Chengzao Sun

Enabling ScFvs as multi-drug carriers: a dendritic approach.

To enable scFvs as multi-drug carriers, we designed and synthesized dendritic linker molecules bearing up to nine chlorambucil residues at the branch ends. A maleimide group was used at the focal point of the dendron for easy linkage to the scFv. Originally designed molecules showed poor water solubility. To address this problem, a lysine residue with an unprotected carboxylic acid group was inserted into the dendron branches. The new molecules showed excellent water solubility and are now suitable for conjugation. Such dendritic molecules will allow studies to understand the relationship between the drug/antibody ratio and the potency of the immunoconjugates. The dendritic approach could also be applied to drugs other than chlorambucil and carriers other than scFvs to greatly increase the drug/carrier ratio.

Syntheses of dendritic linkers containing chlorambucil residues for the preparation of antibody-multidrug immunoconjugates

A novel dendritic molecule with nine chlorambucil (CBL) residues on the surface and a maleimide moiety at the core terminus was synthesized using a convergent synthetic methodology. This molecule is ready for attachment to single-chain Fv antibodies (scFvs) to form antibody-multidrug immunoconjugates in an effort to study the relevance of drug/antibody molar ratio and the potency of these drug-antibody immunoconjugates. A monomer and a trimer with a similar structural motif were also prepared for comparative purposes.

Prevention of Drug-Induced Memory Impairment by Immunopharmacotherapy

One approach to treating drug abuse uses antidrug antibodies to immunize subjects against the illicit substance rather than administering therapeutics that target the specific CNS site of action. At present, passive vaccination has recognized efficacy in treating certain gross symptoms of drug misuse, namely, motor activation, self-administration, and overdose. However, the potential for antibodies to prevent drug-induced changes involving finer cognitive processes, such as benzodiazepine-associated amnesia, remains unexplored. To address this concept, a flunitrazepam hapten was synthesized and employed in the generation of a panel of high affinity monoclonal antibodies. Anti-flunitrazepam mAb RCA3A3 ( K d,app = 200 nM) was tested in a mouse model of passive immunization and subsequent mole-equivalent challenge with flunitrazepam. Not only was flunitrazepam-induced sedation prevented but immunization also conferred protection to memory consolidation as assessed through contextual and cued fear conditioning paradigms. These results provide evidence that immunopharmacotherapeutic blockade of drug intoxication also preserves complex cognitive function.