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1.
J Nucl Med ; 64(8): 1203-1209, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37024305

RESUMO

The goal of reducing the total-body radiation dose of macromolecule-based nuclear medicine with a 2-step pretargeting strategy has been achieved with several pretargeting methodologies in preclinical and clinical settings. However, the lack of modularity, biocompatibility, and in vivo stability in existing pretargeting agents obstructs their respective platforms' wide clinical use. We hypothesized that host-guest chemistry would provide an optimal pretargeting methodology. A cucurbit[7]uril host and an adamantane guest molecule form a high-affinity host-guest complex (association constant, ∼1014 M-1), and in this work, we explored the use of this noncovalent interaction as the basis for antibody-based pretargeted PET. Along with the straightforward modularity of these agents, cucurbit[7]uril and adamantane are recognized to have high in vivo stability and suitability for human use, which is why we proposed this methodology as the ideal approach for pretargeted nuclear medicine. Methods: Three 64Cu-labeled adamantane guest radioligands were developed, and their in vitro stability, lipophilicity, and in vivo blood half-lives were compared. The adamantane radioligands were analyzed for pretargeting using a cucurbit[7]uril-modified carcinoembryonic antigen-targeting full-length antibody, hT84.66-M5A, as the macromolecule pretargeting agent with 2 different dosing schedules. These molecules were evaluated for pretargeting in human pancreatic cancer BxPC3 and MIAPaCa-2 mouse xenografts using PET and in vivo biodistribution studies. The dosimetry of the cucurbit[7]uril-adamantane (CB7-Adma) pretargeting approach in men was calculated and compared with that of the directly 89Zr-labeled hT84.66-M5A. Results: The adamantane radioligands possessed high in vitro stability up to 24 h (>90%). Pretargeted PET with CB7-Adma methodology resulted in specific tumor uptake (P < 0.05) with low background signal. The in vivo formed CB7-Adma complex was demonstrated to be stable, with high tumor uptake up to 24 h after radioligand injection (12.0 ± 0.9 percentage injected dose/g). The total-body radiation dose of the pretargeting strategy was only 3.3% that of the directly 89Zr-labeled hT84.66-M5A. Conclusion: The CB7-Adma strategy is highly suitable for pretargeted PET. The exceptional stability of the pretargeting agents and the specific and high tumor uptake of the pretargeted adamantane radioligands provide great potential for the platform.


Assuntos
Adamantano , Masculino , Humanos , Animais , Camundongos , Adamantano/química , Distribuição Tecidual , Xenoenxertos , Anticorpos/metabolismo
2.
Mol Pharm ; 19(7): 2268-2278, 2022 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-35700402

RESUMO

Pretargeting is a technique that uses macromolecules as targeting agents for nuclear imaging and therapy with the goal of reducing the radiation toxicity to healthy tissues often associated with directly radiolabeled macromolecules. In pretargeting, a macromolecule is radiolabeled in vivo at the target site using a radiolabeled small molecule (radioligand) that interacts with the macromolecule with high specificity. We report an investigation of host-guest chemistry-driven pretargeting using copper-64 radiolabeled ferrocene (Fc; guest) compounds and a cucurbit[7]uril (CB7; host) molecule functionalized carcinoembryonic antigen targeting hT84.66-M5A monoclonal antibody (CB7-M5A). Two novel ferrocene-based radioligands ([64Cu]Cu-NOTA-PEG3-Fc and [64Cu]Cu-NOTA-PEG7-Fc) were prepared, and their in vitro stability, pharmacokinetic in vivo profile in healthy mice, and pretargeting performance in a subcutaneous BxPC3 human pancreatic cancer cell xenograft mouse model were compared. The antibody dosing was optimized using a zirconium-89 radiolabeled M5A antibody ([89Zr]Zr-DFO-M5A) in a BxPC3 xenograft model, and the dosimetry of [89Zr]Zr-DFO-M5A and the pretargeting approach were compared. Finally, the effects of varying lag times up to 9 days between CB7-M5A and radioligand injection were investigated. In vivo pretargeting studies with both ferrocene radioligands resulted in specific tumor uptake (p = 0.0006 and p = 0.003) and also showed that the host-guest-based pretargeting approach excels with extended lag times up to 9 days with good tumor localization, suggesting that host-guest pretargeting may be suitable for use without clearing agents which have complicated clinical application of this technique. To our knowledge, the reported lag time of 9 days is the longest investigated lag time in any reported pretargeting studies.


Assuntos
Radioisótopos de Cobre , Imunoconjugados , Animais , Anticorpos Monoclonais/química , Linhagem Celular Tumoral , Radioisótopos de Cobre/química , Humanos , Imunoconjugados/farmacocinética , Metalocenos , Camundongos , Tomografia por Emissão de Pósitrons/métodos
3.
Bioconjug Chem ; 32(8): 1554-1558, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34156824

RESUMO

Pretargeted positron emission tomography is a macromolecule-driven nuclear medicine technique that involves targeting a preadministered antigen target-bound macromolecule with a radioligand in vivo, aiming to minimize the overall radiation dose. This study investigates the use of antibody based host-guest chemistry methodology for pretargeted positron emission tomography. We hypothesize that the novel pretargeting approach reported here overcomes the challenges the current pretargeting platforms have with the in vivo stability and modularity of the pretargeting components. A cucurbit[7]uril host molecule modified, anti-carcinoembryonic antigen antibody (M5A; CB7-M5A) and a 68Ga-radiolabeled ferrocene guest radioligand ([68Ga]Ga-NOTA-PEG3-NMe2-Fc) were studied as potential host-guest chemistry pretargeting agents for positron emission tomography in BxPC3 xenografted nude mice. The viability of the platform was studied via in vivo biodistribution and positron emission tomography. Tumor uptake of [68Ga]Ga-NOTA-PEG3-NMe2-Fc was significantly higher in mice which received CB7-M5A prior to the radioligand injection (pretargeted) (3.3 ± 0.7%ID/g) compared to mice which only received the radioligand (nonpretargeted) (0.2 ± 0.1%ID/g).


Assuntos
Compostos Ferrosos/química , Compostos Macrocíclicos/química , Metalocenos/química , Neoplasias da Próstata/diagnóstico por imagem , Animais , Antígeno Carcinoembrionário/análise , Humanos , Imunoconjugados/química , Masculino , Camundongos Nus , Células PC-3 , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química
4.
J Nucl Med ; 62(9): 1200-1206, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34016727

RESUMO

The principle of pretargeted radioimmunoimaging and therapy has been investigated over the past 30 y in preclinical and clinical settings with the aim of reducing the radiation burden of healthy tissue for antibody-based nuclear medicine techniques. In the past few decades, 4 pretargeting methodologies have been proposed, and 2 of them-the bispecific antibody-hapten and the streptavidin-biotin platforms-have been evaluated in humans in phase 1 and 2 studies. With this review article, we aim to survey clinical pretargeting studies in order to understand the challenges that these platforms have faced in human studies and to provide an overview of how the clinical approval of the pretargeting system has proceeded in the past several decades. Additionally, we will discuss the successes of the pretargeting human studies and compare and highlight the pretargeting approaches and conditions that will advance clinical translation of the pretargeting platform in the future.


Assuntos
Radioimunodetecção , Radioimunoterapia , Humanos , Estreptavidina
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