Les polymères sensibles à des stimuli ont été largement étudiés ces dernières années notamment en vue d’applications biomédicales. Ceux-ci ont la capacité de changer leurs propriétés de solubilité face à des variations de pH ou de température. Le but de cette thèse concerne la synthèse et l’étude de nouveaux diblocs composés de deux copolymères aléatoires. Les polymères ont été obtenus par polymérisation radicalaire contrôlée du type RAFT (reversible addition-fragmentation chain-transfer). Les polymères à bloc sont formés de monomères de méthacrylates et/ou d’acrylamides dont les polymères sont reconnus comme thermosensibles et sensible au pH. Premièrement, les copolymères à bloc aléatoires du type AnBm-b-ApBq ont été synthétisés à partir de N-n-propylacrylamide (nPA) et de N-ethylacrylamide (EA), respectivement A et B, par polymérisation RAFT. La cinétique de copolymérisation des poly(nPAx-co-EA1-x)-block-poly(nPAy-co-EA1-y) et leur composition ont été étudiées afin de caractériser et évaluer les propriétés physico-chimiques des copolymères à bloc aléatoires avec un faible indice de polydispersité . Leurs caractères thermosensibles ont été étudiés en solution aqueuse par spectroscopie UV-Vis, turbidimétrie et analyse de la diffusion dynamique de la lumière (DLS). Les points de trouble (CP) observés des blocs individuels et des copolymères formés démontrent des phases de transitions bien définies lors de la chauffe. Un grand nombre de macromolécules naturels démontrent des réponses aux stimuli externes tels que le pH et la température. Aussi, un troisième monomère, 2-diethylaminoethyl methacrylate (DEAEMA), a été ajouté à la synthèse pour former des copolymères à bloc , sous la forme AnBm-b-ApCq , et qui offre une double réponse (pH et température), modulable en solution. Ce type de polymère, aux multiples stimuli, de la forme poly(nPAx-co-DEAEMA1-x)-block-poly(nPAy-co-EA1-y), a lui aussi été synthétisé par polymérisation RAFT. Les résultats indiquent des copolymères à bloc aléatoires aux propriétés physico-chimiques différentes des premiers diblocs, notamment leur solubilité face aux variations de pH et de température. Enfin, le changement d’hydrophobie des copolymères a été étudié en faisant varier la longueur des séquences des blocs. Il est reconnu que la longueur relative des blocs affecte les mécanismes d’agrégation d’un copolymère amphiphile. Ainsi avec différents stimuli de pH et/ou de température, les expériences effectuées sur des copolymères à blocaléatoires de différentes longueurs montrent des comportements d’agrégation intéressants, évoluant sous différentes formes micellaires, d’agrégats et de vésicules. / Stimuli-responsive polymers and their use in biomedical applications have been widely investigated in recent years. These polymers change their physical properties such as water-solubility, when subjected to certain stimuli, for example change in temperature or pH. The main purpose of this work is to study new diblock copolymers consisting of two random copolymers, i.e., diblock random copolymers. Polymers with well-defined structures and tunable properties have been made using reversible addition−fragmentation chain-transfer (RAFT) polymerization, one of the controlled radical polymerization techniques. The blocks are made of acrylamide- and/or methacrylate-based monomers, which commonly show thermo-responsiveness and hence, double stimuli-responsive behavior is shown. First, a diblock random copolymer in the form of AnBm-b-ApBq was synthesized with N-n-propylacrylamide (nPA) and N-ethylacrylamide (EA) as A and B using RAFT polymerization. Kinetic study of the copolymerization process confirmed the controlled character of the copolymerization. The diblock random copolymers with the compositions of poly(nPAx-co-EA1-x)-block-poly(nPAy-co-EA1-y) and low polydispersity were obtained. With UV-visible spectroscopy and dynamic light scattering (DLS) we investigate their thermoresponsive characteristics in aqueous solutions. Individual blocks showed tunable cloud points, and the diblock copolymer exhibited a well-separated two-step phase transition upon heating. Macromolecules in nature can often respond to a combination of external stimuli, most commonly temperature and pH, rather than a single stimulus. Therefore, a second type of diblock random copolymer in the form of AnBm-b-ApCq was synthesized by combining a pH- and temperature-responsive block with another, only temperature-responsive block, producing responsiveness to multiple stimuli. This polymer with the composition of poly(nPAx-co-DEAEMA1-x)-block-poly(nPAy-co-EA1-y) where DEAEMA stands for 2-diethylaminoethyl methacrylate with well-defined structure and tunable properties has also been made using sequential RAFT polymerization. The resulting diblock random copolymer changes its physico-chemical properties, such as water-solubility, in a quite controlled manner when subjected to the changes in temperature or pH. What happens when blocks of different lengths change their relative hydrophilicity? It is known that the relative length of the blocks in amphiphilic diblock copolymers affects the aggregation mechanism. We compared three diblock copolymers with different block and chain lengths in aqueous solution when they change their relative hydrophilicity due to the change in the external stimuli. The variation of the length and chemical composition of the blocks allows the tuning of the responsiveness of the block copolymers toward both pH and temperature and determines the formation of either micelles or vesicles during the aggregation.

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

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<p dir="ltr">The gastrointestinal (GI) tract and its diverse microbial community play a significant role in overall health, impacting various aspects such as metabolism, physiology, nutrition, and immune function. Disruptions in the gut microbiota have been associated with metabolic diseases, colorectal cancer, diabetes, obesity, inflammatory bowel disease, Alzheimer's disease, and depression. Despite recognizing the importance of the gut microbiota, the interrelationship between microbiota, diet, and disease prevention remains unclear. Current techniques for monitoring the microbiome often rely on fecal samples or invasive endoscopic procedures, limiting the understanding of spatial variations in the gut microbiota and posing invasiveness challenges. To address these limitations, this dissertation focuses on the design and development of an electronic-free smart capsule platform capable of targeted sampling of GI fluid within specific regions of the GI tract. The capsule can be retrieved for subsequent bacterial culture and sequencing analysis. The capsule design is based on stimuli-responsive polymers and superabsorbent hydrogels, chosen for their proven safety, compatibility, and scalability. By leveraging the pH variation across the GI tract, the pH-sensitive polymeric coatings dissolve at the desired region, activating the sampling process. The superabsorbent hydrogel inside the capsule collects the sampled GI fluid and facilitates capsule closure upon completion of sampling. Systematic studies were conducted to identify suitable pH-responsive polymer coatings, superabsorbent hydrogels, and processing conditions that effectively operated within the physiological conditions of the GI tract. The technology's effectiveness and safety were validated through rigorous <i>in vitro</i> and <i>in vivo</i> studies using pig models. These studies demonstrated the potential of the technology for targeted sampling of GI fluid in both small and large intestinal regions, enabling subsequent bacterial culture and gene sequencing analysis. Additionally, the capsule design was enhanced with the integration of a metal tracer, enabling traceability throughout the GI tract using X-ray imaging and portable metal detectors for ambulatory screening. This technology holds promise as a non-invasive tool for studying real-time metabolic and molecular interactions among the host, diet, and microbiota in challenging-to-access GI regions. Its application in clinical studies can provide new insights into diet-host-microbiome interactions and contribute to addressing the burden faced by patients and their families dealing with GI-related diseases.</p>