Tumor targeting with pH-responsive poly(2-oxazoline)-based nanogels for metronomic doxorubicin treatment

Doerte Hoelzer, Meike N. Leiske, Matthias Hartlieb, Tanja Bus, David Pretzel, Stephanie Hoeppener, Kristian Kempe, René Thierbach, Ulrich S. Schubert

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

The synthesis of a new nanogel drug carrier system loaded with the anti-cancer drug doxorubicin (DOX) is presented. Poly(2-oxazoline) (POx) based nanogels from block copolymer micelles were cross-linked and covalently loaded with DOX using pHsensitive Schiff' base chemistry. DOX loaded POx based nanogels showed a toxicity profile comparable to the free drug, while unloaded drug carriers showed no toxicity. Hemolytic activity and erythrocyte aggregation of the drug delivery system was found to be low and cellular uptake was investigated by flow cytometry and fluorescence microscopy. While the amount of internalized drug was enhanced when incorporated into a nanogel, the release of the drug into the nucleus was delayed. For in vivo investigations the nanogel drug delivery system was combined with a metronomic treatment of DOX. Low doses of free DOX were compared to equivalent DOX loaded nanogels in a xenograft mouse model. Treatment with POx based nanogels revealed a significant tumor growth inhibition and increase in survival time, while pure DOX alone had no effect on tumor progression. The biodistribution was investigated by microscopy of organs of mice and revealed a predominant localization of DOX within tumorous tissue. Thus, the POx based nanogel system revealed a therapeutic efficiency despite the low DOX concentrations and could be a promising strategy to control tumor growth with fewer side effects.

Original languageEnglish
Pages (from-to)22316-22331
Number of pages16
JournalOncotarget
Volume9
Issue number32
DOIs
Publication statusPublished - 27 Apr 2018

Keywords

  • Doxorubicin
  • Drug delivery
  • Metronomic
  • Nanogel
  • Poly(2-oxazoline)

Cite this

Hoelzer, D., Leiske, M. N., Hartlieb, M., Bus, T., Pretzel, D., Hoeppener, S., ... Schubert, U. S. (2018). Tumor targeting with pH-responsive poly(2-oxazoline)-based nanogels for metronomic doxorubicin treatment. Oncotarget, 9(32), 22316-22331. https://doi.org/10.18632/oncotarget.24806