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

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

doi:10.18632/oncotarget.24806

Doerte Hoelzer, René Thierbach + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.24806

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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 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.

Highlights

In modern oncology it is a major challenge to deliver therapeutic agents more safely and directly to the tumor
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 size exclusion chromatography (SEC) measurements of initial polymers could be performed in chloroform, deprotected P(EtOx98-b-AmOx32) (2) had to be measured in N,Ndimethylacetamide (DMAc), explaining the difference in molar mass compared to the precursor polymer

Summary

Introduction

In modern oncology it is a major challenge to deliver therapeutic agents more safely and directly to the tumor. Doxorubicin (DOX) is an anthracycline antibiotic and is one of the most effective as well as commonly used chemotherapeutic drugs It is used as a first-line treatment of various types of cancer, including hematologic malignancies, breast and ovarian carcinoma, neuroblastoma as well as soft tissue and bone sarcoma. Hydrogel nanoparticles with crosslinked hydrophilic polymers, offer several advantages for their use as a drug delivery system [8]. For this reason, the utilization of nanocarriers (e.g. nanoparticles) in terms of delivery of anti-cancer drugs has increased significantly during the last years [9,10,11]. A common strategy is the use of covalently cross-linked drug delivery systems (i.e. core cross-linked micelles or other nanogels) and a likewise covalently but reversibly attached drug [14,15,16]

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