Synthesis, physico-chemical and biological characterization of a paclitaxel macromolecular prodrug.

摘要: Abstract Paclitaxel was attached to poly(hydroxyethylaspartamide) via a succinic spacer arm by two-step protocol: (1) synthesis of 2′- O -succinyl-paclitaxel; (2) PHEA-2′- -succinyl-paclitaxel. The -succinyl-paclitaxel derivative and the macromolecular conjugate were characterized UV, IR, NMR mass spectrometry analysis. reaction yields over 95% purity products 98%. release degradation from occurred at faster rate pH 5.5 than 7.4. After 30 h incubation 7.4 released free paclitaxel about 40 20%, respectively. In plasma both drug found occur higher in buffer suggesting that an enzymatic mechanism could be involved. negligible very slow plasma. Investigation carried out using murine myeloid cell line showed polymeric prodrug maintains partial pharmacological activity paclitaxel. DL50 (over ng/ml) as compared (about 1 correlated release. Finally pharmacokinetic study intravenous inoculation mice demonstrated polymer conjugation modify dramatically vivo fate drug. disappeared bloodstream much more quickly naked polymer. Massive accumulation bioconjugate liver (80% dose) persist throughout week.