Folate-conjugated thermoresponsive block copolymers: highly efficient conjugation and solution self-assembly

Biomacromolecules. 2008 Mar;9(3):1064-70. doi: 10.1021/bm701255v. Epub 2008 Feb 21.


A combination of controlled radical polymerization and azide-alkyne click chemistry was employed to prepare temperature-responsive block copolymer micelles conjugated with biological ligands with potential for active targeting of cancer tissues. Block copolymers of N-isopropylacrylamide (NIPAM) and N,N-dimethylacrylamide (DMA) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization with an azido chain transfer agent (CTA). Pseudo-first-order kinetics and linear molecular weight dependence on conversion were observed for the RAFT polymerizations. CuI-catalyzed coupling with propargyl folate resulted in folic acid residues being efficiently conjugated to the alpha-azido chain ends of the homo and block copolymers. Temperature-induced self-assembly resulted in aggregates capable of controlled release of a model hydrophobic drug. CuI-catalyzed azide-alkyne cycloaddition has proven superior to conventional methods for conjugation of biological ligands to macromolecules, and the general strategy presented herein can potentially be extended to the preparation of folate-functionalized assemblies with other stimuli susceptibility (e.g., pH) for therapeutic and imaging applications.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acrylamides / chemistry*
  • Antineoplastic Agents / administration & dosage*
  • Azides / chemistry
  • Catalysis
  • Copper / chemistry
  • Delayed-Action Preparations / chemical synthesis
  • Delayed-Action Preparations / chemistry
  • Folic Acid / chemistry*
  • Hot Temperature*
  • Humans
  • Ligands
  • Micelles
  • Polymers / chemical synthesis
  • Polymers / chemistry*
  • Solutions


  • Acrylamides
  • Antineoplastic Agents
  • Azides
  • Delayed-Action Preparations
  • Ligands
  • Micelles
  • Polymers
  • Solutions
  • Copper
  • Folic Acid
  • N,N-dimethylacrylamide
  • N-isopropylacrylamide