Pharmacokinetic Analysis and Development of Delivery Systems of Macromolecular Drugs.

Abstract

Various endogenous macromolecular substances have become a new class of therapeutic agents with recent progress in biotechnology. For a successful use of the macromolecular drugs, optimal delivery systems should be developed. In our laboratory, a series of pharmacokinetic studies have been carried out aiming at the development of delivery systems for macromolecular drugs. Aa the first step towards the development of delivery systems, we studied pharmacokinetic characteristics of macromolecules in relation to their physicochemical properties such as molecular weight and electric charge. Based on the findings, we first developed macromolecular prodrugs of an antitumor antibiotic, mitomycin C (MMC). MMC was covalently conjugated with dextran and various types of macromolecular prodrug of MMC were developed for tumor targeting. Similar strategy was applied to the development of delivery systems for various protein drugs. For example, successful targeting of recombinant superoxide dismutase (SOD) to the liver, kidney and blood circulation was achieved by chemical modification of the protein drug. Very recently, we have been trying to develop delivery systems for nucleic acid drugs such as antisense oligonucleotides and plasmid DNA. Based on the same concept, delivery systems have been tested to control the in vivo behavior of the nucleic acid drugs. The strategy for rational design of delivery systems for various types of macromolecular drugs has thus been establised through the pharmacokinetic studies.