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Auger Radiopharmaceutical Therapy Targeting Prostate-Specific Membrane Antigen

2015; Society of Nuclear Medicine and Molecular Imaging; Volume: 56; Issue: 9 Linguagem: Inglês

10.2967/jnumed.115.155929

1535-5667

Ana P. Kiess, Il Minn, Ying Chen, Robert F. Hobbs, George Sgouros, Ronnie C. Mease, Mrudula Pullambhatla, Colette J. Shen, Catherine A. Foss, Martin G. Pomper,

Mass Spectrometry Techniques and Applications

Auger electron emitters such as 125 I have a high linear energy transfer and short range of emission (<10 μm), making them suitable for treating micrometastases while sparing normal tissues. We used a highly specific small molecule targeting the prostate-specific membrane antigen (PSMA) to deliver 125 I to prostate cancer cells. Methods: The PSMA-targeting Auger emitter 2-[3-[1-carboxy-5-(4- 125 I-iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid ( 125 I-DCIBzL) was synthesized. DNA damage (via phosphorylated H2A histone family member X staining) and clonogenic survival were tested in PSMA-positive (PSMA+) PC3 PIP and PSMA-negative (PSMA−) PC3 flu human prostate cancer cells after treatment with 125 I-DCIBzL. Subcellular drug distribution was assessed with confocal microscopy using a related fluorescent PSMA-targeting compound YC-36. In vivo antitumor efficacy was tested in nude mice bearing PSMA+ PC3 PIP or PSMA− PC3 flu flank xenografts. Animals were administered (intravenously) 111 MBq (3 mCi) of 125 I-DCIBzL, 111 MBq (3 mCi) of 125 I-NaI, an equivalent amount of nonradiolabeled DCIBzL, or saline. Results: After treatment with 125 I-DCIBzL, PSMA+ PC3 PIP cells exhibited increased DNA damage and decreased clonogenic survival when compared with PSMA– PC3 flu cells. Confocal microscopy of YC-36 showed drug distribution in the perinuclear area and plasma membrane. Animals bearing PSMA+ PC3 PIP tumors had significant tumor growth delay after treatment with 125 I-DCIBzL, with only 1 mouse reaching 5 times the initial tumor volume by 60 d after treatment, compared with a median time to 5 times volume of less than 15 d for PSMA– PC3 flu tumors and all other treatment groups ( P = 0.002 by log-rank test). Conclusion: PSMA-targeted radiopharmaceutical therapy with the Auger emitter 125 I-DCIBzL yielded highly specific antitumor efficacy in vivo, suggesting promise for treatment of prostate cancer micrometastases.