New hydrazone derivatives of Adriamycin and their immunoconjugates - a correlation between acid stability and cytotoxicity

Abstract

New N-substituted hydrazine linkers were synthesized and their hydrazone derivatives of adriamycin were prepared. These functionalized adriamycin derivatives were conjugated with a monoclonal antibody, 5E9. The release rate of adriamycin from the hydrazones and from some of the conjugates was studied, and their relationship to the IC50's of the conjugate against 5E9-positive Daudi cells was investigated.

A single dose of doxorubicin-functionalized bow-tie dendrimer cures mice bearing C-26 colon carcinomas

“…Additionally, a clinically approved liposomal drug-delivery system for DOX exists (Doxil), which provides a commercially available positive control with which to assess the delivery potential of our bow-tie system. A pH-sensitive acyl hydrazone linkage was chosen as the method of drug attachment, because the drug can be selectively released either in the mildly acidic extracellular environment of a tumor (32) or upon pinocytic uptake and trafficking into acidic endosomal or lysosomal subcellular compartments (33,34).…”

Antibody Drug Conjugates: Preclinical Considerations

“…Thus, this class of linker is stable at physiological pH and releases the payload in the more reducing environment of the cytosol following internalization. The peptide linkers on the other hand, are hydrolyzed by lysosomal proteases (50)(51)(52)(53)(54).…”

Intracellular Cleavable CpG Oligodeoxynucleotide-Antigen Conjugate Enhances Anti-tumor Immunity

“…In order to achieve targeted release of the antigen from the adjuvant inside the cell, an intracellular trigger such as reduction-oxidation (redox) potential, pH, or a specific enzyme can be used. [13][14][15][16][17][18][19] These triggers have been used in a number of devices to enhance the targeted delivery of a drug. 20,21 Triggerable formulations for immunotherapy have been investigated for intracellular targeting to APCs.…”