Pretargeted radioimmunotherapy in tumored mice using an in vivo 212Pb/ 212Bi generator

• Published in: Nuclear medicine and biology Vol. 32; no. 7; pp. 741 - 747
• Main Authors: Su, Fu-Min, Beaumier, Paul, Axworthy, Don, Atcher, Robert, Fritzberg, Alan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2005
• Subjects: Animals; Biotin - analogs & derivatives; Biotin - pharmacokinetics; Biotin - therapeutic use; Bismuth - pharmacokinetics; Bismuth - therapeutic use; Bismuth-212; Cell Line, Tumor; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - radiotherapy; Drug Delivery Systems - methods; Female; Humans; In situ radionuclide generator; Lead Radioisotopes - pharmacokinetics; Lead Radioisotopes - therapeutic use; Lead-212; Metabolic Clearance Rate; Mice; Mice, Inbred BALB C; Organ Specificity; Organometallic Compounds - pharmacokinetics; Organometallic Compounds - therapeutic use; Pre-targeting; Radioimmunotherapy; Radioimmunotherapy - methods; Radioisotopes - pharmacokinetics; Radioisotopes - therapeutic use; Radionuclide therapy; Radiopharmaceuticals - pharmacokinetics; Radiopharmaceuticals - therapeutic use; Rats; Rats, Sprague-Dawley; Tissue Distribution; Tumor; Pre-targeting; Radioimmunotherapy
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2005.06.009

Pretargeting is the concept that combines optimal delivery of the antibody and rapid capture and elimination of the radioactivity. In this study, we evaluated the potential of antibody pretargeting to enable the tumor-targeting 212Pb for in vivo generation of 212Bi for α particle radiotherapy. The 212Pb/ 212Bi chelate of DOTA-biotin, as well as their γ-emitting analogues, 203Pb and 205Bi, was prepared and characterized. The radiolabeled compounds were injected in animals for evaluation of tumor targeting and normal tissue uptake and retention. In the pretargeting protocol, injection of 400 μg of NR-LU-10 antibody–streptavidin conjugate was given at t=0 h, then 100 μg of N-acetyl-galatosamine-biotin clearing agent was injected at t=20–24 h; finally, 1 μg of 212Pb/ 212Bi-DOTA-biotin was injected 6 h later. Both 203Pb and 205Bi-DOTA-biotin were stable for at least 4 days in the different challenging solutions including PBS, 10 mM DTPA and serum. Contrary to its γ-emitting analogues, radiolabeled 212Pb-DOTA-biotin was not stable. There was greater than 30% of free 212Bi released 4 h after 212Pb-labeled DOTA-biotin. The results of pretargeting protocol of 203Pb and 205Bi-DOTA-biotin showed that the tumor target reached 20% injected dose (ID)/g at 4 h postinjection and remained high for 5 days. The %ID/g in the whole blood and other nontarget organs was low after administration of labeled 203Pb and 205Bi-DOTA-biotin similar to the biodistribution of labeled DOTA-biotin alone. In the animals administered 212Pb-DOTA-biotin, radioactivity in nontarget organs was low except the kidneys. The %ID/g in the kidney for 212Bi was 14.5 at 2 h, higher than 212Pb, but dropped to about 6% ID/g by 4 h. However, tumor uptake for 212Pb and 212Bi was >25% ID/g at 1 h postinjection and remained so through 24 h. Antibody pretargeting system with Mab-streptavidin, clearing agent and DOTA-biotin provides the potential of 212Bi for solid tumor radiotherapy despite the release of 212Bi after 212Pb decay. Dosimetry calculations resulted in tumor dose at 93 rad/μCi and ratios of tumor to marrow and kidney at 386:1 and 12:1, respectively.