Soluble, crosslinked N-(2-hydroxypropyl)methacrylamide copolymers as potential drug carriers

Preparation and fractionation of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers containing oligopeptide side-chains crosslinked with dityrosylhexamethylenediamine to a level below the gel point has been described previously [1]. Fractions of mean molecular weight ( M w ) from 34,000 to > 400,000 were radiolabelled with 125I and used to study the effect of molecular weight on the fate of polymer in vivo. The blood clearance and body distribution (60 min) of each molecular weight fraction was measured after intravenous administration to rats. Blood clearance was clearly related to molecular weight. In addition the body distribution of unfractionated HPMA copolymer ( M w = 190,000) was monitored at various times after intraperitoneal, subcutaneous or oral administration to rats. Copolymer administered intraperitoneally progressively moved out of the peritoneal cavity into the bloodstream, and after 24 h most radioactivity was recovered in the urine. Sepharose 4B/6B column chromatography of urine samples showed that most radioactivity represented low molecular weight polymer but low molecular weight degradation products were also present. After subcutaneous administration polymer persisted at the injection site, gradually moving away over 24 h. Material entering the body was recovered principally from the bloodstream, eventually being excreted in the urine and faeces. Oral administration led to rapid transfer of radioactivity along the gastrointestinal tract, after 24 h most radioactivity being recovered in the urine and faeces. Sepharose 4B/6B chromatography of radioactivity recovered from the caecum showed that extensive degradation of copolymer had taken place. Incubation of 126I-labelled HPMA copolymers in rat plasma and a mixture of rat liver lysosomal enzymes, followed by analysis with Sepharose 4B/6B or Sephadex G-15 chromatography, showed that the copolymers used in this study were relatively stable in plasma but degradable by lysosomal enzymes.