pH-Responsive Artesunate Polymer Prodrugs with Enhanced Ablation Effect on Rodent Xenograft Colon Cancer

Int J Nanomedicine. 2020 Mar 16;15:1771-1786. doi: 10.2147/IJN.S242032. eCollection 2020.


Purpose: In this study, pH-sensitive poly(2-ethyl-2-oxazoline)-poly(lactic acid)-poly(β-amino ester) (PEOz-PLA-PBAE) triblock copolymers were synthesized and were conjugated with an antimalaria drug artesunate (ART), for inhibition of a colon cancer xenograft model.

Methods: The as-prepared polymer prodrugs are tended to self-assemble into polymeric micelles in aqueous milieu, with PEOz segment as hydrophilic shell and PLA-PBAE segment as hydrophobic core.

Results: The pH sensitivity of the as-prepared copolymers was confirmed by acid-base titration with pKb values around 6.5. The drug-conjugated polymer micelles showed high stability for at least 96 h in PBS and 37°C, respectively. The as-prepared copolymer prodrugs showed high drug loading content, with 9.57%±1.24% of drug loading for PEOz-PLA-PBAE-ART4. The conjugated ART could be released in a sustained and pH-dependent manner, with 92% of released drug at pH 6.0 and 57% of drug released at pH 7.4, respectively. In addition, in vitro experiments showed higher inhibitory effect of the prodrugs on rodent CT-26 cells than that of free ART. Animal studies also demonstrated the enhanced inhibitory efficacy of PEOz-PLA-PBAE-ART2 micelles on the growth of rodent xenograft tumor.

Conclusion: The pH-responsive artesunate polymer prodrugs are promising candidates for colon cancer adjuvant therapy.

Keywords: artesunate; micelles; pH responsive; poly(2-ethyl-2-oxazoline); poly(β-amino ester); polymer prodrug.

MeSH terms

  • Animals
  • Artesunate / chemistry
  • Artesunate / pharmacokinetics*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / pathology
  • Drug Delivery Systems
  • Drug Liberation
  • Female
  • Humans
  • Hydrogen-Ion Concentration
  • Hydrophobic and Hydrophilic Interactions
  • Mice, Inbred BALB C
  • Micelles
  • Oxazoles / chemistry
  • Polymers / chemistry*
  • Prodrugs / chemistry*
  • Prodrugs / pharmacology*
  • Xenograft Model Antitumor Assays


  • Micelles
  • Oxazoles
  • Polymers
  • Prodrugs
  • Artesunate
  • 2-ethyl-2-oxazoline