Monoclonal Antibody Conjugates of Doxorubicin Prepared with Branched Peptide Linkers: Inhibition of Aggregation by Methoxytriethyleneglycol Chains
| Autor: | Pamela A. Trail, Harold Mastalerz, Raymond A. Firestone, David Willner, Hofstead Sandra J, Shirley J. Lasch, Dalton King, Gene M. Dubowchik |
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| Rok vydání: | 2002 |
| Předmět: |
Immunoconjugates
Stereochemistry media_common.quotation_subject Antineoplastic Agents Peptide Inhibitory Concentration 50 chemistry.chemical_compound Amide Drug Discovery Tumor Cells Cultured medicine Humans Moiety Doxorubicin Internalization media_common chemistry.chemical_classification Dipeptide Hydrolysis Antibodies Monoclonal Dipeptides Hydrogen-Ion Concentration Immunoconjugate chemistry Molecular Medicine Dimerization Linker medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 45:4336-4343 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm020149g |
| Popis: | High mole ratio BR96 immunoconjugates were synthesized using branched peptide-doxorubicin linkers designed to liberate doxorubicin following antigen-specific internalization into lysosomes. However, these immunoconjugates are highly prone to noncovalent, dimeric aggregation. We hypothesize that this is due to (1) the hydrophobic nature of the peptides, (2) the loss of positive charge upon amide formation at the 3'-amino group of doxorubicin, and (3) the proximity of the peptide hydrophobic residues to form efficient intermolecular stacking interactions. By introducing a hydrophilic methoxytriethylene glycol chain onto the doxorubicin portion of the branched peptide linkers, aggregation has been eliminated or greatly reduced in the immunoconjugate products. The methoxytriethylene glycol chain was linked to the doxorubicin moiety of the linker via a hydrazone bond that is stable at pH 7 but hydrolyzes rapidly at pH 5 to release free drug. BR96 immunoconjugates synthesized from methoxytriethylene glycol-modified branched peptide-doxorubicin linkers are highly potent and immunospecific in vitro. The data suggest that the methoxytriethylene glycol chain hydrolyzes as designed upon antigen-specific internalization into tumor lysosomes in vitro, where enzymatic degradation of the peptide linker releases free doxorubicin. |
| Databáze: | OpenAIRE |
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