title: PEG-pHPMAm-based polymeric micelles loaded with doxorubicin-prodrugs in combination antitumor therapy with oncolytic vaccinia viruses.
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 evaluatedin vitroin 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 evaluatedin 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.
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Eduardo
authors: E
authors: Ruiz-Hernández
authors: Department of Biochemistry, Biocenter, University of Würzburg, 97074 Würzburg, Germany.
authors: Michael
authors: M
authors: Hess
authors: Department of Hematooncology & Stem Cell Transplantation Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
authors: Gustavo J
authors: GJ
authors: Melen
authors: Department of Experimental Molecular Imaging, University Clinic and Helmholtz Center for Biomedical Engineering, Aachen, Germany.
authors: Benjamin
authors: B
authors: Theek
authors: 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.
authors: Marina
authors: M
authors: Talelli
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Yang
authors: Y
authors: Shi
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Burcin
authors: B
authors: Ozbakir
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Erik A
authors: EA
authors: Teunissen
authors: Department of Hematooncology & Stem Cell Transplantation Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
authors: Manuel
authors: M
authors: Ramírez
authors: Department of Experimental Molecular Imaging, University Clinic and Helmholtz Center for Biomedical Engineering, Aachen, Germany.
authors: Diana
authors: D
authors: Moeckel
authors: Department of Experimental Molecular Imaging, University Clinic and Helmholtz Center for Biomedical Engineering, Aachen, Germany.
authors: Fabian
authors: F
authors: Kiessling
authors: Department of Controlled Drug Delivery, Targeted Therapeutics Section, University of Twente and MIRA Institute for Biomedical Engineering and Technical Medicine, Enschede, The Netherlands.
authors: Gert
authors: G
authors: Storm
authors: Department of Organic Chemistry, Radboud Univ Nijmegen, Heyendaalse weg 135, 6525 AJ Nijmegen, The Netherlands.
authors: Hans W
authors: HW
authors: Scheeren
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Wim E
authors: WE
authors: Hennink
authors: 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.
authors: Aladar A
authors: AA
authors: Szalay
authors: Department of Biochemistry, Biocenter, University of Würzburg, 97074 Würzburg, Germany.|Genelux Corporation, San Diego Science Center, San Diego, CA 92109, USA.
authors: Jochen
authors: J
authors: Stritzker
authors: 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.
authors: Twan
authors: T
authors: Lammers