred. Furthermore, 2 patients (5.6%) developed grade 4 renal toxicity; no grade 5 renal toxicity occurred. Responders had a significantly longer median survival from time of enrollment than non-responders (45.1 months, range: 37.1-53.1 months vs. 12.6 months, range: 11.0-14.2, hazard ratio: 0.12 (0.027-0.52), p=0.005). Additionally, there was a trend towards longer median survival with (90)Y-DOTATOC plus (177)Lu-DOTATOC as compared to (90)Y-DOTATOC alone (60.2 months, range: 19.8-100.6 months vs. 27.0 months, range: 4.0-50.0, hazard ratio: 0.21 (0.01-3.98), p=0.16). Response to (90)Y-DOTATOC and (90)Y-DOTATOC plus (177)Lu-DOTATOC therapy is associated with a longer survival in patients with metastasized gastrinoma. Both treatment regimens are promising tools for management of progressive gastrinoma.
| S-EPMC4299770 | biostudies-literature
Project description:We developed a merged younger-older adult template of the fornix and demonstrated its utility for studies of aging and preclinical Alzheimer's disease (AD). In Experiment 1, probabilistic tractography was used to reconstruct the fornix in younger and older adults and successful streamlines were then averaged to create a merged template in standard space. The new template includes the majority of the fornix from the hippocampal formation to the subcallosal region and the thalamus/hypothalamus. In Experiment 2, the merged template was validated as an appropriate measure for studies of aging, with comparisons against manual tracing measures indicating identical spatial coverage in younger and older adult groups. In Experiment 3, the merged template was found to outperform age-specific templates in measures of sensitivity and specificity computed on diffusion tensor imaging data of an independent participant cohort. In Experiment 4, relevance to preclinical AD was demonstrated via associations between fractional anisotropy within the new fornix template and cerebrospinal fluid markers of AD pathology (A?42 and the t-tau/A?42 ratio) in a third independent cohort of cognitively normal older adults. Our new template provides an appropriate measure for use in future studies seeking to characterize microstructural alterations in the fornix associated with aging and preclinical AD.
| S-EPMC5137184 | biostudies-literature
Project description:Twenty diseases are recognized as neglected tropical diseases (NTDs) by World Health Assembly resolutions, including human filarial diseases. The end of NTDs is embedded within the Sustainable Development Goals for 2030, under target 3.3. Onchocerciasis afflicts approximately 20.9 million people worldwide with > 90% of those infected residing in Africa. Control programs have made tremendous efforts in the management of onchocerciasis by mass drug administration and aerial larviciding; however, disease elimination is not yet achieved. In the new WHO roadmap, it is recognized that new drugs or drug regimens that kill or permanently sterilize adult filarial worms would significantly improve elimination timelines and accelerate the achievement of the program goal of disease elimination. Drug development is, however, handicapped by high attrition rates, and many promising molecules fail in preclinical development or in subsequent toxicological, safety and efficacy testing; thus, research and development (R&D) costs are, in aggregate, very high. Drug discovery and development for NTDs is largely driven by unmet medical needs put forward by the global health community; the area is underfunded and since no high return on investment is possible, there is no dedicated drug development pipeline for human filariasis. Repurposing existing drugs is one approach to filling the drug development pipeline for human filariasis. The high cost and slow pace of discovery and development of new drugs has led to the repurposing of "old" drugs, as this is more cost-effective and allows development timelines to be shortened. However, even if a drug is marketed for a human or veterinary indication, the safety margin and dosing regimen will need to be re-evaluated to determine the risk in humans. Drug repurposing is a promising approach to enlarging the pool of active molecules in the drug development pipeline. Another consideration when providing new treatment options is the use of combinations, which is not addressed in this review. We here summarize recent advances in the late preclinical or early clinical stage in the search for a potent macrofilaricide, including drugs against the nematode and against its endosymbiont, Wolbachia pipientis.
| S-EPMC8599318 | biostudies-literature
Project description:Pharmacokinetic characterization plays a vital role in drug discovery and development. Although involving numerous laboratory animals with error-prone, labor-intensive, and time-consuming procedures, pharmacokinetic profiling is still irreplaceable in preclinical studies. With physiologically based pharmacokinetic (PBPK) modeling, the in vivo profiles of drug absorption, distribution, metabolism, and excretion can be predicted. To evaluate the application of such an approach in preclinical investigations, the plasma pharmacokinetic profiles of seven commonly used probe substrates of microsomal enzymes, including phenacetin, tolbutamide, omeprazole, metoprolol, chlorzoxazone, nifedipine, and baicalein, were predicted in rats using bottom-up PBPK models built with in vitro data alone. The prediction's reliability was assessed by comparison with in vivo pharmacokinetic data reported in the literature. The overall predicted accuracy of PBPK models was good with most fold errors within 2, and the coefficient of determination (R2) between the predicted concentration data and the observed ones was more than 0.8. Moreover, most of the observation dots were within the prediction span of the sensitivity analysis. We conclude that PBPK modeling with acceptable accuracy may be incorporated into preclinical studies to refine in vivo investigations, and PBPK modeling is a feasible strategy to practice the principles of 3Rs.
| S-EPMC9133488 | biostudies-literature