RT Journal Article
SR Electronic
T1 Auger Radiopharmaceutical Therapy Targeting Prostate-Specific Membrane Antigen
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1401
OP 1407
DO 10.2967/jnumed.115.155929
VO 56
IS 9
A1 Ana P. Kiess
A1 Il Minn
A1 Ying Chen
A1 Robert Hobbs
A1 George Sgouros
A1 Ronnie C. Mease
A1 Mrudula Pullambhatla
A1 Colette J. Shen
A1 Catherine A. Foss
A1 Martin G. Pomper
YR 2015
UL http://jnm.snmjournals.org/content/56/9/1401.abstract
AB 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-(4-125I-iodo-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 (PSMA+) 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 PSMA+ 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, 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 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.