title: Preparation and Evaluation of Radiolabeled Antibody Recruiting Small Molecules That Target Prostate-Specific Membrane Antigen for Combined Radiotherapy and Immunotherapy.
abstract: The feasibility of developing a single agent that can deliver radioactive iodine and also direct cellular immune function by engaging endogenous antibodies as an antibody-recruiting small molecule (ARM) was determined. A library of new prostate-specific membrane antigen (PSMA)-binding ligands that contained antibody-recruiting 2,4-dinitrophenyl (DNP) groups and iodine were synthesized and screened in vitro and in vivo. A lead compound (9b) showed high affinity for PSMA and the ability to bind anti-DNP antibodies. Biodistribution studies of the iodine-125 analogue showed 3% ID/g in LNCaP xenograft tumors at 1 h postinjection with tumor-to-blood and tumor-to-muscle ratios of 10:1 and 44:1, respectively. The radiolabeled analogue was bound and internalized by LNCaP cells, with both functions blocked using a known PSMA inhibitor. A second candidate showed high tumor uptake (>10% ID/g) but had minimal binding to anti-DNP antibodies. The compounds reported represent the first examples of small molecules developed specifically for combination immunotherapy and radiotherapy for prostate cancer.
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.|Department of Chemistry, Faculty of Science, Tanta University , 31527 Tanta, Egypt.
authors.forename: Afaf R
authors.initials: AR
authors.lastname: Genady
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Janzen
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Banevicius
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: El-Gamal
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
authors.forename: Mohamed E
authors.initials: ME
authors.lastname: El-Zaria
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.|Centre for Probe Development and Commercialization , 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
authors.forename: John F
authors.initials: JF
authors.lastname: Valliant
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000187:drug effects*; D045744:Cell Line, Tumor; D004140:Dinitrophenols / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017430:Prostate-Specific Antigen / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000628:therapy*; D016499:Radioimmunotherapy / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D054852:Small Molecule Libraries; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D004140:Dinitrophenols; D008024:Ligands; D019275:Radiopharmaceuticals; D054852:Small Molecule Libraries; D017430:Prostate-Specific Antigen