Dataset Information

Radionuclide generator-based production of therapeutic ¹⁷⁷Lu from its long-lived isomer ^177mLu.

ABSTRACT:

Background

In this work, a lutetium-177 (¹⁷⁷Lu) production method based on the separation of nuclear isomers, ^177mLu & ¹⁷⁷Lu, is reported. The ^177mLu-¹⁷⁷Lu separation is performed by combining the use of DOTA & DOTA-labelled peptide (DOTATATE) and liquid-liquid extraction.

Methods

The ^177mLu cations were complexed with DOTA & DOTATATE and kept at 77?K for periods of time to allow ¹⁷⁷Lu production. The freed ¹⁷⁷Lu ions produced via internal conversion of ^177mLu were then extracted in dihexyl ether using 0.01?M di-(2-ethylhexyl) phosphoric acid (DEHPA) at room temperature. The liquid-liquid extractions were performed periodically for a period up to 35?days.

Results

A maximum ¹⁷⁷Lu/^177mLu activity ratio of 3500?±?500 was achieved with [^177mLu]Lu-DOTA complex, in comparison to ¹⁷⁷Lu/^177mLu activity ratios of 1086?±?40 realized using [^177mLu]Lu-DOTATATE complex. The ¹⁷⁷Lu-^177mLu separation was found to be affected by the molar ratio of lutetium and DOTA. A ¹⁷⁷Lu/^177mLu activity ratio up to 3500?±?500 was achieved with excess DOTA in comparison to ¹⁷⁷Lu/^177mLu activity ratio 1500?±?600 obtained when lutetium and DOTA were present in molar ratio of 1:1. Further, the ¹⁷⁷Lu ion extraction efficiency, decreases from 95?±?4% to 58?±?2% in the presence of excess DOTA.

Conclusion

The reported method resulted in a ¹⁷⁷Lu/ ^177mLu activity ratio up to 3500 after the separation. This ratio is close to the lower end of ¹⁷⁷Lu/^177mLu activity ratios, attained currently during the direct route ¹⁷⁷Lu production for clinical applications (i.e. 4000-10,000). This study forms the basis for further extending the liquid-liquid extraction based ^177mLu-¹⁷⁷Lu separation in order to lead to a commercial ^177mLu/¹⁷⁷Lu radionuclide generator.

SUBMITTER: Bhardwaj R

PROVIDER: S-EPMC6629729 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Radionuclide generator-based production of therapeutic <sup>177</sup>Lu from its long-lived isomer <sup>177m</sup>Lu.

Bhardwaj Rupali R Wolterbeek Hubert Th HT Denkova Antonia G AG Serra-Crespo Pablo P

EJNMMI radiopharmacy and chemistry 20190715 1

<h4>Background</h4>In this work, a lutetium-177 (<sup>177</sup>Lu) production method based on the separation of nuclear isomers, <sup>177m</sup>Lu & <sup>177</sup>Lu, is reported. The <sup>177m</sup>Lu-<sup>177</sup>Lu separation is performed by combining the use of DOTA & DOTA-labelled peptide (DOTATATE) and liquid-liquid extraction.<h4>Methods</h4>The <sup>177m</sup>Lu cations were complexed with DOTA & DOTATATE and kept at 77 K for periods of time to allow <sup>177</sup>Lu production. The fre ...[more]

PMID: 31659496

Similar Datasets

Project description:BackgroundNeuroblastoma (NB) is one of the most frequently diagnosed tumors in infants. NB is a neuroendocrine tumor type with various characteristics and features, and with diverse outcome. The most malignant NBs have a 5-year survival rate of only 40-50%, indicating the need for novel and improved treatment options. 177Lu-octreotate is routinely administered for treatment of neuroendocrine tumors overexpressing somatostatin receptors (SSTR). The aim of this study was to examine the biodistribution of 177Lu-octreotate in mice bearing aggressive human NB cell lines, in order to evaluate the potential usefulness of 177Lu-octreotate for treatment of NB.MethodsBALB/c nude mice bearing CLB-BAR, CLB-GE or IMR-32 tumor xenografts (n = 5-7/group) were i.v. injected with 0.15 MBq, 1.5 MBq or 15 MBq 177Lu-octreotate and sacrificed 1 h, 24 h, 48 h and 168 h after administration. The radioactivity concentration was determined for collected tissue samples, tumor-to-normal-tissue activity concentration ratios (T/N) and mean absorbed dose for each tissue were calculated. Immunohistochemical (IHC) staining for SSTR1-5, and Ki67 were carried out for tumor xenografts from the three cell lines.ResultsHigh 177Lu concentration levels and T/N values were observed in all NB tumors, with the highest for CLB-GE tumor xenografts (72%IA/g 24 h p.i.; 1.5 MBq 177Lu-octreotate). The mean absorbed dose to the tumor was 6.8 Gy, 54 Gy and 29 Gy for CLB-BAR, CLB-GE and IMR-32, respectively, p.i. of 15 MBq 177Lu-octreotate. Receptor saturation was clearly observed in CLB-BAR, resulting in higher concentration levels in the tumor when lower activity levels where administered. IHC staining demonstrated highest expression of SSTR2 in CLB-GE, followed by CLB-BAR and IMR-32.ConclusionT/N values for all three human NB tumor xenograft types investigated were high relative to previously investigated neuroendocrine tumor types. The results indicate a clear potential of 177Lu-octreotate as a therapeutic alternative for metastatic NB.

Project description:BackgroundRadiohybrid PSMA-targeted ligands (rhPSMA) have been introduced as a novel platform for theranostic applications. Among a variety of rhPSMA-ligands developed for radioligand therapy, two stereoisomers [177Lu]Lu-rhPSMA-10.1 and -10.2 have been synthesized and initially characterized in preclinical experiments with the aim to provide an optimized binding profile to human serum albumin, a reduction of charge, and thus accelerated kidney excretion, and unaffected or even improved tumor uptake. As both isomers showed similar in vitro characteristics and tumor uptake at 24 h post injection in tumor bearing mice and in order to identify the isomer with the most favorable pharmacokinetics for radioligand therapy, we carried out in-depth biodistribution and dosimetry studies in tumor-bearing and healthy mice.ResultsrhPSMA-10.1 and -10.2 were radiolabeled with lutetium-177 according to the established procedures of other DOTA-based PSMA ligands and displayed a high and comparable stability in all buffers and human serum (> 97%, 24 h). Biodistribution studies revealed fast clearance from the blood pool (0.3-0.6%ID/g at 1 h) and other background tissues within 48 h. Distinctive differences were found in the kidneys, where [177Lu]Lu-rhPSMA-10.1 displayed lower initial uptake and faster excretion kinetics compared to [177Lu]Lu-rhPSMA-10.2 expressed by a 1.5-fold and ninefold lower uptake value at 1 h and 24 h in healthy animals, respectively. Tumor uptake was comparable and in the range of 8.6-11.6%ID/g for both isomers over 24 h and was maintained up to 168 h at a level of 2.2 ± 0.8 and 4.1 ± 1.4%ID/g for [177Lu]Lu-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.2, respectively.ConclusionOur preclinical data on biodistribution and dosimetry indicate a more favorable profile of [177Lu]Lu-rhPSMA-10.1 compared to [177Lu]Lu-rhPSMA-10.2 for PSMA-targeted radioligand therapy. [177Lu]Lu-rhPSMA-10.1 shows fast kidney clearance kinetics resulting in excellent tumor-to-organ ratios over a therapy relevant time course. Meanwhile, [177Lu]Lu-rhPSMA-10.1 is currently being investigated in clinical phase I/II studies in patients with mCRPC (NCT05413850), in patients with high-risk localized PC (NCT06066437, Nautilus Trial) and after external beam radiotherapy (NCT06105918).

Project description:BackgroundThe [177Lu]Lu-DOTA-TATE mediated peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) is sometimes leading to treatment resistance and disease recurrence. An interesting alternative could be the somatostatin antagonist, [177Lu]Lu-DOTA-JR11, that demonstrated better biodistribution profile and higher tumor uptake than [177Lu]Lu-DOTA-TATE. Furthermore, treatment with alpha emitters showed improvement of the therapeutic index of PRRT due to the high LET offered by the alpha particles compared to beta emitters. Therefore, [225Ac]Ac-DOTA-JR11 can be a potential candidate to improve the treatment of NETs (Graphical abstract). DOTA-JR11 was radiolabeled with [225Ac]Ac(NO3)3 and [177Lu]LuCl3. Stability studies were performed in phosphate buffered saline (PBS) and mouse serum. In vitro competitive binding assay has been carried out in U2OS-SSTR2 + cells for natLa-DOTA-JR11, natLu-DOTA-JR11 and DOTA-JR11. Ex vivo biodistribution studies were performed in mice inoculated with H69 cells at 4, 24, 48 and 72 h after injection of [225Ac]Ac-DOTA-JR11. A blocking group was included to verify uptake specificity. Dosimetry of selected organs was determined for [225Ac]Ac-DOTA-JR11 and [177Lu]Lu-DOTA-JR11.Results[225Ac]Ac-DOTA-JR11 has been successfully prepared and obtained in high radiochemical yield (RCY; 95%) and radiochemical purity (RCP; 94%). [225Ac]Ac-DOTA-JR11 showed reasonably good stability in PBS (77% intact radiopeptide at 24 h after incubation) and in mouse serum (~ 81% intact radiopeptide 24 h after incubation). [177Lu]Lu-DOTA-JR11 demonstrated excellent stability in both media (> 93%) up to 24 h post incubation. Competitive binding assay revealed that complexation of DOTA-JR11 with natLa and natLu did not affect its binding affinity to SSTR2. Similar biodistribution profiles were observed for both radiopeptides, however, higher uptake was noticed in the kidneys, liver and bone for [225Ac]Ac-DOTA-JR11 than [177Lu]Lu-DOTA-JR11.Conclusion[225Ac]Ac-DOTA-JR11 showed a higher absorbed dose in the kidneys compared to [177Lu]Lu-DOTA-JR11, which may limit further studies with this radiopeptide. However, several strategies can be explored to reduce nephrotoxicity and offer opportunities for future clinical investigations with [225Ac]Ac-DOTA-JR11.

Dataset Information

Radionuclide generator-based production of therapeutic ¹⁷⁷Lu from its long-lived isomer ^177mLu.

Background

Methods

Results

Conclusion

Publications

Radionuclide generator-based production of therapeutic <sup>177</sup>Lu from its long-lived isomer <sup>177m</sup>Lu.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Radionuclide generator-based production of therapeutic 177Lu from its long-lived isomer 177mLu.

Background

Methods

Results

Conclusion

Publications

Radionuclide generator-based production of therapeutic <sup>177</sup>Lu from its long-lived isomer <sup>177m</sup>Lu.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Radionuclide generator-based production of therapeutic ¹⁷⁷Lu from its long-lived isomer ^177mLu.