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Preparation of Submicron Particles for Theranostic Applications: Imaging

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Preparation of Submicron Particles for Theranostic Applications: Imaging Preparation of submicron particles for theranostic applications : imaging and therapy Muhammad Iqbal To cite this version: Muhammad Iqbal. Preparation of submicron particles for theranostic applications : imaging and therapy. Other. Université Claude Bernard - Lyon I, 2015. English. NNT : 2015LYO10227. tel- 01290059 HAL Id: tel-01290059 https://tel.archives-ouvertes.fr/tel-01290059 Submitted on 17 Mar 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. N°d’ordre: 227-2015 Année 2015 THESE Présentée devant L’UNIVERSITE CLAUDE BERNARD – Lyon 1 Pour l’obtention du Diplôme de DOCTORAT Spécialité Pharmacotechnie Par Muhammad IQBAL Soutenue publiquement le 13 Novembre 2015 “Préparation de particules submicroniques pour applications théranostiques: imagerie et thérapie” Jury : Salima Saidi Professeur Université d’Oran, Algeria Serge Stoll Professeur Université de Genève, Switzerland Stéphanie Briançon Professeur Université Claude Bernard Lyon 1, France Amane JADA CR1-HDR-CNRS Institut de Sciences Des Matériaux De Mulhouse Hatem Fessi Professeur Co-directeur de thèse (Université Lyon-1) Abdelhamid Elaissari DR-CNRS Directeur de thèse (LAGEP, Université Lyon-1) UNIVERSITE CLAUDE BERNARD - LYON 1 Président de l’Université M. François-Noël GILLY Vice-président du Conseil d’Administration M. le Professeur Hamda BEN HADID Vice-président du Conseil des Etudes et de la Vie Universitaire M. le Professeur Philippe LALLE Vice-président du Conseil Scientifique M. le Professeur Germain GILLET Directeur Général des Services M. Alain HELLEU COMPOSANTES SANTE Faculté de Médecine Lyon Est – Claude Bernard Directeur : M. le Professeur J. ETIENNE Faculté de Médecine et de Maïeutique Lyon Sud – Charles Mérieux Directeur : Mme la Professeure C. BURILLON Faculté d’Odontologie Directeur : M. le Professeur D. BOURGEOIS Institut des Sciences Pharmaceutiques et Biologiques Directeur : Mme la Professeure C. VINCIGUERRA Institut des Sciences et Techniques de la Réadaptation Directeur : M. le Professeur Y. MATILLON Département de formation et Centre de Recherche en Biologie Humaine Directeur : Mme. la Professeure A-M. SCHOTT COMPOSANTES ET DEPARTEMENTS DE SCIENCES ET TECHNOLOGIE Faculté des Sciences et Technologies Directeur : M. F. DE MARCHI Département Biologie Directeur : M. le Professeur F. FLEURY Département Chimie Biochimie Directeur : Mme Caroline FELIX Département GEP Directeur : M. Hassan HAMMOURI Département Informatique Directeur : M. le Professeur S. AKKOUCHE Département Mathématiques Directeur : M. le Professeur Georges TOMANOV Département Mécanique Directeur : M. le Professeur H. BEN HADID Département Physique Directeur : M. Jean-Claude PLENET UFR Sciences et Techniques des Activités Physiques et Sportives Directeur : M. Y.VANPOULLE Observatoire des Sciences de l’Univers de Lyon Directeur : M. B. GUIDERDONI Polytech Lyon Directeur : M. P. FOURNIER Ecole Supérieure de Chimie Physique Electronique Directeur : M. G. PIGNAULT Institut Universitaire de Technologie de Lyon 1 Directeur : M. le Professeur C. VITON Ecole Supérieure du Professorat et de l’Education Directeur : M. le Professeur A. MOUGNIOTTE Institut de Science Financière et d'Assurances Directeur : M. N. LEBOISNE i Acknowledgements This research was conducted at the Laboratoire d'Automatique et de Génie des Procédés (LAGEP) led by professor Hatem Fessi, the director of LAGEP. I wish to express my sincere appreciation to my co-supervisor Dr. Fessi for his continuous support, kindness and providing me all the facilities required to carry out my research work. Words cannot express how grateful I am to my enthusiastic supervisor Dr. A. Elaissari for his professional guidance, discussions, ideas, valuable suggestions and support during these three years. I wish to thank him from the core of my heart for his friendship, kindness, encouragement and motivation. Mr. Elaissari is someone you will instantly love and never forget once you meet him. He was and remains my best role model as a great scientist, excellent mentor, and outstanding teacher. I could not have imagined having a better advisor and mentor for my Ph.D. study. I gratefully acknowledge the members of my Ph.D. committee for their time and valuable feedback on the initial version of this dissertation. I am especially grateful to Nadia Chapel, Geraldine, Jean-Pierre and Olivier for their help and support throughout my research work. I would also like to thank all of my colleagues especially Karim, Dimah, Badri, Talha,Nadia and Mourad. I especially thank Naveed Ahmed and Usman Ahmed for their welcome, kind help and support during my study. Besides my supervisor, I would like to express my sincere gratitude to Dr. Ahmad Bitar for his unconditional support, guidance, helpful discussions and sincere advices many times during my Ph.D study. I admire his positive outlook and his ability to smile despite the situation. I will forever be thankful to him for being my wonderful and sincere friend. Finally, I am highly indebted to my parents for their unbelievable support, sacrifices, prayers, unconditional love and care. ii Résumé L'objectif de cette étude était de préparer et de caractériser les particules submicroniques multifonctionnelles utilisables simultanément pour le diagnostic et le traitement de plusieurs maladies mortelles telles que le cancer. Pour ce faire, une étude systématique a été réalisée afin de comprendre les mécanismes impliqués et d'optimiser les paramètres du procédé de double émulsion-évaporation de solvant pour la préparation de ces particules. Pour l’imagerie in vitro, des nanoparticules polymériques fluorescentes (FluoSpheres®) ont été encapsulées dans une matrice polycaprolactone dégradable en utilisant le procédé de l’émulsion double-évaporation de solvant. Pour l’imagerie in-vivo, des nanoparticules d'or colloïdal ont été préparées et encapsulées via le même procédé et parfaitement caractérisées. Enfin, pour application theranostic, les nanoparticules d'or (comme agent de contraste) et un actif moléculaire (hydrophile Nefopam et hydrophobe benzoate de benzyle) ont été encapsulés simultanément dans des particules de polycaprolactone. Ces particules multifonctionnelles ont été caractérisées et évaluées in vitro comme model de pénétration cutané. iii TABLE OF CONTENTS I. General Introduction 1 II. Bibliography 8 II.1 Applications of particles prepared from preformed polymers in drug delivery systems 9 II.2 Encapsulation via double emulsification process 42 III. Experimental Part 103 III.1 Systematic study of double emulsion prepared using ultra-turrax 104 III.2 Preliminary study of encapsulation via double emulsion using power ultrasound 120 III.3 Encapsulation of fluorescent nanoparticles in polycaprolactone particles to be used as contrast agent 136 III.4 Preparation and encapsulation of gold nanaoparticles 148 IV. General discussion and Conclusion 174 iv PART I GENERAL INTRODUCTION 1 The application of nanotechnology in biomedical field for therapy of various diseases has received substantial attention in recent years. It offers a unique approach against fatal diseases like cancer, CVS, HIV and diabetes, through early diagnosis, prediction, prevention and personalized therapy1,2. It plays a vital role in target-specific drug therapy and techniques for early diagnosis of tumor cells. Nanomedicine has potential for revolutionizing cancer therapy and diagnosis by developing new biocompatible nanocarrier systems for drug delivery purposes. These nanosystem have four unique properties unlike conventional therapeutics. (i) It can be attached to targeting ligands, which have high affinity and specificity for target cells. (ii) It can themselves possess therapeutic or diagnostic properties and can be utilize to carry therapeutic agents. (iii) It can be designed for loading multiple therapeutic agents simultaneously. (iv) It can bypass traditional drug resistance mechanism. Due to targeting strategies nanocarrier can achieve high drug concentration in tumor cells while minimizing toxicity in normal cells, so enhancing the therapeutic effects and reducing systemic toxicity3,4. Combining diagnosis and therapy in one process is referred as theranostic, the basic goal of theranostic is to target specific tissue selectively, to monitor the response to the treatment, to increase drug efficacy and safety, to increase therapeutic and diagnostic accuracy5. This strategy can enable us to make the treatment shorter, safer and more efficient for fetal disease like cancer, HIV, diabetes etc. Biocompatible theranostic particles for cancer therapy are under development, which would accelerate the therapy, reduce the drug toxicity and side effects. Presently, most of the research in theranostic has been focused on the management of cancer, since it is the major disease and leading cause of mortality. Cancer, also known as malignant tumor is a term used for a group of almost 100 diseases. Its two main characteristics are uncontrolled growth of the cells in the human body and the ability of these cells to migrate from the original site and spread
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