ABSTRACT
The linking of amino haptens to carboxymethyldextran (CMD) requires carboxyl activation, for example, via carbodiimdes. We have discovered that substantial N-acylurea, derived from these carbodiimides, can be trapped on the CMD backbone. As an alternative, CMD can be conveniently lactonized by heating in inert solvents, and this carboxymethyldextran lactone (CLD) can be employed directly for amine conjugation.
Subject(s)
Amines/chemistry , Dextrans/chemical synthesis , Drug Carriers/chemical synthesis , Lactones/chemical synthesis , Polymers/chemical synthesisABSTRACT
A maleimide hydrazide has been synthesized as a heterobifunctional cross-linking agent for thiol to formyl coupling. This linker has been applied to the coupling of the monoclonal antibody 17-1A, or an Fab' derived therefrom, to polyaldehyde dextran onto which the antineoplastic agent ellipticine has been attached. High binding avidities for the unshed antigen on the SW1116 colorectal tumor cell are retained in these drug-dextran-linker-antibody conjugates.
Subject(s)
Antibodies, Monoclonal , Antigens, Neoplasm/immunology , Cross-Linking Reagents/chemistry , Formates/chemistry , Immunoglobulin Fab Fragments , Maleic Hydrazide/chemistry , Sulfhydryl Compounds/chemistry , Benzaldehydes/chemistry , Colorectal Neoplasms/immunology , Cross-Linking Reagents/chemical synthesis , Dextrans/chemistry , Ellipticines/chemistry , Hydrazones/chemistry , Molecular Structure , Tumor Cells, CulturedABSTRACT
A new class of radiosensitizing pharmaceuticals derived from 4-nitro-5-imidazolyl sulfones has its clinical potential compromised by a metabolic reaction with plasma glutathione which leads to a much less active metabolite. Entrapment of two members of the class in three different liposomes, one polymerized liposome, and a beta-cyclodextrin system has shown that this glutathione condensation can be suppressed by a rate factor of nearly 50-fold. Stabilizations of these metabolically labile radiosensitizers appear to relate to their lipid-buffer partition coefficients and to the fluidity of the liposome membrane in which they are entrapped.
Subject(s)
Cyclodextrins/chemistry , Glutathione/chemistry , Liposomes/chemistry , Nitroimidazoles/chemistry , Radiation-Sensitizing Agents/chemistry , Sulfones/chemistry , beta-Cyclodextrins , 2-Hydroxypropyl-beta-cyclodextrin , Half-Life , Kinetics , Spectrophotometry, UltravioletABSTRACT
Misonidazole, a clinically-effective 2-nitroimidazole hypoxic cell radiation sensitizer, and 12 4-nitro-5-sulfonatoimidazoles were tested in cultured human SW1116 colorectal adenocarcinoma cells for radiosensitizing efficiency. Octanol-water partition coefficients and HPLC capacity factors were determined for all agents as measurements of lipophilicity, and an excellent correlation was found between the two measurements. Cytotoxicity, in vitro glutathione reactivity, and one-electron reduction potential were also determined for each compound to evaluate potential utility as macromolecularly transported radiosensitizers. Ten members of the set were found to be 40 to 300 times more radiotoxic than misonidazole, but no correlation was found between their radiosensitizing efficiencies and the chemical and physical parameters.
