CYTOTOXIC AND IMMUNOMODULATORY ACTIVITES OF POLYMER-BOUND DRUGS

摘要

Water-soluble synthetic polymers based on N-(2-hydroxypropyl) methacrylamide have been developed as drug carriers to improve the therapeutic index of a variety of anti-tumor agents and the immunosuppressive drug cyclosporin A. HPMA copolymer is a biocompatible, non-immunogenic, non-toxic and targetable carrier to which drugs are bound covalently via a peptidyl spacer, usually Gly-Phe-Leu-Gly. Once the drug is covalently bound to the polymeric backbone, via a tetrapeptide spacer it becomes biologically inactive and non-toxic. Such a drug conjugate is stable during transportation in the bloodstream, thus potentially protecting normal cells, but enables the intracellular cleavage and release of the bound drug by thiol-dependent lysosomal proteases, particularly cathepsins B, H and L. Modification with the polymeric carrier allows much higher doses of drug to be administered while reducing the dangerous side-effects including toxicity.