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Affitin-Dendrimer Conjugates for Multivalency-Enhanced Targeting » THESE DE DOCTORAT DE L'UNIVERSITE DE NANTES COMUE UNIVERSITE BRETAGNE LOIRE ECOLE DOCTORALE N° 605 Biologie Santé UNIVERSIDAD SANTIAGO DE COMPOSTELA ESPAGNE Par Petar VUKOJICIC « Affitin-dendrimer conjugates for multivalency-enhanced targeting » Thèse présentée et soutenue à Nantes, le 28 Janvier 2019 Unité de recherche : CRCINA U1232 CIQUS Rapporteurs avant soutenance : Jan Van HEST Professeur, Eindhoven University of Technology Michael MALKOCH Professeur, Royal Institute of Technology (KTH) Composition du Jury : Président : Elena ISHOW Professeur, Université de Nantes Examinateur : Patrice SOUMILLION Professeur, Université catholique 0de Louvain Dir. de thèse : Barbara MOURATOU Maitre de conférences, Université de Nantes Co-dir. de thèse : Eduardo FERNANDEZ-MEGIA Professeur, Universidad Santiago de Compostela Mom ocu i mojoj baki, u ime večnog zaveta koji sam im dao. (To my father and my grandmother, in the name of the pledge I made.) 1 Table of contents Acknowledgements………………………………………………………………......................3 Synopsis.……………………………………………………………………………………………………6 Abbreviations…………………………………………………………………………………………….9 Chapter I: Introduction…………………………………………………………………………….13 Chapter II: Objectives……………………………………………………………………………..102 Chapter III: Synthesis and characterization of Affitin-dendrimer conjugates for multivalent targeting of Staphylococcus aureus Protein A…………………107 Chapter IV: Interaction of Affitin-dendrimer conjugates with Staphylococcus aureus…………………………………………………………………….…………………………..…170 Chapter V: Conclusions and perspectives………………………………………………..202 2 Acknowledgements The work presented in the following pages is an achievement of my family, friends, coworkers and mentors whose vast, selfless support kept my hand steady in the most difficult of times. No words can fully express the gratitude I feel towards this amazing group of people that I am proud to call my own. Firstly, I need to express deep appreciation to my supervisors Dr Barbara Mouratou and Dr Eduardo Fernandez-Megia for the opportunity to work with them and benefit from their knowledge, experience and leadership. Their persistent confidence in me, along with the support in all professional and personal affairs, made all the difference. I would like to thank the members of thesis committee Dr Jean- Francois Gestin and Dr Anxo Vidal for important insights and stimulating discussions during our meetings. I am also grateful to the members of the jury for my thesis defense Dr Jan Van Hest, Dr Michael Malkoch, Dr Elena Ishow and Dr Patrice Soumillion for agreeing to evaluate this work. During the last years, I was fortunate to work in three different countries and three different laboratories. First, I want to thank my group in France: Fred and Axelle, who always had the most patience to discuss my work in detail in our meetings, inspiring and providing innovative perspectives and thus improving the quality of my research immensely; Ghislaine, whose invaluable experience in the laboratory is exceeded only 3 by her kindness, selflessness and willingness to help; my peers Stanimir, Valentina and Benjamin with whom I have shared everything and who will always stay in the circle of my closest friends. Furthermore, I thank other members of Team 13 and Unit 1232 who supported me – Michel, Stephanie, Bertrand, Stephan, Mike, Laurent, Francois, Cindy, Patricia, Steven and others. Special gratitude goes to people who made Nantes my second home with their friendship: Kubat, Abdulaye, David, Dušan, Zhenya, Roxana, Alex, Barbara and others. For the time I spent in Spain, I had the opportunity to work with Marcos, Juan, Susana, Muna and many others. I thank them for making a mark in my life with their exceptional kindness and invaluable help. I owe a special gratitude to Maun, whose friendship and contribution to my work were truly incredible, as well as to Sorel and Ulung for all the cafeteria lunches, late nights in the lab (and elsewhere) and putting a smile on my face every day. During the two months I spent at Stanford, California, I was privileged to work with Dr Carolyn Bertozzi and Dr Han Xiao and learn so much from them in such a short time. I owe them immense gratitude for this rewarding experience, as well as Asia Avelinho and all others for the amazingly warm welcome I received in their lab. This PhD also blessed me with the opportunity to meet Maha, who quickly became an integral part of all my endeavors. Her kindness, incredible 4 selflessness and commitment are built into this thesis and in everything else I do as the strongest and most reliable foundation. Thank you for making it all worth it. My family and friends back at home, with whom I have grown up and to whom I owe more than I can ever repay, have a claim to all my successes and share in all the happiness. I cannot thank them enough for their unconditional love. My love and gratitude to my mother and my grandfather cannot be properly expressed here – my biggest rewards are the moments when I am able to make them more proud than they already are. Hvala vam. 5 Synopsis Achieving selectivity in order to balance therapeutic and adverse effects has always been a central challenge of medicine. Nanotechnology is a modern field that allows us to tackle the selectivity issue in medicine in a completely new way, using “smart”, targeted nanoparticles. Most of medical research today is about identifying factors characteristic for certain conditions and finding efficient ways to target them in a specific manner, thus avoiding healthy cells and tissues. There are two main ways this targeting is achieved with nanoparticles. First is by modulating the pharmacokinetics of the agents by controlling their size and physicochemical properties, causing them to accumulate in the desired compartments of the organism – passive targeting. Second is by functionalizing their surface with targeting agents that will bind to a defined molecular target in a highly specific manner – active targeting. Dendrimers are a very versatile class of nanoparticles. They are synthetic, tree-like, globular structures obtained through a step-wise synthesis that allows a small-molecule-like level of control. Their monodispersity and highly customizable size, structure and surface functionalization distinguishes them from other nanoparticles as an especially attractive platform. Beside these general advantages of dendrimers, Gallic Acid-Triethylene Glycol (GATG) dendrimers take 6 advantage of terminal azides present in the repeating unit allowing a simple, fast and reliable synthetic procedures and high structural versatility. Among the agents used for molecular targeting, antibodies are traditionally considered to be unmatched in terms of narrow specificity and high affinity towards their targets. Lately, the development of targeting scaffolds alternative to antibodies has been pursued in the search of complementary properties. Affitins are such a scaffold, offering nanomolar affinities and narrow specificities for the targets, that either match or outperform those of antibodies, along with twenty-fold smaller size and high thermal and pH stability. Furthermore, Affitins are easily obtained in high quantities via production in E. coli. The improved selectivity provided by targeted nanoparticles has been most extensively employed for cancer-related purposes. However, considering the increased occurrence of multiresistance to antibiotics in bacteria, highly specific targeting and delivery tools in the field of infectious diseases are quickly gaining in importance. Separating the targeting from the effector function of antimicrobial agents might not only render ineffective most of the resistance mechanisms of bacteria, but also allow for usage of more toxic antimicrobial agents due to the specific delivery that bypasses host cells. The main aim of this thesis was to combine the enhanced targeting properties of Affitins with the advantages that GATG dendrimers offer as 7 carriers and to obtain powerful nanoscale devices with wide potential for diverse applications. Our first objective was to develop a versatile conjugation method that will allow customization of final products in terms of size, structure, surface functionalization and target specificity. Our second objective was to showcase Affitin-dendrimer conjugates by deliberately designing a set of conjugates highly specific for Staphylococcus aureus Protein A (SpA) and demonstrating their usefulness. A click-chemistry conjugation method was developed and used to obtain four distinct populations of conjugates, allowing for fluorescent labelling and surface modification during the process. Products were thoroughly characterized in terms of size, structure and valency. Their enhanced multivalent binding to SpA was demonstrated by surface plasmon resonance, while their narrow specificity for SpA-expressing S. aureus strains was demonstrated in an agglutination assay. Strong, concentration- dependant agglutination triggered by the conjugates was also used to modulate their ability to form biofilms. The high versatility and multivalency of GATG dendrimers as nanocarriers combined with the customizable target-specificity of Affitins provides powerful nanoscale devices for targeting, capable of carrying large amounts of diverse payloads and therefore performing diverse functions. 8 Abbrevations AAC Huisgen 1,3-dipolar Azide-Alkyne Cycloaddition Aap Accumulation-associated protein Ab Antibody ABT Azabisphosphonate ADCs Antibody-drug conjugates Ag Antigens Agr Accessory gene regulator BCN Bicyclononyne
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