Novel Radiotheranostic Ligands Targeting Prostate-Specific Membrane Antigen Based on Dual Linker Approach.

IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Pharmaceutics Pub Date : 2025-01-06 Epub Date: 2024-11-30 DOI:10.1021/acs.molpharmaceut.4c00974
Nobuki Kazuta, Kazuma Nakashima, Yuta Tarumizu, Takumi Sato, Yoshifumi Maya, Hiroyuki Watanabe, Masahiro Ono
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引用次数: 0

Abstract

Radiotheranostics using prostate-specific membrane antigen (PSMA)-targeting radioligands offers precision medicine by performing radionuclide therapy based on results of diagnosis. Albumin binder (ALB) binds to albumin reversibly and contributes to effective radiotheranostics by enhancing tumor accumulation of PSMA-targeting radioligands. We newly developed two ALB-containing PSMA-targeting radioligands including dual functional linkers, a hydrophilic linker, d-glutamic acid, and a hydrophobic linker, 4-(aminomethyl)benzoic acid, with the opposite arrangement (PNT-DA6 and PNT-DA7). A biodistribution study of [111In]In-PNT-DA6 indicated that the introduction and arrangement of dual functional linkers contributed to improved pharmacokinetics. A single photon emission computed tomography study of [111In]In-PNT-DA6 produced a clear PSMA-expressing tumor image. Moreover, [225Ac]Ac-PNT-DA6 showed the inhibition of tumor growth in targeted radionuclide therapy in PSMA-expressing tumor-bearing mice. These results indicated that [111In]In-PNT-DA6 and [225Ac]Ac-PNT-DA6 exhibited useful characteristics as PSMA-targeting radiotheranostic ligands.

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基于双连接体方法的新型前列腺特异性膜抗原放射治疗配体。
放射治疗使用前列腺特异性膜抗原(PSMA)靶向放射配体,根据诊断结果进行放射性核素治疗,提供精准医疗。白蛋白结合剂(ALB)与白蛋白可逆结合,并通过促进psma靶向放射配体的肿瘤积累,有助于有效的放射治疗。我们新开发了两个含alb的psma靶向放射配体,包括双功能连接体,亲水性连接体d-谷氨酸和疏水性连接体4-(氨基甲基)苯甲酸,具有相反的排列(PNT-DA6和PNT-DA7)。[111In]In-PNT-DA6的生物分布研究表明,双功能连接物的引入和安排有助于改善药代动力学。单光子发射计算机断层扫描研究[111In]In-PNT-DA6产生了清晰的表达psma的肿瘤图像。此外,[225Ac]Ac-PNT-DA6在靶向放射性核素治疗表达psma的荷瘤小鼠中显示出肿瘤生长的抑制作用。这些结果表明[111In]In-PNT-DA6和[225Ac]Ac-PNT-DA6具有作为psma靶向放射治疗配体的有用特性。
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来源期刊
Molecular Pharmaceutics
Molecular Pharmaceutics 医学-药学
CiteScore
8.00
自引率
6.10%
发文量
391
审稿时长
2 months
期刊介绍: Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.
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