Auger radiopharmaceutical therapy targeting prostate-specific membrane antigen

Auger electron emitters such as ¹²⁵I 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 ¹²⁵I to prostate cancer cells. Methods: The PSMA-targeting Auger emitter 2-[3-[1-carboxy-5-(4-¹²⁵Iiodo- benzoylamino)-pentyl]-ureido]-pentanedioic acid (¹²⁵I-DCIBzL) was synthesized. DNA damage (via phosphorylated H2A histone family member X staining) and clonogenic survival were tested in PSMA-positive (PSMA1) PC3 PIP and PSMA-negative (PSMA-) PC3 flu human prostate cancer cells after treatment with ¹²⁵I-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 PSMA1 PC3 PIP or PSMA- PC3 flu flank xenografts. Animals were administered (intravenously) 111 MBq (3 mCi) of ¹²⁵I-DCIBzL, 111 MBq (3 mCi) of ¹²⁵I-NaI, an equivalent amount of nonradiolabeled DCIBzL, or saline. Results: After treatment with ¹²⁵I-DCIBzL, PSMA1 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 PSMA1 PC3 PIP tumors had significant tumor growth delay after treatment with ¹²⁵I-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 ¹²⁵I-DCIBzL yielded highly specific antitumor efficacy in vivo, suggesting promise for treatment of prostate cancer micrometastases.