Preclinical Evaluation of
| Autor: | Sangeeta Ray, Banerjee, Il, Minn, Vivek, Kumar, Anders, Josefsson, Ala, Lisok, Mary, Brummet, Jian, Chen, Ana P, Kiess, Kwamena, Baidoo, Cory, Brayton, Ronnie C, Mease, Martin, Brechbiel, George, Sgouros, Robert F, Hobbs, Martin G, Pomper |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Proteasome Endopeptidase Complex Single Photon Emission Computed Tomography Computed Tomography Maximum Tolerated Dose Prostatic Neoplasms Tumor Protein Translationally-Controlled 1 Antineoplastic Agents Kaplan-Meier Estimate Lead Radioisotopes urologic and male genital diseases Alpha Particles Kidney Ligands Radiation Dosage Theranostics Theranostic Nanomedicine Mice Cell Line Tumor Animals Humans Neoplasm Metastasis Radiopharmaceuticals Radiometry |
| Zdroj: | J Nucl Med |
| ISSN: | 1535-5667 |
| Popis: | Targeted radiopharmaceutical therapy (TRT) using α-particle radiation is a promising approach for treating both large and micrometastatic lesions. We developed prostate-specific membrane antigen (PSMA)–targeted low-molecular-weight agents for (212)Pb-based TRT of patients with prostate cancer (PC) by evaluating the matching γ-emitting surrogate, (203)Pb. Methods: Five rationally designed low-molecular-weight ligands (L1-L5) were synthesized using the lysine-urea-glutamate scaffold, and PSMA inhibition constants were determined. Tissue biodistribution and SPECT/CT imaging of (203)Pb-L1–(203)Pb-L5 were performed on mice bearing PSMA(+) PC3 PIP and PSMA(−) PC3 flu flank xenografts. The absorbed radiation dose of the corresponding (212)Pb-labeled analogs was determined using the biodistribution data. Antitumor efficacy of (212)Pb-L2 was evaluated in PSMA(+) PC3 PIP and PSMA(−) PC3 flu tumor models and in the PSMA(+) luciferase-expressing micrometastatic model. (212)Pb-L2 was also evaluated for dose-escalated, long-term toxicity. Results: All new ligands were obtained in high yield and purity. PSMA inhibitory activities ranged from 0.10 to 17 nM. (203)Pb-L1–(203)Pb-L5 were synthesized in high radiochemical yield and specific activity. Whole-body clearance of (203)Pb-L1–(203)Pb-L5 was fast. The absorbed dose coefficients (mGy/kBq) of the tumor and kidneys were highest for (203)Pb-L5 (31.0, 15.2) and lowest for (203)Pb-L2 (8.0, 4.2). The tumor-to-kidney absorbed dose ratio was higher for (203)Pb-L3 (3.2) and (203)Pb-L4 (3.6) than for the other agents, but with lower tumor-to-blood ratios. PSMA(+) tumor lesions were visualized through SPECT/CT as early as 0.5 h after injection. A proof-of-concept therapy study with a single administration of (212)Pb-L2 demonstrated dose-dependent inhibition of tumor growth in the PSMA(+) flank tumor model. (212)Pb-L2 also demonstrated an increased survival benefit in the micrometastatic model compared with (177)Lu-PSMA-617. Long-term toxicity studies in healthy, immunocompetent CD-1 mice revealed kidney as the dose-limiting organ. Conclusion: (203)Pb-L1–(203)Pb-L5 demonstrated favorable pharmacokinetics for (212)Pb-based TRT. The antitumor efficacy of (212)Pb-L2 supports the corresponding (203)Pb/(212)Pb theranostic pair for PSMA-based α-particle TRT in advanced PC. |
| Databáze: | OpenAIRE |
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