| Abstract | Previous studies have shown that pretargeting allows rapid visualization of renal cell carcinomas (RCC) with an (111)In-labeled bivalent peptide. For radioimmunotherapy, a beta-emitting radionuclide labeled to a bivalent peptide is required. Therapeutic efficacy of these radionuclides depends on the E(max), physical half-life, and residence time of the radiolabel in the tumor. The (131)I radiolabel generally clears rapidly from the tumor after internalization and subsequent degradation of the bivalent l-amino acid peptide (l-a.a. peptide) in the tumor cells. To improve the residence time of the iodine label in the tumor, a new bivalent peptide was synthesized that is peptidase resistant and consists of 4 d-amino acids (d-a.a. peptide). Here we investigated the characteristics of the residualizing iodine label in SK-RC-52 RCC tumors. METHODS: The d-a.a. peptide was manually synthesized according to standard solid-phase Fmoc/HBTU (2-[1H-benzotriazole-1-yl]-1,1,3,3-tetramethyluronium hexafluorophosphate) chemistry. The uptake and retention in the tumor of (111)In-/(125)I-labeled bivalent peptides (l-a.a. peptide and d-a.a. peptide) were studied in female BALB/c athymic mice with subcutaneous SK-RC-52 RCC tumors. Tumors were pretargeted with the bispecific monoclonal antibody (bs-mAb) G250xDTIn-1 and, 72 h later, mice were injected intravenously with one of both radiolabeled peptides. The effect of bs-mAb-diDTPA-bs-mAb (DTPA is diethylenetriaminepentaacetic acid) bridging at the tumor cell surface on the internalization of the bs-mAb-diDTPA complex was investigated in SK-RC-52 tumor-bearing mice. RESULTS: The maximum uptake and retention of (125)I-labeled l-a.a. peptide in the tumor were significantly lower compared with that of the (111)In-labeled l-a.a. peptide. In contrast, the tumor uptake and retention of the (125)I-labeled d-a.a. peptide) were similar to that of the (111)In-labeled l-a.a. peptide but were superior at later time points. The biodistribution of the radioiodinated d-a.a. peptide was highly similar to that of the (111)In-labeled d-a.a. peptide, and both radiolabeled peptides were retained significantly better in the tumor than the (111)In-labeled l-a.a. peptide. bs-mAb-diDTPA-bs-mAb bridge formation did not affect internalization of the bs-mAb-diDTPA complex. CONCLUSION: Uptake and retention in the tumor of the iodinated peptide after pretargeting with a bs-mAb can be significantly improved using d-a.a. peptides. Accordingly, the radiation dose to the tumor, correlating with the therapeutic efficacy of pretargeted RCC, can be enhanced substantially. |
| Authors | Frank G van Schaijk, Matthias Broekema, Egbert Oosterwijk, Juliette E M van Eerd, Bill J McBride, David M Goldenberg, Frans H M Corstens, Otto C Boerman
(Affiliation: Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands. F.vanSchaijk at nucmed.umcn.nl)
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| Journal | Journal of nuclear medicine : official publication, Society of Nuclear Medicine
(J Nucl Med)
Vol. 46
Issue 6
Pg. 1016-22
(Jun 2005)
ISSN: 0161-5505 United States |
| PMID | 15937314
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Ac-D-Phe-D-Lys(DTPA)-D-Tyr-D-Lys(DTPA)-NH2
- Antibodies, Bispecific
- Cross-Linking Reagents
- Iodine Radioisotopes
- Oligopeptides
- Pentetic Acid
|
| Topics |
- Animals
- Antibodies, Bispecific
(chemistry, pharmacokinetics)
- Carcinoma, Renal Cell
(metabolism)
- Cross-Linking Reagents
(chemistry)
- Endocytosis
- Female
- Iodine Radioisotopes
(pharmacokinetics)
- Kidney Neoplasms
(metabolism)
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Neoplasm Transplantation
- Oligopeptides
(pharmacokinetics)
- Pentetic Acid
(analogs & derivatives, chemistry, pharmacokinetics)
- Tissue Distribution
- Tumor Cells, Cultured
|
