ABSTRACT
A number of ring- and side-chain-substituted m-iodobenzylguanidine analogues were evaluated for their lipophilicity, in vitro stability, uptake by SK-N-SH human neuroblastoma cells in vitro, and biodistribution in normal mice. As expected, the lipophilicity of m-iodobenzylguanidine increased when a halogen was introduced onto the ring and decreased with the addition of polar hydroxyl, amino, and nitro substitutents. Most of the derivatives showed reasonable stability up to 24 h in PBS at 37 degrees C. While N(1)-hydroxy-N(3)-3-[(131)I]iodobenzylguanidine and 3,4-dihydroxy-5-[(131)I]iodobenzylguanidine generated a more nonpolar product in addition to the free iodide, 3-[(131)I]iodo-4-nitrobenzylguanidine decomposed to a product more polar than the parent compound. The specific uptake of 4-chloro-3-[(131)I]iodobenzylguanidine, 3-[(131)I]iodo-4-nitrobenzylguanidine, and N(1)-hydroxy-N(3)-3-[(131)I]iodobenzylguanidine by SK-N-SH human neuroblastoma cells in vitro, relative to that of m-[(125)I]iodobenzylguanidine, was 117 +/- 10%, 50 +/- 4%, and 12 +/- 2%, respectively. The specific uptake of the known m-iodobenzylguanidine analogues 4-hydroxy-3-[(131)I]iodobenzylguanidine and 4-amino-3-[(131)I]iodobenzylguanidine was 80 +/- 4% and 66 +/- 4%, respectively. None of the other m-iodobenzylguanidine derivatives showed any significant specific uptake by SK-N-SH cells. Heart uptake of 4-chloro-3-[(131)I]iodobenzylguanidine in normal mice was higher than that of m-[(125)I]iodobenzylguanidine at later time points (11 +/- 1% ID/g versus 3 +/- 1% ID/g at 24 h; p < 0.05) while uptake of 3-[(131)I]iodo-4-nitrobenzylguanidine and of N(1)-hydroxy-N(3)-3-[(131)I]iodobenzylguanidine in the heart was lower than that of m-iodobenzylguanidine at all time points. In accordance with the in vitro results, none of the other novel m-iodobenzylguanidine derivatives showed any significant myocardial or adrenal uptake in vivo.
Subject(s)
3-Iodobenzylguanidine/analogs & derivatives , 3-Iodobenzylguanidine/pharmacokinetics , Radiopharmaceuticals/chemical synthesis , 3-Iodobenzylguanidine/chemical synthesis , Adrenal Glands , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Cell Membrane Permeability , Drug Stability , Guanidines/chemical synthesis , Guanidines/pharmacokinetics , Heart , Humans , Male , Mice , Mice, Inbred BALB C , Organ Specificity , Radiopharmaceuticals/pharmacokinetics , Structure-Activity Relationship , Tissue Distribution , Tumor Cells, CulturedABSTRACT
Monoclonal antibody (MAb) internalization can have a major effect on tumor retention of radiolabel. Two anti-HER-2/neu MAbs (TA1 and 520C9) were radioiodinated using the iodogen, N-succinimidyl 5-iodo-3-pyridinecarboxylate (SIPC), and tyramine-cellobiose (TCB) methods. Paired-label studies compared internalization and cellular processing of the labeled MAbs by SKOv3 9002-18 ovarian cancer cells in vitro. Intracellular radioiodine activity for 520C9 was up to 2.6 and 3.0 times higher for SIPC and TCB labeling, respectively, compared with iodogen. Likewise, intracellular activity for TA1 was up to 2.3 and 2.9 times higher with the SIPC and TCB methods compared with iodogen labeling. Unfortunately, similar advantages in tumor accumulation were not achieved in athymic mice bearing SKOv3 9008-18 ovarian cancer xenografts.
Subject(s)
Antibodies, Monoclonal/metabolism , Immunoconjugates/chemistry , Immunoconjugates/metabolism , Iodine Radioisotopes/chemistry , Isotope Labeling/methods , Receptor, ErbB-2/immunology , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacokinetics , Cellobiose/chemistry , Female , Humans , Immunoconjugates/immunology , Immunoconjugates/pharmacokinetics , Mice , Mice, Inbred BALB C , Mice, Nude , Nicotinic Acids/chemistry , Ovarian Neoplasms , Receptor, ErbB-2/biosynthesis , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Succinimides/chemistry , Tissue Distribution , Tumor Cells, Cultured , Tyramine/chemistry , Urea/analogs & derivatives , Urea/chemistryABSTRACT
The HER-2/neu oncogene encodes a 185 kDa phosphoglycoprotein that is overexpressed in breast, ovarian and other cancers. Seven monoclonal antibodies reactive with oncoprotein were labeled with 131I. In vitro experiments with SKOv3 9002-18 cells determined binding affinity, internalization and degradation. The biodistribution of these antibodies in comparison to 125I-labeled nonspecific antibody was measured in athymic mice with SKOv3 9002-18 ovarian carcinoma xenografts. Antibody 520C9 exhibited the highest and most specific retention in tumor, peaking at 17.4 +/- 5.6% ID/g at 24 h.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Iodine Radioisotopes/therapeutic use , Receptor, ErbB-2/immunology , Animals , Antibodies, Monoclonal/pharmacokinetics , Epitopes , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Radioimmunotherapy , Tissue Distribution , Tumor Cells, CulturedABSTRACT
The effect of para vs meta substitution on the biological behavior of an intact antibody and an F(ab')2 fragment was investigated. Paired-label studies were performed using 81C6 IgG and OC 125 F(ab')2 labeled using the N-succinimidyl esters of both p-[125I]- and m-[131I]iodobenzoate as well as with the potential catabolites, p-[125I]- and m-[131I]iodobenzoic acid. In all 3 studies, up to 55% lower uptake of 131I in thyroid and stomach was observed, suggesting that the m-substituted species were more inert to dehalogenation in vivo.
