Targeting of biotinylated oligonucleotides to prostate tumors with antibody-based delivery vehicles.
Specific delivery of therapeutic agents to tumor sites remains a problem and requires a nontoxic carrier able to bind a specific tumor cell marker. Although antibodies have been utilized as protein carriers for different types of drugs, they have not been employed for delivery of antisense oligonucleotides (ODNs). In this study, we modified monoclonal antibodies to target biotinylated ODNs to prostatic tumors which express prostate specific antigen (PSA) and prostate specific membrane antigen (PSMA). Modified antibodies retained immunoreactivity and demonstrated an ability to form complexes with ODNs. Biodistribution of (35)S-oligonucleotide-antibody complexes was also examined in nude mice bearing human derived LNCaP prostatic tumors. Delivering ODNs with modified prostate specific antibodies produced greater tissue uptake and higher blood levels with both PSA and PSMA directed antibodies. While tumor uptake was not significantly improved after 24 h, the overall results of this study provide some additional insights into the complexity of the antibody-mediated delivery of ODNs in vivo. The strategies employed here for the selective delivery of ODNs warrant further investigation.
Mirochnik
Yelena
Y
Division of Cellular Biology, Hektoen Institute of Medicine, Chicago, IL 60612, USA.
Rubenstein
Marvin
M
Guinan
Patrick
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000954:Antigens, Surface / Q000276:immunology; D001710:Biotin / Q000737:chemistry; D019921:Biotinylation / Q000379:methods; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D043425:Glutamate Carboxypeptidase II / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017430:Prostate-Specific Antigen / Q000276:immunology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D013462:Sulfur Radioisotopes; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D018796:Immunoconjugates; D016376:Oligonucleotides, Antisense; D013462:Sulfur Radioisotopes; D001710:Biotin; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017430:Prostate-Specific Antigen