Tumor targeting with pH-responsive poly(2-oxazoline)-based nanogels for metronomic doxorubicin treatment
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Doerte Hoelzer1,*, Meike N. Leiske2,3,*, Matthias Hartlieb2,3,4, Tanja Bus2,3, David Pretzel2,3, Stephanie Hoeppener2,3, Kristian Kempe2,3,5, René Thierbach1 and Ulrich S. Schubert2,3
1Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany
2Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, 07743 Jena, Germany
3Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, 07743 Jena, Germany
4Current address: Institute of Biomaterial Science, Helmholtz-Zentrum Geesthacht, 14513 Teltow, Germany
5Current address: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
*These authors contributed equally to the work
Ulrich S. Schubert, email: firstname.lastname@example.org
Keywords: poly(2-oxazoline); doxorubicin; drug delivery; nanogel; metronomic
Received: October 18, 2017 Accepted: February 24, 2018 Published: April 27, 2018
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 pH-sensitive 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.
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