title: Auger Radiopharmaceutical Therapy Targeting Prostate-Specific Membrane Antigen.
abstract: 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).
  
  
  CONCLUSIONS
  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.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Kiess
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Il
authors.initials: I
authors.lastname: Minn
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Robert
authors.initials: R
authors.lastname: Hobbs
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland.|Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University, Baltimore, Maryland.
authors.forename: George
authors.initials: G
authors.lastname: Sgouros
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ronnie C
authors.initials: RC
authors.lastname: Mease
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Mrudula
authors.initials: M
authors.lastname: Pullambhatla
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Colette J
authors.initials: CJ
authors.lastname: Shen
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Foss
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland.|Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007610:Kallikreins / Q000378:metabolism* / Q000528:radiation effects; D008239:Lysine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods*; D017430:Prostate-Specific Antigen / Q000378:metabolism* / Q000528:radiation effects; D011471:Prostatic Neoplasms / Q000473:pathology / Q000503:physiopathology* / Q000532:radiotherapy*; D011829:Radiation Dosage; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D011878:Radiotherapy / Q000379:methods; D016896:Treatment Outcome; D014508:Urea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: C572626:2-(3-(1-carboxy-5-((6-fluoropyridine-3-carbonyl)amino)pentyl)ureido)pentanedioic acid; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D014508:Urea; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; D008239:Lysine
keywords: Auger; PSMA; iodine; prostate cancer; radiopharmaceutical therapy; radiotherapy