NANOTECHNOLOGY SOLUTIONS FOR MUCOSAL VACCINE 

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Nanoparticle based drug delivery system

The application of nanotechnology in drug delivery has gained increasing interest over the past few decades. Nanoparticles (NPs) are made of organic or inorganic materials to deliver drugs into the body for the treatment of various diseases. NPs such as polymeric micelles, quantum dots, liposomes, polymer-drug conjugates, dendrimers, biodegradable nanoparticles, silica, etc. are few examples of nanoparticulate materials undergoing preclinical development, or already used in clinic (Kabanov and Alakhov 2002; Duncan 2003; Farokhzad and Langer 2006; Davis, Chen, and Shin 2008; Peer et al. 2007; Tasciotti et al. 2008). These nanomaterials can deliver low molecular weight compounds, proteins and nucleotides to target disease cells or tumors to maximize clinical benefit while limiting untoward side effects. Such NPs are also expected to drastically improve drug delivery for treatment diseases. Nanoparticles require site-specific cellular entry to deliver their cargo to subcellular position.

Endocytosis of nanoparticles

Macromolecules and particles can be taken up by eukaryotic cells from the surrounding medium by an active process called endocytosis. Endocytosis involves multiple stages. First, the material is enclosed in an area of plasma membrane, which then buds off inside the cell to form a vesicle named as endosomes (or phagosomes in case of phagocytosis). Second, the endosomes deliver the cargo to various specialized cellular compartment, which enables sorting of materials towards different destinations. Finally, the cargo is delivered to intracellular compartments, recycled to the extracellular milieu or delivered across cells (a process known as “transcytosis” in polarized cells). Depending on the cell type, as well as the proteins, lipids, and other molecules involved in the process, endocytosis can be classified into several types (Doherty and McMahon 2009; Kumari, Mg, and Mayor 2010). Five main different mechanisms of endocytosis are: phagocytosis, clathrin-mediated endocytosis (CME), caveolin-mediated endocytosis (CavE), clathrin/caveolae-independent endocytosis, and macropinocytosis. Some authors may consider the last four mechanisms subtypes as process of pinocytosis. Compared to phagocytosis, which takes place mainly in professional phagocytes, pinocytotic mechanisms are more common and occur in many cell types (Fig 2) (Salatin and Yari Khosroushahi 2017; Sahay, Alakhova, and Kabanov 2010).

Effect of nanoparticle’s charge

The modification of NPs with positively charged functional groups facilitates electrostatic interaction with negatively cell membrane (He et al. 2010; Lankoff et al. 2013). Hence, generally cationic NPs have higher uptake than negatively charged (Harush-Frenkel et al. 2007). The internalization of NPs with negative charge surface decreases by increasing the surface charge, while an increase of uptake of cationic NPs is observed while increasing the charge density (He et al. 2009). The permeability of positively charged drug carriers to gastrointestinal mucous barrier is higher than neutral and negatively charged NPs because of the presence of negatively charged proteins in outer surface of gastrointestinal epithelial cells (El-Shabouri 2002). The cationic nature of chitosan-based NPs facilitates the electrostatic interaction with cell membrane and subsequently cellular internalization (Tahara et al. 2009; Duceppe and Tabrizian 2010; Amidi et al. 2010). However, in some cases, surface modified by negative charge can enhance the uptake of nanoparticles. By increasing the negative surface charge of carboxymethyl dextran-modified iron oxide NPs, these particles are highly taken via non- specific pathways (Ayala et al. 2013). Super paramagnetic iron oxide NPs coated with anionic silica have a cellular uptake 3-fold higher than cationic one (Prijic et al. 2010). Citrate groups grafted on NP giving a negative surface charge of NPs, increases the stability on NPs in serum-free culture medium and subsequently their cellular internalization (Kolosnjaj-Tabi et al. 2013).

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Table of contents :

TABLE OF CONTENTS
ACKNOWLEDGMENTS
LIST OF PUBLICATIONS
ABBREVIATIONS
LIST OF FIGURES
LIST OF TABLES
AIM AND OUTLINE OF THE THESIS
ABSTRACT
RÉSUMÉ
RÉSUMÉ DE LA THÈSE
PART I: INTRODUCTION
1. Nanoparticle based drug delivery system
1.1. Endocytosis of nanoparticles
1.2. Parameters affecting endocytosis
1.2.1. Surface chemistry of nanoparticle
1.2.2. Size of the nanoparticle
1.2.3. Effect of nanoparticle’s charge
1.3. Examples of nanoparticle as drug delivery system in clinics
1.4. Conclusion
PUBLICATION 1: NANOTECHNOLOGY SOLUTIONS FOR MUCOSAL VACCINE 
2. Influenza and vaccination
2.1. Influenza virus
2.1.1. Influenza virology
2.1.2. Mechanism of replication
2.2. Influenza vaccines
2.2.1. Conventional vaccine against influenza
2.2.1.1. Inactivated influenza vaccines
2.2.1.2. Live-Attenuated influenza Vaccines
2.2.2. Strategies for influenza vaccines
2.2.2.1. Adjuvants for influenza vaccine
2.2.2.2. Nucleic acid influenza vaccines
2.2.2.3. Universal influenza vaccines
2.3. Intranasal universal influenza vaccine – UniVac Flu Project
PART II: RESULTS
PUBLUCATION 2: RESIDENCE TIME AND UPTAKE OF ZWITTERIONIC NANOPARTICLES IN THE NASAL MUCOSA: COMPARISION WITH ANIONIC AND CATIONIC NANOPARTICLES
PUBLICATION 3: ZWITTERIONIC NANOPARTICLES ARE MORE EFFICIENT
VECTORS FOR PROTEIN DELIVERY INTO NASAL MUCOSAL CELLS THAN CATIONIC OR ANIONIC NANOPARTICLES
PUBLICATION 4: ZWITTERIONIC NANOPARTICLES CARRYING CTA1-DD
ADJUVANT INDUCE PROTECTION FROM VIRUS INFECTION AND
TRANSMISSION
PART III: DISCUSSION
PART IV: CONCLUSION AND PERSPECTIVES
Bibliography

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