Auger Radiopharmaceutical Therapy Targeting Prostate-Specific Membrane Antigen.

Abstract

UNLABELLED:

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.

• Authors: Ana P Kiess, Il Minn, Ying Chen, Robert Hobbs, George Sgouros, Ronnie C Mease, Mrudula Pullambhatla, Colette J Shen, Catherine A Foss, Martin G Pomper
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 56 Issue 9 Pg. 1401-1407 (Sep 2015) ISSN: 1535-5667 [Electronic] United States
• PMID: 26182968 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Chemical References

• 2-(3-(1-carboxy-5-((6-fluoropyridine-3-carbonyl)amino)pentyl)ureido)pentanedioic acid
• Iodine Radioisotopes
• Radiopharmaceuticals
• Urea
• KLK3 protein, human
• Kallikreins
• Prostate-Specific Antigen
• Lysine

Topics

• Apoptosis (radiation effects)
• Cell Line, Tumor
• Cell Survival (radiation effects)
• Humans
• Iodine Radioisotopes (pharmacokinetics, therapeutic use)
• Kallikreins (metabolism, radiation effects)
• Lysine (analogs & derivatives, pharmacokinetics, therapeutic use)
• Male
• Molecular Targeted Therapy (methods)
• Prostate-Specific Antigen (metabolism, radiation effects)
• Prostatic Neoplasms (pathology, physiopathology, radiotherapy)
• Radiation Dosage
• Radiopharmaceuticals (pharmacokinetics)
• Radiotherapy (methods)
• Treatment Outcome
• Urea (analogs & derivatives, pharmacokinetics, therapeutic use)