Novel PEGylated Nanoassemblies Made of Self-Assembled Squalenoyl Nucleoside Analogues

Authors

  • Fawzia Bekkara-Aounallah,

    1. Université Paris-Sud XI, Faculté de Pharmacie, UMR IFR CNRS 8612 5 rue JB Clément, 92296 Châtenay-Malabry Cedex (France)
    2. Université Djillali Liabès de Sidi Bel Abbès, Faculté des Sciences, LCOPM, BP 89 Sidi Bel Abbès 22000 (Algérie)
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  • Ruxandra Gref,

    Corresponding author
    1. Université Paris-Sud XI, Faculté de Pharmacie, UMR IFR CNRS 8612 5 rue JB Clément, 92296 Châtenay-Malabry Cedex (France)
    • Université Paris-Sud XI, Faculté de Pharmacie, UMR IFR CNRS 8612 5 rue JB Clément, 92296 Châtenay-Malabry Cedex (France).
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  • Mohammad Othman,

    1. Université Paris-Sud XI, Faculté de Pharmacie, UMR IFR CNRS 8612 5 rue JB Clément, 92296 Châtenay-Malabry Cedex (France)
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  • L. Harivardhan Reddy,

    1. Université Paris-Sud XI, Faculté de Pharmacie, UMR IFR CNRS 8612 5 rue JB Clément, 92296 Châtenay-Malabry Cedex (France)
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  • Barbara Pili,

    1. Université Paris-Sud XI, Faculté de Pharmacie, UMR IFR CNRS 8612 5 rue JB Clément, 92296 Châtenay-Malabry Cedex (France)
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  • Vanessa Allain,

    1. Université Paris-Sud XI, Faculté de Pharmacie, UMR IFR CNRS 8612 5 rue JB Clément, 92296 Châtenay-Malabry Cedex (France)
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  • Claudie Bourgaux,

    1. Université Paris-Sud XI, Faculté de Pharmacie, UMR IFR CNRS 8612 5 rue JB Clément, 92296 Châtenay-Malabry Cedex (France)
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  • Hervé Hillaireau,

    1. Université Paris-Sud XI, Faculté de Pharmacie, UMR IFR CNRS 8612 5 rue JB Clément, 92296 Châtenay-Malabry Cedex (France)
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  • Sinda Lepêtre-Mouelhi,

    1. Université Paris XI, Faculté de Pharmacie, UMR CNRS 8076 Biocis 92296 Châtenay-Malabry Cedex (France)
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  • Didier Desmaële,

    1. Université Paris XI, Faculté de Pharmacie, UMR CNRS 8076 Biocis 92296 Châtenay-Malabry Cedex (France)
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  • Julien Nicolas,

    1. Université Paris-Sud XI, Faculté de Pharmacie, UMR IFR CNRS 8612 5 rue JB Clément, 92296 Châtenay-Malabry Cedex (France)
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  • Nafa Chafi,

    1. Université Djillali Liabès de Sidi Bel Abbès, Faculté des Sciences, LCOPM, BP 89 Sidi Bel Abbès 22000 (Algérie)
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  • Patrick Couvreur

    1. Université Paris-Sud XI, Faculté de Pharmacie, UMR IFR CNRS 8612 5 rue JB Clément, 92296 Châtenay-Malabry Cedex (France)
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  • The authors wish to acknowledge the French national research center (CNRS) and the “Agence Nationale de la Recherche” (ANR, grant SYLIANU) for financial support. The authors wish to thank Martine Appel, Madeleine Besnard, and Hélène Chacun for excellent technical assistance, Sonia Baconnais (Laboratoire de Microscopie Moléculaire et Cellulaire, UMR 8126, Interactions Moléculaires et Cancer CNRS—Université Paris sud—Institut de cancérologie Gustave Roussy, Villejuif, 94805, France) for TEM observations, Thierry Pouget (LVMH Recherche Parfums et Cosmétiques, Département Innovation Matériaux et Technologies, 185 Avenue de Verdun, 45804 Saint Jean de Braye, France) for FF-TEM observations. Heinz Amenitsch (Austrian SAXS beamline group at Elettra, Trieste, Italy) is gratefully acknowledged for his support during X-Ray measurements. Supporting Information is available online from Wiley InterScience or from the authors.

  • We dedicate this manuscript to the memory of our beloved colleague and scientist Dr. Michel Ollivon, recently deceased, who pioneered the X-Ray studies with our nanoassemblies.

Abstract

This study describes a new simple method to obtain high loading of anticancer or antiviral nucleoside analogues into “stealth” poly(ethylene glycol) (PEG)-coated nanoassemblies. These nanodevices are obtained by co-nanoprecipitation in water of (i) squalenoyl prodrugs obtained by the bioconjugation of the natural lipid squalene with either the anticancer drug gemcitabine (Gem-Sq) or the antiviral drug deoxycytidine (ddC-Sq) with (ii) a PEG derivative of either cholesterol (Chol-PEG) or squalene (Sq-PEG). It was found that both PEG derivatives (Chol-PEG or Sq-PEG) were efficiently incorporated in the resulting composite nanoassemblies (CNAs), as shown by radioactivity studies, Zeta potential determination, and size measurements. Optimal compositions were defined for each PEG derivative to ensure the best stability in water and in buffer solutions. X-ray diffraction and electron microscopy investigations revealed that depending on the structure of the squalenoyl nucleoside analogue used (Gem-Sq or ddC-Sq), these nanoassemblies might be toroids or cubosomes. Following PEGylation, the Gem-Sq nanoassemblies displayed superior in vitro anticancer activity on gemcitabine-resistant leukemia L1210 10K cells than either their non-PEGylated counterparts or gemcitabine alone.

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