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1.
J Nucl Med ; 65(9): 1435-1442, 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39142831

RESUMEN

Here we describe an anti-prostate-specific membrane antigen (PSMA) minibody (IAB2MA) conjugated to an octadentate, macrocyclic chelator based on four 1-hydroxypyridin-2-one coordinating units (Lumi804 [L804]) labeled with 89Zr (PET imaging) and 177Lu (radiopharmaceutical therapy), with the goal of developing safer and more efficacious treatment options for prostate cancer. Methods: L804 was compared with the current gold standard chelators, DOTA and deferoxamine (DFO), conjugated to IAB2MA for radiolabeling with 177Lu and 89Zr in cell binding, preclinical biodistribution, imaging, dosimetry, and efficacy studies in the PSMA-positive PC3-PIP tumor-bearing mouse model of prostate cancer. Results: Quantitative radiolabeling (>99% radiochemical yield) of L804-IAB2MA with 177Lu or 89Zr was achieved at ambient temperature in under 30 min, comparable to 89Zr labeling of DFO-IAB2MA. In contrast, DOTA-IAB2MA was radiolabeled with 177Lu for 30 min at 37°C in approximately 90% radiochemical yield, requiring further purification. Using europium(III) as a luminescent surrogate, high binding affinity of Eu-L804-IAB2MA to PSMA was demonstrated in PC3-PIP cells (dissociation constant, 4.6 ± 0.6 nM). All 4 radiolabeled constructs showed significantly higher levels of internalization after 30 min in the PC3-PIP cells than in PSMA-negative PC3-FLU cells. The accumulation of 177Lu- and 89Zr-L804-IAB2MA in PC3-PIP tumors and all organs examined (i.e., heart, liver, spleen, kidney, muscle, salivary glands, lacrimal glands, carcass, and bone) was significantly lower than that of 177Lu-DOTA-IAB2MA and 89Zr-DFO-IAB2MA at 96 and 72 h after injection, respectively. Generally, SPECT/CT and PET/CT imaging data showed no significant difference in the SUVmean of the tumors or muscle between the radiotracers. Dosimetry analysis via both organ-level and voxel-level dose calculation methods indicated significantly higher absorbed doses of 177Lu-DOTA-IAB2MA in tumors, kidney, liver, muscle, and spleen than of 177Lu-L804-IAB2MA. PC3-PIP tumor-bearing mice treated with single doses of 177Lu-L804-IAB2MA (18.4 or 22.2 MBq) exhibited significantly prolonged survival and reduced tumor volume compared with unlabeled minibody control. No significant difference in survival was observed between groups of mice treated with 177Lu-L804-IAB2MA or 177Lu-DOTA-IAB2MA (18.4 or 22.2 MBq). Treatment with 177Lu-L804-IAB2MA resulted in lower absorbed doses in tumors and less toxicity than that of 177Lu-DOTA-IAB2MA. Conclusion: 89Zr- and 177Lu-L804-IAB2MA may be a promising theranostic pair for imaging and therapy of prostate cancer.


Asunto(s)
Antígenos de Superficie , Quelantes , Glutamato Carboxipeptidasa II , Lutecio , Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Radioisótopos , Radiofármacos , Circonio , Masculino , Circonio/química , Radioisótopos/uso terapéutico , Radioisótopos/química , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/metabolismo , Glutamato Carboxipeptidasa II/metabolismo , Animales , Radiofármacos/química , Radiofármacos/uso terapéutico , Radiofármacos/farmacocinética , Quelantes/química , Antígenos de Superficie/metabolismo , Ratones , Humanos , Distribución Tisular , Línea Celular Tumoral , Nanomedicina Teranóstica
2.
J Nucl Med ; 64(7): 1062-1068, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37142300

RESUMEN

227Th is a promising radioisotope for targeted α-particle therapy. It produces 5 α-particles through its decay, with the clinically approved 223Ra as its first daughter. There is an ample supply of 227Th, allowing for clinical use; however, the chemical challenges of chelating this large tetravalent f-block cation are considerable. Using the CD20-targeting antibody ofatumumab, we evaluated chelation of 227Th4+ for α-particle-emitting and radiotheranostic applications. Methods: We compared 4 bifunctional chelators for thorium radiopharmaceutical preparation: S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 2-(4-isothicyanatobenzyl)-1,2,7,10,13-hexaazacyclooctadecane-1,4,7,10,13,16-hexaacetic acid (p-SCN-Bn-HEHA), p-isothiacyanatophenyl-1-hydroxy-2-oxopiperidine-desferrioxamine (DFOcyclo*-p-Phe-NCS), and macrocyclic 1,2-HOPO N-hydroxysuccinimide (L804-NHS). Immunoconstructs were evaluated for yield, purity, and stability in vitro and in vivo. Tumor targeting of the lead 227Th-labeled compound in vivo was performed in CD20-expressing models and compared with a companion 89Zr-labeled PET agent. Results: 227Th-labeled ofatumumab-chelator constructs were synthesized to a radiochemical purity of more than 95%, excepting HEHA. 227Th-HEHA-ofatumumab showed moderate in vitro stability. 227Th-DFOcyclo*-ofatumumab presented excellent 227Th labeling efficiency; however, high liver and spleen uptake was revealed in vivo, indicative of aggregation. 227Th-DOTA-ofatumumab labeled poorly, yielding no more than 5%, with low specific activity (0.08 GBq/g) and modest long-term in vitro stability (<80%). 227Th-L804-ofatumumab coordinated 227Th rapidly and efficiently at high yields, purity, and specific activity (8 GBq/g) and demonstrated extended stability. In vivo tumor targeting confirmed the utility of this chelator, and the diagnostic analog, 89Zr-L804-ofatumumab, showed organ distribution matching that of 227Th to delineate SU-DHL-6 tumors. Conclusion: Commercially available and novel chelators for 227Th showed a range of performances. The L804 chelator can be used with potent radiotheranostic capabilities for 89Zr/227Th quantitative imaging and α-particle therapy.


Asunto(s)
Linfoma , Radioinmunoterapia , Humanos , Radioinmunoterapia/métodos , Medicina de Precisión , Radioisótopos/uso terapéutico , Radioisótopos/química , Quelantes/química , Radiofármacos/uso terapéutico , Linfoma/patología , Línea Celular Tumoral , Circonio/química
3.
EBioMedicine ; 71: 103571, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34530385

RESUMEN

BACKGROUND: Malignant gliomas are deadly tumours with few therapeutic options. Although immunotherapy may be a promising therapeutic strategy for treating gliomas, a significant barrier is the CD11b+ tumour-associated myeloid cells (TAMCs), a heterogeneous glioma infiltrate comprising up to 40% of a glioma's cellular mass that inhibits anti-tumour T-cell function and promotes tumour progression. A theranostic approach uses a single molecule for targeted radiopharmaceutical therapy (TRT) and diagnostic imaging; however, there are few reports of theranostics targeting the tumour microenvironment. METHODS: Utilizing a newly developed bifunctional chelator, Lumi804, an anti-CD11b antibody (αCD11b) was readily labelled with either Zr-89 or Lu-177, yielding functional radiolabelled conjugates for PET, SPECT, and TRT. FINDINGS: 89Zr/177Lu-labeled Lumi804-αCD11b enabled non-invasive imaging of TAMCs in murine gliomas. Additionally, 177Lu-Lumi804-αCD11b treatment reduced TAMC populations in the spleen and tumour and improved the efficacy of checkpoint immunotherapy. INTERPRETATION: 89Zr- and 177Lu-labeled Lumi804-αCD11b may be a promising theranostic pair for monitoring and reducing TAMCs in gliomas to improve immunotherapy responses. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.


Asunto(s)
Glioma/diagnóstico , Glioma/terapia , Linfocitos Infiltrantes de Tumor/metabolismo , Terapia Molecular Dirigida , Tomografía de Emisión de Positrones , Radiofármacos , Macrófagos Asociados a Tumores/metabolismo , Animales , Biomarcadores de Tumor , Línea Celular Tumoral , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Glioma/etiología , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunofenotipificación , Lutecio , Linfocitos Infiltrantes de Tumor/patología , Ratones , Imagen Multimodal/métodos , Tomografía de Emisión de Positrones/métodos , Radioisótopos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Circonio
4.
J Am Chem Soc ; 141(28): 11071-11081, 2019 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-31268312

RESUMEN

A series of highly luminescent europium(III) complexes which exhibit photoluminescence from the Eu(III) center following energy transfer from the UV absorbing organic sensitizer have been investigated using a combination of ultrafast optical transient absorption and Eu L3 X-ray transient absorption techniques. We have previously demonstrated that the latter can be used as a signature of 4f-4f excitation responsible for the photoluminescence in these Eu(III) coordination complexes, but the long time scale of the earlier measurements did not allow direct observation of the ligand-to-metal energy transfer step, preventing a determination of the sensitization mechanism. Here, we provide the first direct experimental verification that Dexter electron exchange from the ligand triplet state is the dominant energy transfer mechanism in these photoluminescent systems. Moreover, the optical transient absorption results obtained herein imply that energy transfer for all three compounds has near unity yield, regardless of differences in the sensitization efficiencies, suggesting that the variations in the sensitization efficiencies are determined almost entirely by differences in the ligand-centered intersystem crossing rates. The implications for the rational design of more effective photoluminescent lanthanide complexes are discussed.


Asunto(s)
Complejos de Coordinación/química , Europio/química , Sustancias Luminiscentes/química , Transferencia de Energía , Ligandos , Espectrofotometría Ultravioleta , Espectroscopía de Absorción de Rayos X
5.
Inorg Chem ; 55(1): 114-24, 2016 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-26679038

RESUMEN

A series of 10 tetradentate 1-hydroxy-pyridin-2-one (1,2-HOPO) ligands and corresponding eight-coordinated photoluminescent Eu(III) and Sm(III) complexes were prepared. Generally, the ligands differ by the linear (nLI) aliphatic linker length, from 2 to 8 methylene units between the bidentate 1,2-HOPO chelator units. The photoluminescent quantum yields (Φtot) were found to vary with the linker length, and the same trend was observed for the Eu(III) and Sm(III) complexes. The 2LI and 5LI bridged complexes are the brightest (Φtotxε). The change in ligand wrapping pattern between 2LI and 5LI complexes observed by X-ray diffraction (XRD) is further supported by density functional theory (DFT) calculations. The bimodal Φtot trends of the Eu(III) and Sm(III) complexes are rationalized by the change in ligand wrapping pattern as the bridge (nLI) is increased in length.


Asunto(s)
Europio/química , Samario/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Ligandos , Luminiscencia , Espectroscopía de Protones por Resonancia Magnética , Soluciones , Agua/química
6.
J Am Chem Soc ; 137(8): 2816-9, 2015 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-25607882

RESUMEN

We report the preparation and new insight into photophysical properties of luminescent hydroxypyridonate complexes [M(III)L](-) (M = Eu or Sm) of the versatile 3,4,3-LI(1,2-HOPO) ligand (L). We report the crystal structure of this ligand with Eu(III) as well as insights into the coordination behavior and geometry in solution by using magnetic circular dichroism. In addition TD-DFT calculations were used to examine the excited states of the two different chromophores present in the 3,4,3-LI(1,2-HOPO) ligand. We find that the Eu(III) and Sm(III) complexes of this ligand undergo a transformation after in situ preparation to yield complexes with higher quantum yield (QY) over time. It is proposed that the lower QY in the in situ complexes is not only due to water quenching but could also be due to a lower degree of f-orbital overlap (in a kinetic isomer) as indicated by magnetic circular dichroism measurements.


Asunto(s)
Europio/química , Compuestos Heterocíclicos con 1 Anillo/química , Compuestos Organometálicos/química , Piridonas/química , Samario/química , Ligandos , Mediciones Luminiscentes , Modelos Moleculares , Conformación Molecular
7.
J Am Chem Soc ; 136(11): 4186-91, 2014 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-24606064

RESUMEN

We report time-resolved X-ray absorption near edge structure (TR-XANES) measurements at the Eu L3 edge upon photoexcitation of several Eu(III)-based luminescent lanthanide complexes. We find an unambiguous signature of the 4f intrashell excitation that occurs upon energy transfer from the photoactive organic antennas to the lanthanide species. Phenomenologically, this observation provides the basis for direct investigation of a crucial step in the energy transfer pathways that lead to sensitized luminescence in lanthanide-based dyes. Interestingly, the details of the TR-XANES feature suggest that the degree of 4f-5d hybridization may itself vary depending on the excited state of the Eu(III) ion.

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