Le diabète est caractérisé par une hyperglycémie chronique mais également par un stress oxydant et une inflammation chronique conduisant à des complications cardiovasculaires telles que l'athérosclérose. La curcumine est un polyphénol connu pour ses propriétés antioxydantes et antiinflammatoires. Elle est capable de neutraliser les radicaux libres et les médiateurs inflammatoires impliqués dans le développement des maladies métaboliques. De ce fait, la curcumine peut avoir une action préventive contre le diabète de type 2 et ses complications cardiovasculaires. Cependant la curcumine, comme de nombreux médicaments hydrophobes, est très peu absorbée dans l'organisme. De plus sa métabolisation et son élimination rapide de l'organisme limite ses effets thérapeutiques. Ainsi ce travail de thèse a consisté à mettre en place un système de vectorisation pour le transport de molécules hydrophobes comme la curcumine en utilisant les carraghénanes, des polysaccharides de macroalgues. Pour ce faire, les polysaccharides ont été tout d'abord extraits des macroalgues issues des Mascareignes en mettant en place et en optimisant un protocole d'éco-extraction. Ces polysaccharides ont ensuite été caractérisés par RMN puis fonctionnalisés pour former des micelles de taille nanométrique. Nos résultats montrent que ces nanovecteurs sont biodégradables, non toxiques et permettent d'améliorer l'introduction de la curcumine dans des cellules endothéliales humaines, ainsi que d'accroitre ses propriétés antiinflammatoires. Ces nanomicelles représentent donc potentiellement un moyen de transport prometteur de médicaments hydrophobes tels que la curcumine. / Diabetes is characterized by high blood glucose but also by an oxidative stress and a chronic inflammation which lead to cardiovascular complications like atherosclerosis. Curcumin is a polyphenol known for its antioxidant and anti-inflammatory properties. It can react against free radical and downregulate inflammatory factors involved in the development of metabolic diseases. Therefore, curcumin can prevent the occurrence of type 2 diabetes and its cardiovascular complications. However, as many others hydrophobic drugs, curcumin is poorly incorporated in the body. Furthermore, its rapid biotransformation and elimination from the body limit its therapeutic effects. This PhD work consisted in the development of a drug delivery device for hydrophobic drugs like curcumin using carrageenan which are polysaccharides from seaweeds. For this, polysaccharides were first extracted from seaweeds of the Mascareignes by implementing and optimizing an eco-extraction protocol. After their characterization by NMR, these polysaccharides were then functionalized to form nanometric micelles. Our results showed that these biodegradable nanomicelles were non-toxic and allowed the enhancement of curcumin uptake by human endothelial cells and its anti-inflammatory properties. They thus potentially represent a promising device for drug delivery such as curcumin.

Daily injections for basal insulin therapy are far from ideal resulting in hypo/hyperglycemic episodes associated with fatal complications in type-1 diabetes patients. The purpose of this study was to develop a thermosensitive copolymer-based in situ depot forming delivery system to provide controlled release of insulin for extended duration following a single subcutaneous injection, closely mimicking physiological basal insulin requirement. Size and nature of the incorporated therapeutic were observed to affect the release profile of insulin. Modification with zinc and chitosan preserved thermal, conformational, and chemical stability of insulin during the entire duration of storage (up to 9 months at 4 °C) and release (up to 3 months at 37 °C). In vivo, daily administration of long-acting insulin, glargine, resulted in fluctuating blood glucose levels between 91 – 443 mg/dL in type 1 diabetic rats. However, single administration of oleic acid-grafted-chitosan-zinc-insulin complexes incorporated in copolymer formulation demonstrated slow diffusion of insulin complexes maintaining peak-free basal insulin level of 21 mU/L for 91 days. Sustained release of basal insulin also correlated with efficient glycemic control (blood glucose <120 mg/dL), prevention of diabetic ketoacidosis and absence of cataract development, unlike other treatment groups. The suggested controlled basal insulin delivery system has the potential to significantly improve patient compliance by improving glycemic control and eliminating life-threatening diabetes complications. Furthermore, oleic acid-grafted-chitosan (CO) nanomicelles were investigated as a non-viral vector to deliver plasmid DNA encoding short hairpin RNA (shRNA) against pro-inflammatory cytokines to adipose tissue macrophages and adipocytes for the treatment of insulin resistance. Nanomicelles modified using mannose (COM) and adipose homing peptide (AHP) (COA) showed significantly higher uptake and transfection efficiency in inflamed macrophages- adipocytes co culture owing to glucose transporter-1 and prohibitin receptor mediated internalization, respectively. Ligand modified nanomicelles loaded with shRNA against tumor necrosis factor alpha (COM-TNFα) and monocyte chemoattractant protein-1 (COA-MCP1) demonstrated significant attenuation of pro-inflammatory cytokines and improved insulin sensitivity and glucose tolerance in obese-diabetic mice for six weeks post treatment with single dose of optimized formulation. Overall, chitosan nanomicelles mediated targeted gene therapy can help attenuate inflammation, the chief underlying cause of insulin resistance, thereby helping reverse the progression of diabetes. / National Institutes of Health (NIH) grant R15GM114701 / ND EPSCoR seed award FAR0030636

Une faible biodisponibilité et une haute toxicité des médicaments anticancéreux, ajoutées à une résistance aux médicaments, constituent des obstacles majeurs pour le traitement du cancer. L'application des nanotechnologies pour la délivrance de médicaments est largement pressentie pour aborder ces problèmes. Premièrement, nous avons utilisé un peptide CRGDK comme ligand spécifique pour les cellules cancéreuses que nous avons conjugué au DSPE-PEG2000 pour préparer les nanomicelles encapsulant le médicament anticancéreux doxorubicine. Le peptide CRGDK conjugué aux nanomicelles provoque la liaison aux récepteurs à NRP-1, conduisant à l'absorption cellulaire spécifique et à l’amélioration de l'activité anticancéreuse in vitro. Les résultats in vivo ont également confirmé que les nanomicelles décorées de CRGDK pourraient efficacement pénétrer et s’accumuler dans les tumeurs profondes.Deuxièmement, nous avons a été consacrée à la mise au point de nanomicelles originales utilisant un dendrimère amphiphile (AmDM). Ces nanomicelles sont capables d’encapsuler efficacement la doxorubicine. Les taux de remplissage de ces nanomicelles sont extrêmement élevés. Ces nanomicelles montrent une efficacité supérieure à la doxorubicine libre et ceci sur divers types de cellules cancéreuses. De plus, ce mécanisme de pénétration cellulaire permet à ces nanomicelles de contourner le relargage du médicament médié par la pompe à efflux glycoprotéine, et ainsi surmonter la résistance à la doxorubicine. L’étude sur souris montre également un excellent effet anticancéreux associé à une diminution des effets toxiques de la doxorubicine. / Poor tumor penetration and high toxicity of anticancer drugs, together with the developed drug resistance constitute challenging hurdles for cancer therapy. The application of nanotechnology for anticancer drug delivery is expected to address these issues and bring new hope for cancer treatment. In the first part of my PhD thesis, we used a new tumor-penetrating peptide, CRGDK, to conjugate onto the surface of doxorubicin encapsulated DSPE-PEG2000 nanomicelles. The CRGDK peptide conjugated on the nanomicelles triggered specific binding to Nrp-1 receptors, leading to enhanced cellular uptake and anticancer activity in vitro. The in vivo results further confirmed that the CRGDK-decorated nanomicelles could efficiently accumulate and penetrate into deeper tumors. In the second part of my PhD thesis, we established an original nanomicellar drug delivery system based on an amphiphilic dendrimer (AmDM), which could generate supramolecular micelles to effectively encapsulate the anticancer drug doxorubicin (DOX) with high drug loading capacity (> 40%), thanks to the unique dendritic structure creating large void space for drug accommodation. The resulting AmDM/DOX nanomicelles are able to specifically accumulate at tumor sites via EPR effect and penetrate deeper into tumor tissues thanks to their small size. Most importantly, these nanomicelles exhibit significantly improved anticancer activity and reduced systemic toxicity, and are very effective even towards drug resistant cancers by virtue of their macropinocytotic cell uptake mechanism and their ability to bypass cell drug efflux pumps.