Dataset Information

Synthesis and comparative biological evaluation of bifunctional ligands for radiotherapy applications of (90)Y and (177)Lu.

ABSTRACT: Zevalin® is an antibody-drug conjugate radiolabeled with a cytotoxic radioisotope ((90)Y) that was approved for radioimmunotherapy (RIT) of B-cell non-Hodgkin's lymphoma. A bifunctional ligand that displays favorable complexation kinetics and in vivo stability is required for effective RIT. New bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA for potential use in RIT were efficiently prepared by the synthetic route based on regiospecific ring opening of aziridinium ions with prealkylated triaza- or tetraaza-backboned macrocycles. The new bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA along with the known bimodal ligands 3p-C-NETA and 3p-C-DEPA were comparatively evaluated for potential use in targeted radiotherapy using ?-emitting radionuclides (90)Y and (177)Lu. The bifunctional ligands were evaluated for radiolabeling kinetics with (90)Y and (177)Lu, and the corresponding (90)Y or (177)Lu-radiolabeled complexes were studied for in vitro stability in human serum and in vivo biodistribution in mice. The results of the comparative complexation kinetic and stability studies indicate that size of macrocyclic cavity, ligand denticity, and bimodality of donor groups have a substantial impact on complexation of the bifunctional ligands with the radiolanthanides. The new promising bifunctional chelates in the DE4TA and NE3TA series were rapid in binding (90)Y and (177)Lu, and the corresponding (90)Y- and (177)Lu-radiolabeled complexes remained inert in human serum or in mice. The in vitro and in vivo data show that 3p-C-DE4TA and 3p-C-NE3TA are promising bifunctional ligands for targeted radiotherapy applications of (90)Y and (177)Lu.

SUBMITTER: Chong HS

PROVIDER: S-EPMC4376478 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synthesis and comparative biological evaluation of bifunctional ligands for radiotherapy applications of (90)Y and (177)Lu.

Chong Hyun-Soon HS Sun Xiang X Chen Yunwei Y Sin Inseok I Kang Chi Soo CS Lewis Michael R MR Liu Dijie D Ruthengael Varyanna C VC Zhong Yongliang Y Wu Ningjie N Song Hyun A HA

Bioorganic & medicinal chemistry 20141223 5

Zevalin® is an antibody-drug conjugate radiolabeled with a cytotoxic radioisotope ((90)Y) that was approved for radioimmunotherapy (RIT) of B-cell non-Hodgkin's lymphoma. A bifunctional ligand that displays favorable complexation kinetics and in vivo stability is required for effective RIT. New bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA for potential use in RIT were efficiently prepared by the synthetic route based on regiospecific ring opening of aziridinium ions with prealkylated triaza- o ...[more]

PMID: 25648683

Similar Datasets

Project description:IntroductionTherapeutic potential of β-emitting cytotoxic radionuclides (90)Y and (177)Lu has been demonstrated in numerous preclinical and clinical trials. A bifunctional chelate that can effectively complex with the radioisotopes is a critical component for molecular targeted radiotherapy (90)Y and (177)Lu. A new bifunctional chelate 5p-C-NETA with a relatively long alkyl spacer between the chelating backbone and the functional unit for conjugation to a tumor targeting moiety was synthesized. 5p-C-NETA was conjugated to a model targeting moiety, a cyclic Arg-Gly-Asp-D-Tyr-Lys (RGDyK) peptide binding integrin αvβ3 protein overexpressed on various cancers. 5p-C-NETA was conjugated to c(RGDyK) peptide and evaluated for potential use in molecular targeted radiotherapy of (90)Y and (177)Lu.Methods5p-C-NETA conjugated with c(RGDyK) was evaluated in vitro for radiolabeling, serum stability, binding affinity, and the result of the in vitro studies of 5p-C-NETA-c(RGDyK) was compared to that of 3p-C-NETA-c(RGDyK). (177)Lu-5p-C-NETA-c(RGDyK) was further evaluated for in vivo biodistribution using gliobastoma bearing mice.ResultThe new chelate rapidly and tightly bound to a cytotoxic radioisotope for cancer therapy, (90)Y or (177)Lu with excellent radiolabeling efficiency and maximum specific activity under mild condition (>99%, RT, <1 min). (90)Y- and (177)Lu-radiolabeled complexes of the new chelator remained stable in human serum without any loss of the radiolanthanide for 14 days. Introduction of the tumor targeting RGD moiety to the new chelator made little impact on complexation kinetics and stability with (90)Y or (177)Lu. (177)Lu-radiolabeled 5p-C-NETA-c(RGDyK) conjugate was shown to target tumors in mice and produced a favorable in vivo stability profile.ConclusionThe results of in vitro and in vivo evaluation suggest that 5p-C-NETA is an effective bifunctional chelate of (90)Y and (177)Lu that can be applied for generation of versatile molecular targeted radiopharmaceuticals.

Project description:Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands allow for labeling with 18F and radiometals for endoradiotherapy. rhPSMA-7.3 has been designated as a lead compound with promising preclinical data for 177Lu-rhPSMA-7.3, which has shown higher tumor uptake than 177Lu-PSMA I&T. In this retrospective analysis, we compared pretherapeutic clinical dosimetry data of both PSMA ligands. Methods: Six patients with metastatic castration-resistant prostate cancer underwent both 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T pretherapeutic dosimetry. Whole-body scintigraphy was performed at 1 h, 4 h, 24 h, 48 h, and 7 d after injection. Regions of interest covering the whole body, organs, bone marrow, and tumor lesions were drawn for each patient. Absorbed doses for individual patients and pretherapeutic applications were calculated using OLINDA/EXM. To facilitate the comparison of both ligands, we introduced the therapeutic index (TI), defined as the ratio of mean pretherapeutic doses to tumor lesions over relevant organs at risk. Results: Mean whole-body pretherapeutic effective doses for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T were 0.12 ± 0.07 and 0.05 ± 0.03 Sv/GBq, respectively. Mean absorbed organ doses for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T were, for example, 1.65 ± 0.28 and 0.73 ± 0.18 Gy/GBq for the kidneys, 0.19 ± 0.09 and 0.07 ± 0.03 Gy/GBq for the liver, 2.35 ± 0.78 and 0.80 ± 0.41 Gy/GBq for the parotid gland, and 0.67 ± 0.62 and 0.30 ± 0.27 Gy/GBq for the bone marrow, respectively. Tumor lesions received mean absorbed doses of 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T of 6.44 ± 6.44 and 2.64 ± 2.24 Gy/GBq, respectively. The mean TIs for the kidneys were 3.7 ± 2.2 and 3.6 ± 2.2 for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T, respectively, and those for the bone marrow were 15.2 ± 10.2 and 15.1 ± 10.2 for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T, respectively. Conclusion: Pretherapeutic clinical dosimetry confirmed preclinical results of mean absorbed doses for tumors that were 2-3 times higher for 177Lu-rhPSMA-7.3 than for 177Lu-PSMA I&T. Absorbed doses to normal organs also tended to be higher for 177Lu-rhPSMA-7.3, resulting overall in similar average TIs for both radiopharmaceuticals with considerable interpatient variability. 177Lu-rhPSMA-7.3 has promise for a therapeutic efficacy similar to that of 177Lu-PSMA I&T at smaller amounts of injected activity, simplifying radiation safety measurements (especially for large patient numbers or dose escalation regimens).

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).

Dataset Information

Synthesis and comparative biological evaluation of bifunctional ligands for radiotherapy applications of (90)Y and (177)Lu.

Publications

Synthesis and comparative biological evaluation of bifunctional ligands for radiotherapy applications of (90)Y and (177)Lu.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets