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AVERTISSEMENT
Ce document est le fruit d'un long travail approuvé par le
jury de soutenance et mis à disposition de l'ensemble de la
communauté universitaire élargie.
Il est soumis à la propriété intellectuelle de l'auteur. Ceci
implique une obligation de citation et de référencement lors
de l’utilisation de ce document.
D’autre part, toute contrefaçon, plagiat, reproduction
illicite encourt une poursuite pénale.
➢ Contact SCD Nancy 1 : theses.sciences@scd.uhp-nancy.fr
LIENS
Code de la Propriété Intellectuelle. articles L 122. 4
Code de la Propriété Intellectuelle. articles L 335.2- L 335.10
http://www.cfcopies.com/V2/leg/leg_droi.php
http://www.culture.gouv.fr/culture/infos-pratiques/droits/protection.htm Poznan University of Medical Sciences
Nancy University
ELIZA GŁÓWKA
Encapsulation of fluorogenic probes
and pharmacologically active molecules
into nanoparticles for enhancing cellular uptake
Doctoral dissertation
Doctorat co-tutelle
Mentors: Prof. Dr Janina Lulek
Prof. Dr Philippe Maincent
Members of the Committee:
Prof. Dr Janina Lulek Prof. Dr Philippe Maincent
Prof. Dr Małgorzata Sznitowska Prof. Dr Elias Fattal
Prof. Dr Edmund Grześkowiak Dr Anne Sapin-Minet
Poznań 2009
Keywords: nanoparticles, nanospheres, nanoencapsulation, encapsulation, salmon
calcitonin, glutathion, sustained release, oral delivery, intracellular
targeting, bioavailability
Słowa kluczowe: nanocząstki, nanosfery, inkorporowanie, kalcytonina łososiowa,
glutation, przedłużone uwalnianie leku, podanie doustne, przenikanie
dokomórkowe, biodostępność
Mots clés: nanoparticules, nanosphères, nanoencapsulation, encapsulation,
calcitonine de saumon, glutathion, libération prolongée, administration
orale, pénétration intracellulaire, biodisponibilité
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ACKNOWLEDGEMENTS
The present work was carried out between July 2005 and June 2009 in the framework
of the doctoral studies (doctorat co-tutelle) between Poznan University of Medical Sciences
(Poland) and Nancy University (France).
First of all, I would like to express my deepest gratitude to my supervisors. Professor
Janina Lulek (Department of Pharmaceutical Technology, Poznan University of Medical
Sciences) and Professor Philippe Maincent (Department of Pharmaceutical Technology,
Nancy University) are gratefully acknowledged for offering me the opportunity to work in
this project, for the constructive discussions, support and constant interest, the friendly
atmosphere within both departments and for involving me in the program of Euro PhD in
Advanced Drug Delivery Systems provided by the GALENOS Network.
Professor Pierre Leroy (Nancy University), who co-supervised the first part of this
thesis (Encapsulation of fluorogenic probes into nanoparticles), is also gratefully
acknowledged for the generous support concerning mainly analytical issues of this project, for
reviewing the present thesis, and in principle for inspiring me to do the doctoral studies.
Professor Małgorzata Sznitowska (Medical University of Gdansk) and Professor
Elias Fattal (University of Paris-XI) are thanked for kindly being co-referees for this thesis.
Very special acknowledgements to Dr Anne Sapin-Minet for her continual support
with all scientific, administrative and technical issues during my stay in Nancy. Furthermore,
I would like to address sincere thanks to all my colleagues and friends within both
departments for their invaluable support, good cooperation, professional and private
discussions, and for the friendly atmosphere and great time we spent as co-residents in the
laboratory. I am especially grateful to: Dr Ahmed Sheik Hassan, Julien Scala Bertola,
Fatima El Ghazouani, and Javier Camargo (special thanks for taking SEM micrographs)
within the Department of Pharmaceutical Technology in Nancy, and to Bartłomiej
Milanowski, Magdalena Olejniczak-Rabinek, Hanna Wosicka, Małgorzata Geszke, and
Dr Joanna Karolewska, within the Department of Pharmaceutical Technology in Poznań.
3
Professor Jadwiga Jodynis-Liebert and Dr Marek Murias (Department of
Toxicology, Poznan University of Medical Sciences) are thanked for offering me facilities to
work in their laboratory.
Moreover, I am obliged to Dr hab. Janusz Kasperczyk and Dr Katarzyna Jelonek
(Center of Polymer and Carbon Materials, Polish Academy of Science, Zabrze) for
1generously performing H-NMR measurements and giving a word of advice. Additional
thanks to Dr hab. Arkadiusz Szymański (Faculty of Chemistry, Adam Mickiewicz
University, Poznań) for performing the DSC analysis.
Above all, I am in debt of my husband Bartosz and my parents for their
encouragement, understanding and continuous support during all the years of my
pharmaceutical education.
The GALENOS NETWORK is acknowledged for providing the financial support
with the Galenos Fellowship in the Framework of the EU Project “Towards a European PhD
in Advanced Drug Delivery”, Marie Curie Contract MEST-CT-2004-504992.
The part of the in vivo study (oral administration in rats) was supported by a grant
from the Polish Ministry of Science and Education (the project number: N405 040 32/2741).
1Additionally, the DSC and H-NMR studies were supported by the financial resources
from Poznan University of Medical Sciences (the project numbers: 501-01-3307415-
50387/2007 and 501-01-03314429-50387/2008).
4
Parts of this thesis have been presented at the following conferences/workshops:
1. E. Główka, A. Lamprecht, N. Ubrich, P. Leroy, J. Lulek, J. Coulon, P. Maincent, Nanoparticles
increase the uptake of glutathione selective fluorogenic probes in yeast cells (poster presentation),
6th International Conference and Workshop on Cell Culture and In vitro Models for Drug
Absorption and Delivery, Saarland University, Saarbrücken, Germany, March 1-10, 2006.
2. E. Główka, Encapsulation of fluorogenic probes and salmon calcitonin in polymeric
nanoparticles (oral presentation), 4th Marie Curie Early Stage Training Galenos Thematic
Workshop, University of Cagliari, Cagliari, Italy, September 7-9, 2006.
3. E. Główka, Preparation, characterization, and in vivo evaluation of salmon calcitonin
nanoparticles (oral presentation), 3rd Lab Course at Charles University (Galenos Intensive
Course), Charles University, Hradec Králové, Prague, Czech Republic, January 29 - February 8,
2007.
4. E. Główka, N. Ubrich, A. Sapin, P. Leroy, J. Lulek, P. Maincent, Preparation and in vitro study
on polymeric nanoparticles as drug delivery system for salmon calcitonin (poster presentation),
Young Pharmaceutical Scientists Meet in Amsterdam - Pre-Satellite Meeting of the 3rd
Pharmaceutical Sciences World Congress (Poster Award) and 3rd Pharmaceutical Sciences World
Congress: Optimizing Drug Therapy - an Imperative for World Health, Amsterdam, the
Netherlands, April 20-25, 2007.
5. E. Główka, N. Ubrich, P. Maincent, P. Leroy, J. Lulek, Otrzymywanie i charakterystyka
nanocząstek jako nośników substancji o różnych właściwościach fizykochemicznych (poster
presentation), I Krajowa Konferencja Nanotechnologii, Politechnika Wrocławska, Wrocław,
Poland, May 26-28, 2007.
6. E. Główka, N. Ubrich, P. Maincent, P. Leroy, J. Lulek, The preparation and evaluation of
polymeric nanoparticles containing a lipophilic or hydrophilic active agent (poster presentation),
4th Polish-German Symposium, Martin Luther University Halle-Wittenberg, Halle, Germany,
June 6, 2007.
7. E. Główka, A. Szymański, A. Sapin-Minet, P. Maincent, J. Lulek, Charakterystyka
fizykochemiczna polimerowych nanosfer do transportu leków (poster presentation), II Krajowa
Konferencja Nanotechnologii, Uniwersytet Jagielloński, Kraków, Poland, June 25-28, 2008.
8. E. Główka, A. Szymański, A. Sapin-Minet, P. Maincent, J. Lulek, Kalcytonina łososiowa w
polimerowych nanosferach (oral presentation), Innowacyjne rozwiązania w technologii postaci
leku w celu optymalizacji farmakoterapii. 80-lecie Katedry Technologii Postaci Leku i
Biofarmacji, Uniwersytet Jagielloński, Kraków, Poland, October 24-25, 2008.
5
Parts of this thesis have been published in the following journals:
1. E. Główka, A. Lamprecht, N. Ubrich, P. Maincent, J. Lulek, J. Coulon, P. Leroy
Enhanced cellular uptake of a glutathione selective fluorogenic probe encapsulated in
nanoparticles
Nanotechnology, 17, 2546-2552 (2006)
2. E. Główka, A. Sapin-Minet, P.