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Chemotherapeutic Delivery from a Self-Assembling Peptide Nanofiber Hydrogel for the Management of Glioblastoma

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Abstract

Purpose

Localized chemotherapy has gained significant impetus for the management of malignant brain tumors. In the present study, we appraised the versatility of an in-situ gel forming self-assembling peptide, ac-(RADA)4-CONH2, as a biocompatible delivery depot of the chemotherapeutic drug doxorubicin (DOX) and the anticancer agent curcumin (CUR), respectively.

Methods

The morphology and mechanical properties of ac-(RADA)4-CONH2 were assessed with scanning electron microscopy (SEM) and rheological studies. The in vitro drug release from ac-(RADA)4-CONH2 was monitored in phosphate-buffered saline pH 7.4. Distribution of the fluorescent actives within the peptide matrix was visualized with confocal laser scanning microscopy (CLSM). The in vitro biological performance of the ac-(RADA)4-CONH2-DOX and ac-(RADA)4-CONH2-CUR was evaluated on the human glioblastoma U-87 MG cell line.

Results

SEM studies revealed that the ac-(RADA)4-CONH2 hydrogel contains an entangled nanofiber network. Rheology studies showed that the more hydrophobic CUR resulted in a stiffer hydrogel compared with ac-(RADA)4-CONH2 and ac-(RADA)4-CONH2-DOX, due to the interaction of CUR with the hydrophobic domains of the peptide nanofibers as confirmed by CLSM. In vitro release studies showed a complete DOX release from ac-(RADA)4-CONH2 within 4 days and a prolonged release for ac-(RADA)4-CONH2-CUR over 20 days. An increased cellular uptake and a higher cytotoxic effect were observed for ac-(RADA)4-CONH2-DOX, compared with DOX solution. Higher levels of early apoptosis were observed for the cells treated with the ac-(RADA)4-CONH2-CUR, compared to CUR solution.

Conclusions

The current findings highlight the potential utility of the in-situ depot forming ac-(RADA)4-CONH2 hydrogel for the local delivery of both water soluble and insoluble chemotherapeutic drugs.

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Abbreviations

BBB:

Blood brain barrier

CLSM:

Confocal laser scanning microscopy

CUR:

Curcumin

DOX:

Doxorubicin

GBM:

Glioblastoma multiforme

IC50 :

Half-maximal inhibitory concentration

PBS:

Phosphate-buffered saline

SEM:

Scanning electron microscopy

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ACKNOWLEDGMENTS AND DISCLOSURES

C.K. is supported by the Onassis Foundation with a PhD scholarship. We thank Orestis L. Katsamenis from μ-VIS X-ray Imaging Centre, Faculty of Engineering and the Environment, University of Southampton, Southampton for the SEM studies. We would like to thank Dr. A. Lazaridou from Department of Food Science and Technology, School of Agriculture, Aristotle University of Thessaloniki, Greece for her assistance in the rheology measurements. The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. School of Pharmacy, Department of Pharmaceutical Technology, Aristotle University of Thessaloniki, GR-54124, Thessaloniki, Greece

    Christina Karavasili & Dimitrios G. Fatouros

  2. Department of Botany, School of Biology, Aristotle University of Thessaloniki, GR-54124, Thessaloniki, Greece

    Emmanuel Panteris

  3. School of Pharmacy, Laboratory of Pharmacology, Aristotle University of Thessaloniki, GR-54124, Thessaloniki, Greece

    Ioannis S. Vizirianakis

  4. Center for Biomedical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts, 02139, USA

    Sotirios Koutsopoulos

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  1. Christina Karavasili
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The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Corresponding author

Correspondence to Dimitrios G. Fatouros.

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Karavasili, C., Panteris, E., Vizirianakis, I.S. et al. Chemotherapeutic Delivery from a Self-Assembling Peptide Nanofiber Hydrogel for the Management of Glioblastoma. Pharm Res 35, 166 (2018). https://doi.org/10.1007/s11095-018-2442-1

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  • DOI: https://doi.org/10.1007/s11095-018-2442-1

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