Sequential functionalization of janus-type dendrimer-like poly(ethylene oxide)s with camptothecin and folic acid

Xiaoshuang Feng, Julien Pinaud, Elliot L. Chaikof, Daniel Taton*, Yves Gnanou

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Janus-type dendrimer-like poly(ethylene oxide)s (PEOs) of 1st, 2nd, and 3rd generation carrying terminal hydroxyl functions on one side and cleavable ketal groups on the other were used as substrates to conjugate folic acid as a folate receptor and camptothecin (CPT) as a therapeutic drug in a sequential fashion. The conjugation of both FA and CPT was accomplished by "click chemistry" based on the 1,3 dipolar cycloaddition coupling reaction. First, the hydroxyl functions present at one face of Janus-type dendrimer-like PEOs were transformed into alkyne groups through a simple Williamson-type etherification reaction. Next, the ketals carried by the other face of the dendrimer-like PEOs were hydrolyzed, yielding twice as many hydroxyls which were subsequently subjected to an esterification reaction using 2-bromopropionic bromide. Before substituting azides for the bromide of 2-bromopropionate esters just generated in the presence of NaN3, an azido-containing amidified FA derivative was reacted through click chemistry with alkyne functions introduced on the other face of the dendrimer-like PEOs. A purposely designed alkyne-functionalized biomolecule derived from CPT was conjugated to the azido functions carried by the dendritic PEOs by a second "click reaction." In this case, twice as many CPT as FA moieties were finally conjugated to the two faces of the Janus-type dendrimer-like PEOs, the numbers of folate and CPT introduced being 2 and 4, 4 and 8, and 8 and 16 for samples of 1st, 2nd, and 3rd generation, respectively (route A). An alternate route for functionalizing the dendrimer-like PEO of 1st generation consisted, first, in conjugating the azido-containing CPT onto the alkyne groups present on one face of the dendritic PEO scaffold. The alkyne-functionalized FA was further introduced by click chemistry after the bromides of 2-bromopropionate esters were chemically transformed into azido groups. The corresponding prodrug thus contains 2 CPT and 4 FA external moieties (route B). Every reaction step product was thoroughly characterized by 1H NMR spectroscopy. A preliminary investigation into the water solution properties of these functionalized dendritic PEOs is also presented.

Original languageEnglish (US)
Pages (from-to)2839-2849
Number of pages11
JournalJournal of Polymer Science, Part A: Polymer Chemistry
Volume49
Issue number13
DOIs
StatePublished - Jul 1 2011

Keywords

  • bioconjugates
  • camptothecin
  • conjugation
  • dendrimer
  • dendrimer-like
  • folic acid
  • poly(ethylene oxide)

ASJC Scopus subject areas

  • Polymers and Plastics
  • Organic Chemistry
  • Materials Chemistry

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