title: (2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy.
abstract: Alpha-particle emitters have a high linear energy transfer and short range, offering the potential for treating micrometastases while sparing normal tissues. We developed a urea-based,211At-labeled small molecule targeting prostate-specific membrane antigen (PSMA) for the treatment of micrometastases due to prostate cancer (PC).
  
  
  METHODS
  PSMA-targeted (2S)-2-(3-(1-carboxy-5-(4-211At-astatobenzamido)pentyl)ureido)-pentanedioic acid (211At- 6: ) was synthesized. Cellular uptake and clonogenic survival were tested in PSMA-positive (PSMA+) PC3 PIP and PSMA-negative (PSMA-) PC3 flu human PC cells after211At- 6: treatment. The antitumor efficacy of211At- 6: was evaluated in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts at a 740-kBq dose and in mice bearing PSMA+, luciferase-expressing PC3-ML micrometastases. Biodistribution was determined in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts. Suborgan distribution was evaluated using α-camera images, and microscale dosimetry was modeled. Long-term toxicity was assessed in mice for 12 mo.
  
  
  RESULTS
  211At- 6: treatment resulted in PSMA-specific cellular uptake and decreased clonogenic survival in PSMA+ PC3 PIP cells and caused significant tumor growth delay in PSMA+ PC3 PIP flank tumors. Significantly improved survival was achieved in the newly developed PSMA+ micrometastatic PC model. Biodistribution showed uptake of211At- 6: in PSMA+ PC3 PIP tumors and in kidneys. Microscale kidney dosimetry based on α-camera images and a nephron model revealed hot spots in the proximal renal tubules. Long-term toxicity studies confirmed that the dose-limiting toxicity was late radiation nephropathy.
  
  
  CONCLUSIONS
  PSMA-targeted211At- 6: α-particle radiotherapy yielded significantly improved survival in mice bearing PC micrometastases after systemic administration.211At- 6: also showed uptake in renal proximal tubules resulting in late nephrotoxicity, highlighting the importance of long-term toxicity studies and microscale dosimetry.
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Kiess
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Il
authors.initials: I
authors.lastname: Minn
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: Ganesan
authors.initials: G
authors.lastname: Vaidyanathan
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Hobbs
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Anders
authors.initials: A
authors.lastname: Josefsson
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Colette
authors.initials: C
authors.lastname: Shen
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Mary
authors.initials: M
authors.lastname: Brummet
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: Jaeyeon
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: Eftychia
authors.initials: E
authors.lastname: Koumarianou
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Kwamena
authors.initials: K
authors.lastname: Baidoo
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ronnie C
authors.initials: RC
authors.lastname: Mease
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: George
authors.initials: G
authors.lastname: Sgouros
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland mpomper@jhmi.edu.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
mesh_terms: D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D045744:Cell Line, Tumor; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D020714:Maximum Tolerated Dose; D051379:Mice; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011854:Radiochemistry; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: C000618270:2-(3-(1-carboxy-5-(4-astatobenzamido)pentyl)ureido)pentanedioic acid; D000954:Antigens, Surface; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D014508:Urea; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: alpha emitter; astatine; oncology: GU; prostate cancer; prostate-specific membrane antigen; radiation dosimetry; radionuclide therapy; radiopharmaceuticals