Dataset Information

Evaluation of polydentate picolinic acid chelating ligands and an ?-melanocyte-stimulating hormone derivative for targeted alpha therapy using ISOL-produced ²²⁵Ac.

ABSTRACT:

Background

Actinium-225 (²²⁵Ac, t_1/2 = 9.9 d) is a promising candidate radionuclide for use in targeted alpha therapy (TAT), though the currently limited global supply has hindered the development of a suitable Ac-chelating ligand and ²²⁵Ac-radiopharmaceuticals towards the clinic. We at TRIUMF have leveraged our Isotope Separation On-Line (ISOL) facility to produce ²²⁵Ac and use the resulting radioactivity to screen a number of potential ²²⁵Ac-radiopharmaceutical compounds.

Results

MBq quantities of ²²⁵Ac and parent radium-225 (²²⁵Ra, t_1/2 = 14.8 d) were produced and separated using solid phase extraction DGA resin, resulting in a radiochemically pure ²²⁵Ac product in >?98% yield and in an amenable form for radiolabeling of ligands and bioconjugates. Of the many polydentate picolinic acid ("pa") containing ligands evaluated (H₄octapa [N₄O₄], H₄CHXoctapa [N₄O₄], p-NO₂-Bn-H₄neunpa [N₅O₄], and H₆phospa [N₄O₄]), all out-performed the current gold standard, DOTA for ²²⁵Ac radiolabeling ability at ambient temperature. Moreover, a melanocortin 1 receptor-targeting peptide conjugate, DOTA-modified cyclized ?-melanocyte-stimulating hormone (DOTA-CycMSH), was radiolabeled with ²²⁵Ac and proof-of-principle biodistribution studies using B16F10 tumour-bearing mice were conducted. At 2?h post-injection, tumour-to-blood ratios of 20.4?±?3.4 and 4.8?±?2.4 were obtained for the non-blocking (molar activity [M.A.] >?200?kBq/nmol) and blocking (M.A. = 1.6?kBq/nmol) experiment, respectively.

Conclusion

TRIUMF's ISOL facility is able to provide ²²⁵Ac suitable for preclinical screening of radiopharmaceutical compounds; [²²⁵Ac(octapa)]^-, [²²⁵Ac(CHXoctapa)]^-, and [²²⁵Ac(DOTA-CycMSH)] may be good candidates for further targeted alpha therapy studies.

SUBMITTER: Ramogida CF

PROVIDER: S-EPMC6684685 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Evaluation of polydentate picolinic acid chelating ligands and an α-melanocyte-stimulating hormone derivative for targeted alpha therapy using ISOL-produced 225Ac.

Ramogida Caterina F CF Robertson Andrew K H AKH Jermilova Una U Zhang Chengcheng C Yang Hua H Kunz Peter P Lassen Jens J Bratanovic Ivica I Brown Victoria V Southcott Lily L Rodríguez-Rodríguez Cristina C Radchenko Valery V Bénard François F Orvig Chris C Schaffer Paul P

EJNMMI radiopharmacy and chemistry 20190806 1

<h4>Background</h4>Actinium-225 (225Ac, t1/2 = 9.9 d) is a promising candidate radionuclide for use in targeted alpha therapy (TAT), though the currently limited global supply has hindered the development of a suitable Ac-chelating ligand and 225Ac-radiopharmaceuticals towards the clinic. We at TRIUMF have leveraged our Isotope Separation On-Line (ISOL) facility to produce 225Ac and use the resulting radioactivity to screen a number of potential 2 ...[more]

PMID: 31659557

Similar Datasets

Project description:BackgroundAs 225Ac-labeled radiopharmaceuticals continue to show promise as targeted alpha therapeutics, there is a growing need to standardize quality control (QC) testing procedures. The determination of radiochemical purity (RCP) is an essential QC test. A significant obstacle to RCP testing is the disruption of the secular equilibrium between actinium-225 and its daughter radionuclides during labeling and QC testing. In order to accelerate translation of actinium-225 targeted alpha therapy, we aimed to determine the earliest time point at which the RCP of an 225Ac-labeled radiopharmaceutical can be accurately quantified.ResultsSix ligands were conjugated to macrocyclic metal chelators and labeled with actinium-225 under conditions designed to generate diverse incorporation yields. RCP was determined by radio thin layer chromatography (radioTLC) followed by exposure of the TLC plate on a phosphor screen either 0.5, 2, 3.5, 5, 6.5, or 26 h after the plate was developed. The dataset was used to create models for predicting the true RCP for any pre-equilibrium measurement taken at an early time point. The 585 TLC measurements span RCP values of 1.8-99.5%. The statistical model created from these data predicted an independent data set with high accuracy. Predictions made at 0.5 h are more uncertain than predictions made at later time points. This is primarily due to the decay of bismuth-213. A measurement of RCP > 90% at 2 h predicts a true RCP > 97% and guarantees that RCP will exceed 90% after secular equilibrium is reached. These findings were independently validated using NaI(Tl) scintillation counting and high resolution gamma spectroscopy on a smaller set of samples with 10% ≤ RCP ≤ 100%.ConclusionsRCP of 225Ac-labeled radiopharmaceuticals can be quantified with acceptable accuracy at least 2 h after radioTLC using various methods of quantifying particle emissions. This time point best balances the need to accurately quantify RCP with the need to safely release the batch as quickly as possible.

Project description:PurposeIn this study, we aim to evaluate the efficacy and safety of 225AC-DOTATATE targeted alpha therapy in advanced-stage paragangliomas (PGLs).MethodsNine (6 males and 3 females) consecutive patients with histologically proven PGLs were treated with 225Ac-DOTATATE targeted alpha therapy (TAT) and concomitant radiosensitizer, capecitabine, at 8-weekly intervals up to a cumulative activity of ~ 74 MBq. The primary endpoint included evaluating therapy response and disease control rate (DCR) using the RECIST 1.1 criteria. Additional secondary endpoints comprised clinical response assessment using EORTC QLQ-H&N35 questionnaire, Karnofsky Performance Scale (KPS), Eastern Cooperative Oncology Group performance status (ECOG), analgesic score (AS), dose alterations of anti-hypertensive drugs (anti-HTN), and the safety and side-effect profile evaluation as per CTCAE criteria version 5.0.ResultsFollowing 225Ac-DOTATATE treatment, morphological response revealed partial response in 50%, stable disease in 37.5%, and disease progression in 12.5%, with a DCR of 87.5%. Similarly, the symptomatic response was remarkable, and anti-HTN drugs were stopped in 25% and reduced in 37.5%. Another significant finding in our study revealed a morphologic DCR of 66.6% (2/3) in patients who failed previous lutetium-177 peptide receptor radionuclide therapy (177Lu-PRRT). Regarding the KPS, ECOG, and AS performance scores, a notable improvement was observed post-225Ac-DOTATATE treatment. The QLQ-H&N35 symptom scores evaluated in seven H&N PGL patients showed significant improvement in all aspects. No improvement in sexual function was noted (P = 0.3559). Despite the significant reduction in the analgesic score post-treatment (P = 0.0031), the QLQ-H&N35 revealed only marginal significance concerning the intake of pain killers (P = 0.1723). No grade III/IV hematological, renal, and hepatological toxicities were noted.ConclusionThe evidence from this study suggests 225Ac-DOTATATE therapy is effective and safe in the treatment of advanced-stage PGLs and also reports a clear benefit even in patient's refractory to the previous 177Lu-PRRT.

Project description:It is estimated that melanoma accounted for 76,380 new cases and 10,130 deaths in the United States in 2016. The melanocortin 1 receptor (MC1R) is highly expressed in the vast majority of melanomas, which makes it an attractive target for molecular imaging and radionuclide therapy. Lactam bridge-cyclized ?-melanocyte-stimulating hormone (Ac-Nle4-cyclo[Asp5-His-D-Phe7-Arg-Trp-Lys10]-NH2, or Nle-CycMSHhex) analogues have been successfully developed and studied for MC1R-targeted imaging, predominantly with single-photon emission computed tomography (SPECT). The goal of this study was to design and evaluate novel peptides for melanoma imaging with positron emission tomography (PET). We designed and synthesized three peptides, DOTA-PEG2-Nle-CycMSHhex (CCZ01047), DOTA-4-amino-(1-carboxymethyl) piperidine (Pip)-Nle-CycMSHhex (CCZ01048), and DOTA-Pip-Pip-Nle-CycMSHhex (CCZ01056). All three peptides exhibited high binding affinity to MC1R with sub-nanomolar Ki values, rapid internalization into B16F10 melanoma cells and high in vivo stability with more than 93% remaining intact at 15 min post-injection (p.i.) in blood plasma. All three 68Ga-labeled tracers produced high contrast PET images in C57BL/6J mice bearing B16F10 tumors, and their respective tumor uptakes were 8.0 ± 3.0, 12.3 ± 3.3, and 6.5 ± 1.4 %ID/g at 1 h p.i. Minimal normal organ activity was observed at 1 h p.i., except for kidneys (5.1 ± 1.4, 4.7 ± 0.5, and 6.2 ± 2.0 %ID/g, respectively), and thyroid (4.1 ± 0.6 %ID/g for CCZ01047 and 2.4 ± 0.6 %ID/g for CCZ01048). Due to high accumulation at tumor sites and rapid background clearance of 68Ga-CCZ01048, we further evaluated it at 2 h p.i., and a tumor uptake of 21.9 ± 4.6 %ID/g was observed, with background activity further decreased. Exceptional image contrast was also achieved, i.e. tumor-to-blood, tumor-to-muscle, tumor-to-bone and tumor-to-kidney ratios were 96.4 ± 13.9, 210.9 ± 20.9, 39.6 ± 11.9 and 4.0 ± 0.9, respectively. A blocking study was also performed by co-injection of excess amount of non-radioactive Ga-coupled of CCZ01048, which confirmed that the tumor uptake was MC1R mediated. In conclusion, the introduction of a cationic Pip linker to Nle-CycMSHhex, CCZ01048, not only improved tumor uptake, but also generated high tumor-to-normal tissue contrast with PET imaging in a preclinical melanoma model. Therefore, CCZ01048 is a promising candidate for PET imaging of melanoma, and potentially as a theranostic agent for radionuclide therapy of melanoma when labeled with ? or ? emitters.

Project description:PurposeFibroblast activation protein (FAP), which has high expression in cancer-associated fibroblasts of epithelial cancers, can be used as a theranostic target. Our previous study used 64Cu and 225Ac-labelled FAP inhibitors (FAPI-04) for a FAP-expressing pancreatic cancer xenograft imaging and therapy. However, the optimal therapeutic radionuclide for FAPI needs to be investigated further. In this study, we evaluated the therapeutic effects of beta-emitter (177Lu)-labelled FAPI-46 and alpha-emitter (225Ac)-labelled FAPI-46 in pancreatic cancer models.MethodsPET scans (1 h post injection) were acquired in PANC-1 xenograft mice (n = 9) after the administration of [18F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [177Lu]FAPI-46 and [225Ac]FAPI-46 were evaluated in the xenograft model (total n = 12). For the determination of treatment effects, [177Lu]FAPI-46 and [225Ac]FAPI-46 were injected into PANC-1 xenograft mice at different doses: 3 MBq (n = 6), 10 MBq (n = 6), 30 MBq (n = 6), control (n = 4) for [177Lu]FAPI-46, and 3 kBq (n = 3), 10 kBq (n = 2), 30 kBq (n = 6), control (n = 7) for [225Ac]FAPI-46. Tumour sizes and body weights were followed.Results[18F]FAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration. [177Lu]FAPI-46 and [225Ac]FAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both [177Lu]FAPI-46 and [225Ac]FAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of [177Lu]FAPI-46 were relatively slow but lasted longer than those of [225Ac]FAPI-46.ConclusionThis study suggested the possible application of FAPI radioligand therapy in FAP-expressing pancreatic cancer. Further evaluation is necessary to find the best radionuclide with shorter half-life, as well as the combination with therapies targeting tumour cells directly.

Dataset Information

Evaluation of polydentate picolinic acid chelating ligands and an ?-melanocyte-stimulating hormone derivative for targeted alpha therapy using ISOL-produced ²²⁵Ac.

Background

Results

Conclusion

Publications

Evaluation of polydentate picolinic acid chelating ligands and an α-melanocyte-stimulating hormone derivative for targeted alpha therapy using ISOL-produced <sup>225</sup>Ac.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Evaluation of polydentate picolinic acid chelating ligands and an ?-melanocyte-stimulating hormone derivative for targeted alpha therapy using ISOL-produced 225Ac.

Background

Results

Conclusion

Publications

Evaluation of polydentate picolinic acid chelating ligands and an α-melanocyte-stimulating hormone derivative for targeted alpha therapy using ISOL-produced <sup>225</sup>Ac.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Evaluation of polydentate picolinic acid chelating ligands and an ?-melanocyte-stimulating hormone derivative for targeted alpha therapy using ISOL-produced ²²⁵Ac.