title: [Development of drug delivery systems for macromolecular drugs].
abstract: With a rapid progress in biotechnology, a variety of endogenous macromolecular substances have become a novel class of therapeutic agents. This review will focus on the development of delivery systems for macromolecular drugs. Current status and future perspectives in this research field are reviewed mainly based on the results obtained in our laboratory. First of all, we studied pharmacokinetic characteristics of macromolecules in relation to their physicochemical properties such as molecular weight and electric charge. Based on this information, we first developed macromolecular prodrugs as a delivery system for low molecular weight drugs. An antitumor antibiotic, mitomycin C (MMC) were covalently conjugated with dextran and various types of macromolecular prodrug of MMC were developed for tumor targeting. Secondly, delivery systems for protein drugs such as soybean trypsin inhibitor, uricase, and recombinant superoxide dismutase (SOD) were developed. In particular, successful targeting of SOD to the liver, kidney and blood circulation was achieved by chemical modification of the protein drug. Finally, we have been trying to develop delivery systems for nucleic acid drugs involving antisense oligonucleotides and plasmid DNA. Prior to the development of delivery systems, we found that the pharmacokinetics of the nucleic acid drugs are decided by their physicochemical properties as polyanions even if these materials contain genetic information. Several approaches were tested to control the in vivo behavior of the oligonucleotides and plasmid DNA based on the finding. Thus, we have established the strategy for rational design of delivery systems for various types of macromolecular drugs based on the pharmacokinetic considerations. This methodology can be a formidable tool for the development of clinically applicable macromolecular drugs.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Takakura
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D004247:DNA / Q000008:administration & dosage / Q000493:pharmacokinetics; D003911:Dextrans; D016503:Drug Delivery Systems; D015195:Drug Design; D046911:Macromolecular Substances; D016685:Mitomycin / Q000008:administration & dosage / Q000493:pharmacokinetics; D009369:Neoplasms / Q000188:drug therapy; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics; D010957:Plasmids; D011355:Prodrugs; D011994:Recombinant Proteins; D013482:Superoxide Dismutase
chemical_list: D000903:Antibiotics, Antineoplastic; D003911:Dextrans; D046911:Macromolecular Substances; D016376:Oligonucleotides, Antisense; D011355:Prodrugs; D011994:Recombinant Proteins; D016685:Mitomycin; D004247:DNA; D013482:Superoxide Dismutase