With the emergence of novel and more effective drug therapies, increased importance is being placed upon the methods by which these drugs are being delivered to the body. In conventional drug delivery systems, there is very little control over the release of drug. The effective concentration at the target site can be achieved by intermittent administration of grossly excessive doses, which, often results in constantly, unpredictable variations in plasma concentrations, with the risk of reaching levels below or above the therapeutic range leading to marked side effects. A plethora of formulation strategies mainly based on polymeric/lipid nanoparticles, are described in literature. Even though these systems are therapeutically advantageous in comparison to conventional systems, they remain insensitive to the changing metabolic states of the body although the symptoms of most metabolic diseases follow a rhythmic pattern.A more appropriate and effective approach of managing some of these conditions lies in the chronotherapy. This approach allows for pulsed or self-regulated drug delivery which is adjusted to the staging of biological rhythms, since the onset of certain diseases exhibits strong circadian temporal dependence. In order to reach the objective of mimicking the biophysical and biochemical processes of pathological states, many innovations in material design for drug delivery systems (DDS) that are able to release the therapeutic payload-on-demand were done to release the therapeutic agent only when it is required, according to the physiological need. The development of multidisciplinary research teams has brought huge advantages in the design, fabrication and utilization of such smart systems, especially in the pharmaceutical field. Interestingly, numerous smart polymeric materials exhibit a response to a specific stimulus. A step further, the elaboration of purpose-built monomers can give rise to compounds with tunable sensitivities or multi-stimuli responsiveness. These smart polymers demonstrate an active responsiveness to environmental (or external) signals and change their physicochemical properties as designed (e.g. conformation, solubility, shape, charge or size). As far as the stimuli are concerned, they consist of physical (e.g. temperature, ultrasound, light, electricity, magnetic or mechanical stress), chemical (e.g. pH, ionic strength) and biological signals (e.g. enzymes, biomolecules). Due to the intrapersonal variabilities which may make internal stimuli hazardous, externally controlled systems rely on externally applied stimuli that are produced by stimuli-generating devices, which results in pulsed drug delivery. This type of delivery may be rapid and allows a transient release of a determined amount of drug within a short period of time immediately after a pre-determined off-release period. A novel strategy for the formation of multi-stimuli responsive materials endowed with pH, magnetic and light sensitivity was achieved. The approach relied on the incorporation of magnetic tetrahalogenoferrate(III) anions along a polymeric backbone based on poly(2-(N,N-dimethylamino) ethyl meth-acrylate) (PDMAEMA). Starting from the same PDMAEMA, quaternized pending amine groups with various halide derivatives gave rise to magnetic materials after anion metathesis. Measuring the magnetic susceptibility of these materials exhibited that the magnetic susceptibility increased as the substituted group size decreased (become smaller) which was apparently related to the steric hindrance around the ionic pendants. Additionally, a good correlation between the magnetic susceptibility and ferric content was found. Additional experimental and theoretical Raman analyses allowed the determination of the nature of the magnetic species constituting the materials. This strategy further offers the opportunity to tailor the magnetic response through partial ammonium salt formation. In order to merge the magnetic properties of ferric-based materials with another stimuli-responsive functionality, random copolymers containing DMAEMA (D) with diazobenzene (A) unit were prepared. So, three copolymers PDA were synthesized (with targeted D/A ratios 4/6 (PDA4), 6/4 (PDA6) and 8/2 (PDA8)). Meanwhile, different degrees of amine quaternization (10, 50 and 100 %) were applied, which led to the following polymeric salts PDAX/Y where X = 4, 6, 8 (referring to the percentage of the DMAEMA unit) and Y = 10, 50 and 100 (referring to the percentage of quaternized amine groups). Finally, the aforementioned materials were converted into magnetic polymers by anion exchange. As a result, magnetic responses correlated well with amount of iron oxide in these compounds and the amount of ionic pending groups along the backbone. Moreover, the remaining tertiary amines conferred pH sensitivity to the polymers whereas the diazobenzene units ensured light responsiveness through the well-established trans-to-cis isomerization.In order to functionalize these materials in the pharmaceutical field, an intelligent delivery system was prepared. Firstly, an attempt to formulate riboflavin-5’-phosphate sodium (RPS) loaded on PDA8 microspheres was made using double emulsion evaporation method. Meanwhile, prednisolone (PRD) microspheres were prepared using s/o/w emulsion technique. Subsequently, coating systems of cochineal red tablets were developed. These tablets were coated with polymer solution (using each of three types of copolymers: PDA8, PDA6, and PDA4) until the desired percentage of the coating was achieved (10, 15, and 20 % w/w). The cumulative release profiles of cochineal red tablets coated with PDA8, PDA6, and PDA4 showed a pH-sensitive release behavior. The release in the neutral media (pH ≈ 7.0) was very slow (less than 3 % after one hour). Then, after changing the pH to 1.2, an increase in the release of cochineal was observed. Furthermore, the cumulative release of cochineal red was at the highest value for the PDA8 and the lowest for PDA4 depending on the percentage of PDMAEMA moieties. Moreover, by increasing the percentage of the coating from (10, 15 to 20 % w/w), the cumulative release of cochineal decreased. Therefore, the copolymer PDAX can be used for controlling the release of drug by changing the pH value.Finally, the cochineal tablets coated with PDA6 (10 %) showed features of light sensitivity. The release of cochineal red from coated tablets was only due to the switching in the conformational trans/cis isomerization of azobenzene moieties upon irradiation, which was confirmed by comparing the release of coated tablets with uncoated tablets upon irradiation. / Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie) / info:eu-repo/semantics/nonPublished

Thèse de recherche en chimie dans le domaine des polymères / Les polymères photostimulables sont une classe spécifique de polymères stimulables capables de subir un changement de conformation sous l’action de l’irradiation lumineuse. La lumière est un stimulus externe physique pouvant avoir un impact sur un matériau sans modifier directement sa composition chimique. De plus, la taille d’un faisceau lumineux comme le laser peut atteindre des dimensions de l’ordre de la centaine de nanomètres, permettant son utilisation pour les travaux de précision. Enfin, pouvoir allumer et éteindre la source de lumière de manière instantanée rend ce stimulus attrayant pour un vaste choix d’applications en raison de la possibilité de contrôler avec précision les échelles de temps d’utilisation du stimulus. C’est pourquoi les chercheurs s’intéresse à la lumière en tant que stimulus et à ses potentielles applications pour les polymères stimulables. Dans les deux premiers chapitres de ce manuscrit, la lumière sera utilisée pour induire indirectement une réponse au sein de polymères thermostimulables. Pour cela, des matériaux photothermiques capables de convertir la lumière en chaleur seront combinés avec des polymères thermostimulables à base de microgels de poly(N-isopropylacrylamide) (PNIPAM) afin de préparer des matériaux composites. Ces types de matériaux sont déjà bien connus dans la littérature. Cependant, à l’échelle micrométrique, ils souffrent d’une mauvaise optimisation en raison de la ségrégation des matériaux lors de leur préparation. Le premier chapitre traitera tout d’abord de la préparation d’un tel composite à base de microgels de PNIPAM et de nanoparticules d’or (AuNPs). Différents paramètres permettant d’améliorer la dispersion des AuNPs dans les microgels seront identifiés dans le but d’optimiser la synthèse de ces matériaux composites. Ensuite, les microgels composites seront immobilisés en surface, et leur gonflement en surface en fonction de la température et de l’irradiation sera étudié à l’aide de la technique Surface Force Apparatus (SFA). Cette étude innovante rapporte pour la première fois la caractérisation quantitative du gonflement de polymères photo- et thermostimulables immobilisés en surface à l’échelle du nanomètre. En effet, ce type de système n’a jusqu’à maintenant été étudié que de manière qualitative. Dans un second chapitre, les AuNPs qui ont servi de nanoparticules photothermiques modèles ont été remplacées par la polydopamine (PDA), une nanoparticule aux propriétés photothermiques dont l’intérêt s’est développé plus récemment. La PDA, comme les AuNPs, interagit et se complexe avec les amines primaires contenus dans nos microgels de PNIPAM. Ainsi, les deux systèmes composites sont présumés similaires en termes de conformation et de structure. Les microgels composites à base de PDA ont été préparés dans des proportions équivalentes de nanoparticules photothermiques à celles à base de AuNPs de l’étude précédente, ce qui a permis leur comparaison. Les deux matériaux composites ont démontré des propriétés photothermiques similaires, avec cependant des performances légèrement supérieures pour les microgels composites à base de PDA. Utilisant des sources d’irradiation de même puissance, la PDA, lorsqu’irradiée à 360 nm, semble démontrer des propriétés photothermiques environ 25% supérieures à celles des AuNPs sphériques irradiées à leur longueur d’onde de résonance plasmonique. Bien qu’étant supérieur en termes de propriétés photothermiques, le gonflement en surface des microgels composites à base de PDA était inférieur à celui des microgels composites à base d’AuNPs. Cette différence de comportement s’explique par une densité de greffage des microgels composites à base de PDA inférieure à la densité de greffage des microgels composites à base d’AuNPs. Il en résulte une augmentation de l’espace adjacent pour les microgels moins densément greffés pouvant gonfler dans toutes les directions contrairement à une densité de greffage importante qui favorise le gonflement des microgels de manière perpendiculaire au substrat. Enfin, dans le troisième chapitre, des brosses de polymères aux propriétés réversiblement photo-dimérisables ont été préparées. Pour cela, des chaînes pendantes de coumarine ont été introduites dans les brosses de polymères. La coumarine est un groupement qui peut subir une dimérisation sous l’effet de la lumière UVA (λUVA > 310 nm) et peut se dédimériser réversiblement sous l’irradiation des UVC (λUVC < 260 nm). La photo-dimérisation de la coumarine ne peut avoir lieu que si elle respecte certains critères stricts, à savoir une orientation parallèle ou antiparallèle des groupements de coumarine et une distance de séparation inférieure à 4,2 Å. Ainsi, l’immobilisation de la coumarine sur une surface peut affecter la photo-dimérisation en raison de la difficulté de contrôler la distance de séparation entre les groupements de coumarine situés sur les chaînes de polymères adjacentes immobilisées en bout de chaînes. Dans cette partie, la propriété de photo-dimérisation réversible des brosses de polymères contenant des chaînes pendantes de coumarine a ainsi été étudiée en fonction de la distance de séparation entre les chaînes polymériques. De plus, la caractérisation de la capacité de gonflement de la couche de polymères ainsi obtenue dans l’eau a permis d’estimer la nature de la photo-dimérisation des chaînes polymériques, qui est favorisée de manière intermoléculaire pour un greffage dense de chaînes de polymères. / Photo-responsive polymers are a specific class of stimuli-responsive polymers which undergo conformational changes under light irradiation. Light is an external physical stimulus which can impact a medium without affecting its chemical composition. Width beam can be as low as a few hundreds of nanometers, which makes it usable for precision work. Furthermore, the capacity to turn off and on the light source instantaneously makes it very attractive for all kind of applications because of the possibility to control the timescale of the stimulus. Therefore, the work will focus on the study of light as a stimulus and its potentials of applications in order to trigger a response in stimuli-responsive polymers either directly, or indirectly. In the first two chapters of this manuscript, light will be used to trigger indirectly a response in thermo-responsive polymers. For this, photothermal materials that can convert light into heat will be combined with thermo-responsive polymers based on poly(N-isopropylacrylamide) (PNIPAM) microgels in order to prepare composite materials. These types of materials are already well known in the literature. However, at the microscale level, they suffer from poor optimization because of segregation of materials during the preparation process. The first chapter will treat the preparation of such composite based on PNIPAM microgels and gold nanoparticles (AuNPs). Different parameters allowing the improvement of AuNPs dispersion in the microgels will be identified in order to optimize the synthesis of the composite materials. Then, the composite microgels were immobilized on surface, and their swelling as a function of the temperature, and triggered by light were studied using the Surface Force Apparatus (SFA). This innovative study reports the first quantitative characterization of the swelling of photo- and thermo-responsive polymers immobilized on surfaces and at the nanometer scale. Indeed, these systems have been reported multiple times in the literature. However, the nature and scale at which these materials are studied were so far limited to qualitative characterizations only. In the second chapter, the AuNPs which served as model photothermal nanoparticles were swapped with polydopamine (PDA), a nanoparticle with photothermal properties whose interest has recently grown. PDA, like AuNPs, can interact and complex with primary amines that are present in our PNIPAM microgels. Thus, both composite systems were expected to be similar in terms of conformation and structure. The PDA containing composite microgels were prepared using equivalent proportions of photothermal nanoparticles compared to the precedent study, allowing a comparison of both PDA and AuNPs containing composite microgels. Both composites demonstrated similar photothermal properties, albeit a slightly better performance for the composite microgels based on PDA. Using light sources of equivalent power, PDA demonstrated photothermal properties when irradiated at 360 nm, approximately 25% superior than that of spherical AuNPs irradiated at their localized surface plasmon resonance. Despite being slightly superior in terms of photothermal responsive properties, the surface swelling of the PDA containing composites were inferior to that of AuNPs containing composites because of differences in terms of grafting caused by differences of interactions between the composites with silica-based substrates. Finally, in the third chapter, polymer brushes with reversibly photo-dimerizable properties were prepared. For this purpose, pendant chains of coumarin were introduced into polymer brushes. Coumarin is a functional group that can undergo dimerization under the influence of UVA light (λUVA > 310 nm) and can reversibly dedimerize upon irradiation with UVC (λUVC < 260 nm). The photo-dimerization of coumarin can only occur if strict criteria are met, including a parallel or antiparallel orientation of the coumarin groups and a separation distance of less than 4.2 Å. Thus, the immobilization of coumarin on a surface can affect the photo-dimerization due to the difficulty of controlling the separation distance between the coumarin groups located on end-tethered adjacent polymer chains. In this part, the reversible property of photo-dimerization of polymer brushes containing pendant chains of coumarin was studied as a function of the separation distance between the polymer chains. Furthermore, the characterization of the swelling capacity of the resulting polymer layer in water allowed us to assess the nature of the photo-dimerization of the polymer chains, which is favored in an intermolecular manner for densely grafted polymer chains.