Carboranyl peptide-antibody conjugates for neutron-capture therapy: preparation, characterization, and in vivo evaluation
| Autor: | R. J. Paxton, Barbara G. Beatty, M. F. Hawthorne, Aravamuthan Varadarajan |
|---|---|
| Rok vydání: | 1992 |
| Předmět: |
Boron Compounds
Biodistribution Stereochemistry medicine.drug_class Transplantation Heterologous Biomedical Engineering Mice Nude Pharmaceutical Science Bioengineering Peptide Conjugated system Monoclonal antibody Iodine Radioisotopes Mice chemistry.chemical_compound In vivo medicine Animals Tissue Distribution Dansyl Compounds Pharmacology chemistry.chemical_classification Drug Carriers Dipeptide Organic Chemistry Antibodies Monoclonal Neoplasms Experimental Carcinoembryonic Antigen Amino acid chemistry Biochemistry Female Indicators and Reagents Oligopeptides Neoplasm Transplantation Biotechnology Conjugate |
| Zdroj: | Bioconjugate Chemistry. 3:241-247 |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/bc00015a007 |
| Popis: | Two model peptides rich in boron and prepared by Merrifield syntheses, dansyl.(nido-CB)2, (1) and dansyl.(nido-CB)10.Lys.Ac (2), where nido-CB represents the alpha-amino acid [nido-7-CH3-8-(CH2)3CH-(NH2)COOH-7,8-C2B9H10]-, were conjugated with the anti-CEA mAb T84.66 using peptide active ester reagents. The dansyl groups provided a means of fluorimetric analysis of mAb conjugates which was augmented by conventional amino acid analyses for nido-CB. The conjugate of 1 contained an average of 63 B atoms per mAb molecule. The mAb conjugate of 2 was chromatographically separated into a strongly fluorescent high molecular weight aggregated fraction (HMW) and a less intensely fluorescent monomeric fraction. Both fractions retained immunoreactivity. The HMW species contained an average of ca. 490 B atoms/mAb molecule, as determined by amino acid analysis. Biodistribution data were collected using nude mice bearing LS174T xenografts and 125I-labeled mAb conjugates. While the lightly B-loaded dipeptide conjugate gave biodistribution results which resembled those of native T84.66 mAb, the undecapeptide conjugate displayed greatly enhanced liver uptake and decreased tumor accretion. These results suggest that as the boron-containing burden on the supporting immunoprotein is greatly increased, as in the case of the T84.66-2 conjugate, loss of circulating conjugate to liver effectively competes with the desired tumor localization. Means which might be taken to circumvent this difficulty have been described elsewhere (ref 15). |
| Databáze: | OpenAIRE |
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