Properties of HPMA copolymer-doxorubicin conjugates with pH-controlled activation: effect of polymer chain modification

J Control Release. 2006 Sep 28;115(1):26-36. doi: 10.1016/j.jconrel.2006.06.028. Epub 2006 Jun 30.

Abstract

Various conjugates of anticancer drug doxorubicin (DOX) covalently attached via hydrolytically degradable hydrazone bond to water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer drug carriers were synthesized. Three types of precursors containing either positively or negatively charged groups or a hydrophobic substituent were employed. In vitro incubation of the conjugates in buffers showed relative stability at pH 7.4 (modelling blood) and a fast DOX release at pH 5 (modelling intracellular environment). The presence of carboxylic groups in the copolymer structure resulted in an increase in the DOX release rate of 15-20% while no effect of the introduction of positively charged groups was observed if compared with the unmodified conjugate. Self-assembling of the oleoyl groups-containing conjugate led into formation of polymeric micelles with high apparent molecular weight (M(w)=170,000) in aqueous solution and resulted in a decrease in the DOX release rate of approximately 20%. The cytostatic activity of the conjugates tested on several cancer cell lines was comparable with that of free DOX.HCl, depending on the sensitivity of a particular cell line to DOX. All the conjugates showed a much higher antitumour activity in vivo than the free drug tested in mice bearing EL4 T-cell lymphoma and treated using the therapeutic regime of drug administration. The highest activity (100% long-term survivors) exhibited polymer-DOX conjugate containing negatively charged GFLG sequences.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / administration & dosage*
  • Antibiotics, Antineoplastic / chemistry*
  • Antibiotics, Antineoplastic / pharmacology
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Proliferation / drug effects
  • Chemical Phenomena
  • Chemistry, Physical
  • Delayed-Action Preparations
  • Doxorubicin / administration & dosage*
  • Doxorubicin / chemistry*
  • Doxorubicin / pharmacology
  • Humans
  • Hydrogen-Ion Concentration
  • Indicators and Reagents
  • Kinetics
  • Male
  • Methacrylates / chemical synthesis
  • Methacrylates / chemistry*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Weight
  • Neoplasm Transplantation
  • Particle Size
  • Polymers / chemistry
  • Solubility
  • Spectrophotometry, Ultraviolet
  • Structure-Activity Relationship
  • Survival Analysis

Substances

  • Antibiotics, Antineoplastic
  • Delayed-Action Preparations
  • Indicators and Reagents
  • Methacrylates
  • Polymers
  • Doxorubicin
  • hydroxypropyl methacrylate