Development and Evaluation of Novel 68Ga/177Lu-Labeled PSMA Inhibitors with Enhanced Pharmacokinetics and Tumor Imaging for Prostate Cancer

被引：0
作者：
Li, Haiyang [1 ,2 ,4 ]
Liu, Yang [1 ,2 ,3 ]
Yuan, Hongmei [1 ,2 ,4 ]
Cai, Ping [1 ,2 ,4 ]
Wu, Tongtong [1 ,2 ,4 ]
Yang, Zhicong [1 ,2 ,4 ]
Nie, Jiaqi [1 ,2 ,4 ]
Zhang, Wei [5 ]
Huang, Zhanwen [1 ,2 ,3 ]
Liu, Nan [5 ]
Chen, Yue [1 ,2 ,3 ]
Zhou, Zhijun [1 ,2 ,3 ,4 ]
机构：
[1] Southwest Med Univ, Affiliated Hosp, Dept Nucl Med, Luzhou 646000, Sichuan, Peoples R China
[2] Nucl Med & Mol Imaging Key Lab Sichuan Prov, Luzhou 646000, Sichuan, Peoples R China
[3] Southwest Med Univ, Inst Nucl Med, Luzhou 646000, Sichuan, Peoples R China
[4] Southwest Med Univ, Sch Pharm, Dept Pharmaceut, Luzhou 646000, Sichuan, Peoples R China
[5] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Dept Nucl Med, Chengdu 610072, Sichuan, Peoples R China
来源：
MOLECULAR PHARMACEUTICS | 2025年 / 22卷 / 03期
基金：
中国国家自然科学基金;
关键词：
positron emission tomography (PET); Ga-68/Lu-177; prostate-specific membrane antigen (PSMA); prostate cancer; polyethylene glycol (PEG); MEMBRANE ANTIGEN;
D O I：
10.1021/acs.molpharmaceut.4c01302
中图分类号：
R-3 [医学研究方法]; R3 [基础医学];
学科分类号：
1001 ;
摘要：
Prostate-specific membrane antigen (PSMA) has been a key target for diagnosing and treating prostate cancer, particularly in high-grade, metastatic, and therapy-resistant tumors. This study presents a series of novel Ga-68- and Lu-177-labeled PSMA inhibitors, derived from the previously developed [Ga-68]Ga-Flu-1. We explored the impact of PEG chains, lipophilic macrocycles, and dimerization on their in vivo properties. The Ga-68- and Lu-177-labeled inhibitors were assessed for biodistribution and tumor targeting in PC3-PIP tumor xenografts, leading to the identification of several promising candidates based on imaging and tumor-specific uptake. Positron emission tomography (PET) imaging revealed that the poly(ethylene glycol)-modified [Ga-68]Ga-BisPSMA-P4 demonstrated rapid tumor penetration and excellent tumor-to-background contrast. In comparative biodistribution studies, the naphthalene ring-modified [Ga-68]Ga-BisPSMA-Nph-P4 showed higher tumor uptake (similar to 60% ID/g at 1 h postinjection) and rapid renal clearance (similar to 25% ID/g at 2 h postinjection). Additionally, [Lu-177]Lu-BisPSMA-Nph-P4 displayed superior retention, with significant uptake on day 7, highlighting its potential as a novel PSMA inhibitor for prostate cancer diagnosis and treatment.
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页码：1584 / 1597
页数：14
相关论文
共 38 条
  • [31] De Decker A., Vliegen G., Van Rompaey D., Peeraer A., Bracke A., Verckist L., Jansen K., Geiss-Friedlander R., Augustyns K., De Winter H., Novel Small Molecule-Derived, Highly Selective Substrates for Fibroblast Activation Protein (FAP), ACS Med. Chem. Lett., 10, 8, pp. 1173-1179, (2019)
  • [32] Ibrahim M., Ramadan E., Elsadek N.E., Emam S.E., Shimizu T., Ando H., Ishima Y., Elgarhy O.H., Sarhan H.A., Hussein A.K., Polyethylene glycol (PEG): The nature, immunogenicity, and role in the hypersensitivity of PEGylated products, J. Controlled Release, 351, pp. 215-230, (2022)
  • [33] Eberlein B., Mathes S., Darsow U., Biedermann T., Brockow K., Allergy to PEG (polyethylene glycol) - sensitivity of basophil activation test with COVID-19 mRNA-vaccine BNT162B2, Hum Vaccin Immunother, 20, 1, (2024)
  • [34] Czarnobilska M., Bulanda M., Kurnik-Lucka M., Gil K., Hypersensitivity to polyethylene glycol (PEG), Folia Med. Cracov., 61, 4, pp. 55-69, (2021)
  • [35] Davis M.I., Bennett M.J., Thomas L.M., Bjorkman P.J., Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase, Proc. Natl. Acad. Sci. U. S. A., 102, 17, pp. 5981-5986, (2005)
  • [36] Maung J., Mallari J.P., Girtsman T.A., Wu L.Y., Rowley J.A., Santiago N.M., Brunelle A.N., Berkman C.E., Probing for a hydrophobic a binding register in prostate-specific membrane antigen with phenylalkylphosphonamidates, Bioorg. Med. Chem., 12, 18, pp. 4969-4979, (2004)
  • [37] Nowok A., Dulski M., Grelska J., Szeremeta A.Z., Jurkiewicz K., Grzybowska K., Musial M., Pawlus S., Phenyl Ring: A Steric Hindrance or a Source of Different Hydrogen Bonding Patterns in Self-Organizing Systems?, J. Phys. Chem. Lett., 12, 8, pp. 2142-2147, (2021)
  • [38] Liu X., Chen L., Li Y., He C., Zhang X., Zhou H., Bao G., Zhu X., Xiang G., Ma X., Synthesis of novel DOTA-/AAZTA-based bifunctional chelators: Solution thermodynamics, peptidomimetic conjugation, and radiopharmaceutical evaluation, Biomed Pharmacother, 165, (2023)
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