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Polym Chem. 2014 Mar 7;(5):1674-1681.

PEG-pHPMAm-based polymeric micelles loaded with doxorubicin-prodrugs in combination antitumor therapy with oncolytic vaccinia viruses.

Author information

1
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
2
Department of Biochemistry, Biocenter, University of Würzburg, 97074 Würzburg, Germany.
3
Department of Hematooncology & Stem Cell Transplantation Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
4
Department of Experimental Molecular Imaging, University Clinic and Helmholtz Center for Biomedical Engineering, Aachen, Germany.
5
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands ; Department of Inorganic and Bioinorganic Chemistry, Facultad de Farmacia, Universidad Complutense de Madrid, Spain.
6
Department of Controlled Drug Delivery, Targeted Therapeutics Section, University of Twente and MIRA Institute for Biomedical Engineering and Technical Medicine, Enschede, The Netherlands.
7
Department of Organic Chemistry, Radboud Univ Nijmegen, Heyendaalse weg 135, 6525 AJ Nijmegen, The Netherlands.
8
Department of Biochemistry, Biocenter, University of Würzburg, 97074 Würzburg, Germany ; Genelux Corporation, San Diego Science Center, San Diego, CA 92109, USA ; Department of Radiation Oncology, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
9
Department of Biochemistry, Biocenter, University of Würzburg, 97074 Würzburg, Germany ; Genelux Corporation, San Diego Science Center, San Diego, CA 92109, USA.
10
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands ; Department of Experimental Molecular Imaging, University Clinic and Helmholtz Center for Biomedical Engineering, Aachen, Germany ; Department of Controlled Drug Delivery, Targeted Therapeutics Section, University of Twente and MIRA Institute for Biomedical Engineering and Technical Medicine, Enschede, The Netherlands.

Abstract

An enzymatically activatable prodrug of doxorubicin was covalently coupled, using click-chemistry, to the hydrophobic core of poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl)-methacrylamide-lactate] micelles. The release and cytotoxic activity of the prodrug was evaluated in vitro in A549 non-small-cell lung cancer cells after adding β-glucuronidase, an enzyme which is present intracellularly in lysosomes and extracellularly in necrotic areas of tumor lesions. The prodrug-containing micelles alone and in combination with standard and β-glucuronidase-producing oncolytic vaccinia viruses were also evaluated in vivo, in mice bearing A549 xenograft tumors. When combined with the oncolytic viruses, the micelles completely blocked tumor growth. Moreover, a significantly better antitumor efficacy as compared to virus treatment alone was observed when β-glucuronidase virus treated tumor-bearing mice received the prodrug-containing micelles. These findings show that combining tumor-targeted drug delivery systems with oncolytic vaccinia viruses holds potential for improving anticancer therapy.

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