HPMA-based polymer conjugates with drug combination

Eur J Pharm Sci. 2009 Jun 28;37(3-4):405-12. doi: 10.1016/j.ejps.2009.03.011. Epub 2009 Apr 1.

Abstract

Synthesis and physico-chemical behavior of new polymer-drug conjugates intended for the treatment of cancer were investigated. In the polymer conjugate with the expected dual therapeutic activity, two drugs, a cytostatic agent doxorubicin (DOX) and anti-inflammatory drug dexamethason (DEX) were covalently attached to the same polymer backbone via hydrolytically labile pH-sensitive hydrazone bonds. The precursor, a copolymer of N-(2-hydroxypropyl)methacrylamide (HPMA) bearing hydrazide groups randomly distributed along the polymer chain, was conjugated with DOX (through its C13 keto group) or with a keto ester (DEX). Two derivatives of DEX, 4-oxopentanoate and 4-(2-oxopropyl)benzoate esters, were synthesized and employed for conjugation reaction. As a control, also a few polymer conjugates containing only a single drug (DOX or DEX) attached to the polymer carrier were synthesized. Physico-chemical properties of the polymer conjugates strongly depend on the attached drug, spacer structure and the drug content. Polymer-drug conjugates incubated in buffers modeling intracellular environment released the drug (DOX) or a drug derivatives (DEX) at the rate significantly exceeding the release rate observed under conditions mimicking situation in the blood stream. Incubation of the DEX conjugates in a buffer containing carboxyesterase resulted in complete ester hydrolysis thus demonstrating susceptibility of the system to release free active drug in the two-step release profile.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / chemistry
  • Carboxylesterase / chemistry
  • Doxorubicin / administration & dosage
  • Doxorubicin / chemistry
  • Drug Combinations
  • Excipients
  • Magnetic Resonance Spectroscopy
  • Methacrylates / chemical synthesis
  • Methacrylates / chemistry*
  • Polymers
  • Spectrophotometry, Ultraviolet

Substances

  • Antibiotics, Antineoplastic
  • Drug Combinations
  • Excipients
  • Methacrylates
  • Polymers
  • Doxorubicin
  • Carboxylesterase
  • hydroxypropyl methacrylate