Le but général de ce travail correspond à l’amélioration de la biodisponibilité de principes actifs connus pour leur faible biodisponibilité (testostérone) ou pour leur caractère lipidique (acides gras oméga 3). Des systèmes nanoparticulaires à base de lipides et des systèmes nanocristaux ont été développés notamment dans le cas de la testostérone, afin d’obtenir une biodisponibilité supérieure au système oral actuellement commercialisé, Andriol Testocaps®. L’autre partie de ce travail consistait en la conception d’une formule d’acides gras omega -3 dans des nanoparticules lipidiques, susceptibles malgré l’utilisation d’une huile de poisson bon marché comme source d’acides gras omega-3, de n’avoir que peu d’effets sur le goût et l’odorat tout en s’avérant stable. Le développement de systèmes oraux à base de testostérone a été possible autant sur la base de la technologie des nanoparticules lipidiques (Nanostructured Lipid Carriers, NLC), que sur celle des nanocristaux. Dans les deux cas, les systèmes développés ont permis de répondre aux exigences en matière d’incorporation (NLC) et de stabilité (NLC et suspensions Nano). Les NLC ont permis d’incorporer jusqu’à 30% d’undecanoate de testostérone en phase lipidique. La formulation a également été possible avec différents lipides, susceptibles, d’augmenter l’absorption lymphatique et de ce fait également la biodisponibilité de l’hormone. Les nanocristaux ont pu être produits à partir de la testostérone (T) ainsi que d’undecanoate de testostérone (TU), avec des tailles moyennes respectives d’environ 470 nm (TU) et 860 nm (T). Cette taille particulaire doit permettre une absorption lymphatique accrue. Les biodisponibilités des systèmes développés à base de NLC, se sont avérées, chez le rat Wistar, toujours plus élevées que la formulation commerciale, quand ils ont été administrés sans lipides additionnels ce qui permet de supposer, que l’influence simultanée de l’absorption de nourriture sur la biodisponibilité devrait être moins prononcée qu’elle ne l’est pour l’Andriol Testocaps®. En partant de ces résultats, à savoir l’augmentation de la biodisponibilité orale avec les nanoparticules lipidiques, le développement d’un système de nanoparticules avec les acides gras oméga-3 d’huile de poisson bon marché était un pas logique. La biodisponibilité orale des acides gras oméga-3 est largement supérieure à celle du TU (environ 70 %). L’utilisation de la technologie NLC a ainsi permis la réduction de l’odeur et du goût du produit. La formulation avait un pourcentage remarquablement élevé de 70 % en phase lipidique tout en restant pâteuse et redispersible. Ceci permet d’envisager son utilisation dans des boissons et dans la nutrition ce qui facilitera l’assistance des patients (et donc la biodisponibilité) avec les acides gras omega-3 essentiels. / The overall goal of this work consisted in ameliorating the bioavailability of drugs known for their poor hydrosolubility (testosterone) or for their lipidic character (omega-3 fatty acids). This was achieved using lipid nanoparticle systems and nanocrystals In case of testosterone the work consisted of the development of an oral dosage form with superior properties compared to the currently commercially available oral system (Andriol Testocaps®). The other part of this work was the design of a lipid nanoparticle-based omega- 3 fatty acid formulation, which, despite the use of cheap fish oil as source of omega-3 fatty acids, has low smell and taste properties while nevertheless being stable. The development of the oral testosterone drug delivery system was accomplished on the basis of lipid nanoparticles technology and also using drug nanocrystal technology. In both cases, systems could be developed that met the requirements with regards to drug loading (NLC) and stability (NLC and drug nanocrystals). Up to 30 % of testosterone undecanoate could be incorporated into the lipid phase of the NLC. Furthermore, the production of particles with different lipids, which are supposed to promote lymphatic absorption and hence the bioavailability of the hormone. Drug nanocrystals of testosterone (T) and testosterone undecanoate (TU) were prepared with a mean size of about 470 nm (TU) and 860 nm (T). Also with this system, an enhanced lymphatic absorption was expected. The bioavailabilites of the developed NLC based drug delivery systems were all higher than the bioavailability of the product on the market when no additional lipid was supplied. This gives reason to believe, that the influence of co-administered food on the bioavailability of the systems is less pronounced than with Andriol Testocaps®. Based on the findings that lipid nanoparticles can improve oral bioavailability, the development of an omega-3 fatty acids nanoparticulate system (NLC) out of cheap fish oil was a logic step. The oral bioavailability of the omega-3 fatty acids is much higher than the one of TU (about 70 %). Through the use of NLC technology, the taste and smell is even more reduced. It was rather unexpected that we achieved to have a formulation that consisted of 70 % lipid phase (and 30 % water) but still was paste-like and easy to redisperse. This makes the use of the paste as an additive in food and beverages possible to better supply the patient with essential omega-3 fatty acids.

Ce travail porte sur la conception d'un système lipo-polysaccharidique sous forme d'un assemblage de taille micrométrique entre des nanoparticules lipidiques solides (SLNs) et un biopolymère. Le but est de formuler un vecteur pouvant : transporter un principe actif hydrophobe, résister aux conditions gastriques, et permettre un relargage contrôlé en conditions spécifiques. Le choix de la molécule active s'est porté sur un polyphénol, la curcumine, pour ses activités anti-oxydantes et anti-inflammatoires. Etant hydrophobe, la curcumine a été encapsulée dans des nanoparticules de beurre de karité qui est un lipide d'origine naturelle et solide à température ambiante. Les systèmes lipidiques ne résistant pas aux conditions gastriques, les nanoparticules ont été incluses dans une matrice de chitosane sous forme d'un assemblage micrométrique contrôlé par des interactions électrostatiques. Ce polymère naturel, chargé positivement grâce à la présence de groupements amines, résiste aux attaque des enzymes gastriques et présente des interactions spécifiques avec la muqueuse intestinale et notamment les mucines permettant ainsi un ciblage vers l'intestin et le côlon. La première partie de cette étude est focalisée sur le système beurre de karité-curcumine en absence de chitosane. L'effet du polyphénol sur la cristallisation du lipide a tout d'abord été étudié. L'influence de la composition du mélange ternaire (beurre de karité, tensioactif, eau) sur les propriétés des nanoparticules formées a ensuite été étudiée en utilisant la méthodologie des plans de mélanges. Cela a permis de contrôler la taille des SLNs formulées et de mettre ensuite en évidence l'influence de la taille des particules sur le taux d'encapsulation de la curcumine. La seconde partie est axée sur l'assemblage entre les nanoparticules et le chitosane. Des particules micrométriques ont ainsi été obtenues par interactions électrostatiques entre les SLNs encapsulant la curcumine et stabilisées par des phospholipides et le chitosane / This work deals with the design of a lipo-polysaccharidic system as a micrometric assembly between solid lipid nanoparticles (SLNs) and a biopolymer. The aim is to formulate a vector can: carry a hydrophobic active molecule, resist to gastric conditions, and allow a controlled release in specific conditions. Choosing the active molecule is carried on a polyphenol, curcumin, for its antioxidant and anti-inflammatory activities. Being hydrophobic, curcumin was encapsulated in shea butter nanoparticles, which is a natural lipid and solid at room temperature. Lipid nanocarriers are not resistant to gastric conditions; the nanoparticles have been included in a chitosan matrix in the form of a micrometric assembly controlled by electrostatic interactions. This natural polymer, positively charged due to the presence of amine groups, is resistant to attack by gastric enzymes and has specific interaction with the intestinal mucosa and in particular the mucin which can be useful as a carrier for curcumin in colon targeted drug delivery. The first part of this study focused on shea butter–curcumin system with the absence of chitosan. The effect of polyphenols on the lipid crystallization was studied. The influence of the composition of the ternary mixture (shea butter, surfactant, water) on the properties of the nanoparticles was then investigated by using the response surface methodology. This helped to control the size of SLNs and then to show the influence of particle size on the encapsulation efficiency of curcumin. The second part focuses on the assembling between the nanoparticles and chitosan. Micrometric particles were obtained through electrostatic interactions between SLNs encapsulated curcumin and chitosan

Developing nanoparticulate delivery systems that will allow easy movement and localisation of a drug to the target tissue and provide more controlled release of the drug in vivo is a challenge for researchers in nanomedicine. The aim of this study was to evaluate the biodistribution of two nano-delivery systems namely, poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles containing samarium-153 oxide ([153Sm]Sm2O3) as radiotracer and solid lipid nanoparticles (SLNs) containing technetium-99m-methylene diphosphonate (99mTc-MDP), after oral and intravenous administration to rats to prove that orally administered nanoparticles indeed alter the biodistribution of a drug as compared to the drug on its own. Stable samarium-152 oxide ([152Sm]Sm2O3) was encapsulated in polymeric PLGA nanoparticles. These were then activated in a nuclear reactor to produce radioactive [153Sm]Sm2O3 loaded-PLGA nanoparticles. Both the stable nanoparticles as well as the fully decayed activated nanoparticles, were characterized for size, Zeta potential and morphology using dynamic light scattering and scanning electron microscopy (SEM) or transmission electron microscopy (TEM), respectively. SLNs were a form of delivery system which was used to encapsulate the radiotracer, 99mTc-MDP. 99mTc-MDP SLNs were characterized before and after encapsulation for size and Zeta potential. Both nanoparticle compounds were orally and intravenously (IV) administered to rats in order to trace their uptake and biodistribution through imaging and ex vivo biodistribution studies. The PLGA nanoparticles containing [153Sm]Sm2O3 were spherical in morphology and smaller than 500 nm, therefore meeting the objective of producing radiolabelled nanoparticles smaller than 500 nm. Various parameters were optimized to obtain an average particle size ranging between 250 and 300 nm, with an average polydispersity index (PDI) ≤ 0.3 after spray drying. The particles had a Zeta potential ranging between 5 and 20 mV. The Sm2O3-PLGA nanoparticles had an average size of 281 ± 6.3 nm and a PDI average of 0.22. The orally administered [153Sm]Sm2O3-PLGA nanoparticles were deposited in various organs which includes bone with a total of 0.3% of the Injected Dose (ID) per gram vs the control of [153Sm]Sm2O3which showed no uptake in any organs except the GI-tract. The IV injected [153Sm]Sm2O3-PLGA nanoparticles exhibit the highest localisation of nanoparticles in the spleen (8.63%ID/g) and liver (3.07%ID/g). The 99mTc-MDP-labelled SLN were spherical and smaller than 500 nm. Optimization of the MDP-loaded SLN emulsions yielded a slightly higher PDI of ≥0.5 and a size range between 150 and 450 nm. The Zeta potential was between -30 and -2 mV. The MDP-loaded SLN had an average size of 256 ± 5.27 and an average PDI of 0.245.The orally administered 99mTc-MDP SLN had the highest localisation of nanoparticles in the kidneys (8.50%ID/g) and stomach (8.04%ID/g) while the control, 99mTc-MDP had no uptake in any organs except the GI-tract. The IV injected 99mTc-MDP SLN also exhibited a high localisation of particles in the kidneys (3.87%ID/g) followed by bone (2.66%ID/g). Both the IV and oral 99mTc-MDP SLN reported significantly low deposition values in the heart, liver and spleen. Based on the imaging and the biodistribution studies, it can be concluded that there was a significant transfer of the orally administrated radiolabelled nanoparticles from the stomach to other organs vs the controls. Furthermore, this biodistribution of the nano carriers warrants surface modification and optimisation of the nanoparticles to avoid higher particle localisation in the stomach. / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Developing nanoparticulate delivery systems that will allow easy movement and localisation of a drug to the target tissue and provide more controlled release of the drug in vivo is a challenge for researchers in nanomedicine. The aim of this study was to evaluate the biodistribution of two nano-delivery systems namely, poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles containing samarium-153 oxide ([153Sm]Sm2O3) as radiotracer and solid lipid nanoparticles (SLNs) containing technetium-99m-methylene diphosphonate (99mTc-MDP), after oral and intravenous administration to rats to prove that orally administered nanoparticles indeed alter the biodistribution of a drug as compared to the drug on its own. Stable samarium-152 oxide ([152Sm]Sm2O3) was encapsulated in polymeric PLGA nanoparticles. These were then activated in a nuclear reactor to produce radioactive [153Sm]Sm2O3 loaded-PLGA nanoparticles. Both the stable nanoparticles as well as the fully decayed activated nanoparticles, were characterized for size, Zeta potential and morphology using dynamic light scattering and scanning electron microscopy (SEM) or transmission electron microscopy (TEM), respectively. SLNs were a form of delivery system which was used to encapsulate the radiotracer, 99mTc-MDP. 99mTc-MDP SLNs were characterized before and after encapsulation for size and Zeta potential. Both nanoparticle compounds were orally and intravenously (IV) administered to rats in order to trace their uptake and biodistribution through imaging and ex vivo biodistribution studies. The PLGA nanoparticles containing [153Sm]Sm2O3 were spherical in morphology and smaller than 500 nm, therefore meeting the objective of producing radiolabelled nanoparticles smaller than 500 nm. Various parameters were optimized to obtain an average particle size ranging between 250 and 300 nm, with an average polydispersity index (PDI) ≤ 0.3 after spray drying. The particles had a Zeta potential ranging between 5 and 20 mV. The Sm2O3-PLGA nanoparticles had an average size of 281 ± 6.3 nm and a PDI average of 0.22. The orally administered [153Sm]Sm2O3-PLGA nanoparticles were deposited in various organs which includes bone with a total of 0.3% of the Injected Dose (ID) per gram vs the control of [153Sm]Sm2O3which showed no uptake in any organs except the GI-tract. The IV injected [153Sm]Sm2O3-PLGA nanoparticles exhibit the highest localisation of nanoparticles in the spleen (8.63%ID/g) and liver (3.07%ID/g). The 99mTc-MDP-labelled SLN were spherical and smaller than 500 nm. Optimization of the MDP-loaded SLN emulsions yielded a slightly higher PDI of ≥0.5 and a size range between 150 and 450 nm. The Zeta potential was between -30 and -2 mV. The MDP-loaded SLN had an average size of 256 ± 5.27 and an average PDI of 0.245.The orally administered 99mTc-MDP SLN had the highest localisation of nanoparticles in the kidneys (8.50%ID/g) and stomach (8.04%ID/g) while the control, 99mTc-MDP had no uptake in any organs except the GI-tract. The IV injected 99mTc-MDP SLN also exhibited a high localisation of particles in the kidneys (3.87%ID/g) followed by bone (2.66%ID/g). Both the IV and oral 99mTc-MDP SLN reported significantly low deposition values in the heart, liver and spleen. Based on the imaging and the biodistribution studies, it can be concluded that there was a significant transfer of the orally administrated radiolabelled nanoparticles from the stomach to other organs vs the controls. Furthermore, this biodistribution of the nano carriers warrants surface modification and optimisation of the nanoparticles to avoid higher particle localisation in the stomach. / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Objetivo: determinar a viabilidade da identificação do linfonodo-sentinela em pacientes com câncer invasor de colo uterino estádio Ib1. Material e Métodos: 16 pacientes consecutivas com câncer de colo uterino agendadas para histerectomia radical com linfadenectomia pélvica bilateral realizaram estudo para detecção de linfonodo-sentinela. Onze pacientes injetaram 1 mCi de tecnécio 99 (99Tc) em quatro pontos do estroma superficial do colo uterino ao redor do tumor, às 12, 3, 6 e 9 h ( 16 horas antes da cirurgia ). No dia da cirurgia, as pacientes foram submetidas ao mapeamento linfático com gamma-probe e azul patente injetado nos mesmos pontos que o 99Tc.Cinco pacientes realizaram a detecção apenas com azul patente. Resultados: foi detectado pelo menos um (1 a 3 por paciente) linfonodo-sentinela em cada uma das 15 pacientes (93,7 %) que realizaram a técnica combinada.Foi detectado pelo menos 1 linfonodo-sentinela em 4 pacientes ( 80% )com azul patente apenas. A maioria dos linfonodos-sentinela foi localizada nas regiões: obturadora (37 %), ilíaca externa (22,2 %) e inter-ilíacas (18,5 %). Seis pacientes (40 %) tiveram linfonodos-sentinela bilaterais. Dos 27 linfonodos-sentinela detectados, 11 (40,7 %) foram detectados pelo corante, 9 (33,3%) pela radioatividade e 7 (26 %) pela radioatividade e corante. O índice de detecção intra-operatória com o gamma-probe foi de 90,9 % ( 11 pacientes ). Destes, 7 linfonodos foram azul e quente (31,8 %), 6 linfonodos foram apenas azuis (27,2 %) e 9 linfonodos foram apenas quentes (40,9 %). A sensibilidade, especificidade e valor preditivo negativo para a detecção do linfonodo-sentinela foram 100%, 85,7 % e 100 % respectivamente. Conclusão: A combinação do radiofármaco 99Tc e azul patente é efetiva na detecção do linfonodosentinela em câncer de colo uterino inicial. / Objective: to establish the feasibility of sentinel lymph node identification in patients with stages Ib1 invasive cervical cancer. Material and Methods: 16 consecutive patients with cervical cancer, were scheduled for radical hysterectomy with bilateral pelvic lymphadenectomy, were submitted to sentinel lymph node detection. Eleven patients was injected 1 mCi of technetium-99 (99Tc) into four points of the superficial cervical stroma around the tumor, at the 12, 3, 6 and 9 o’clock positions (sixteen hours before surgery ). On the day of the surgery, the patients were submitted to gamma-probe-guided lymphatic mapping and patent blue dye was injected into the same points as the 99Tc. Five patients were submitted to detection with patent blue only. Results: at least one sentinel lymph node (one to three per patient) was detected in each of the 15 patients (93.7%) in whom a combination of both methods was used. At least one sentinel lymph node was detected in four patients ( 80 % ) with patent blue only. Most sentinel lymph nodes were identified in the obturator (37%), external iliac (22.2%) and interiliac (18.5%) regions. Six patients (40%) had bilateral sentinel lymph nodes. Of the 27 sentinel lymph nodes detected, 11 (40.7%) were identified by the blue-dye technique, 9 (33.3%) by radiation, and 7 (26%) by radiation and by the blue-dye technique. The intraoperative detection rate was 90.9% with gamma-probe only ( 11 patients ). Of these, 7 lymph nodes were blue-stained and hot (31.8), 6 were just blue-stained (27.2%) and 9 were just hot (40.9%). Sensitivity, specificity and the negative predictive value for sentinel lymph node detection were 100%, 85,7% and 100 % respectively. Conclusion: the combination of 99Tc and patent blue dye is effective in the detection of sentinel lymph nodes in early-stage cervical cancer.

Objetivo: determinar a viabilidade da identificação do linfonodo-sentinela em pacientes com câncer invasor de colo uterino estádio Ib1. Material e Métodos: 16 pacientes consecutivas com câncer de colo uterino agendadas para histerectomia radical com linfadenectomia pélvica bilateral realizaram estudo para detecção de linfonodo-sentinela. Onze pacientes injetaram 1 mCi de tecnécio 99 (99Tc) em quatro pontos do estroma superficial do colo uterino ao redor do tumor, às 12, 3, 6 e 9 h ( 16 horas antes da cirurgia ). No dia da cirurgia, as pacientes foram submetidas ao mapeamento linfático com gamma-probe e azul patente injetado nos mesmos pontos que o 99Tc.Cinco pacientes realizaram a detecção apenas com azul patente. Resultados: foi detectado pelo menos um (1 a 3 por paciente) linfonodo-sentinela em cada uma das 15 pacientes (93,7 %) que realizaram a técnica combinada.Foi detectado pelo menos 1 linfonodo-sentinela em 4 pacientes ( 80% )com azul patente apenas. A maioria dos linfonodos-sentinela foi localizada nas regiões: obturadora (37 %), ilíaca externa (22,2 %) e inter-ilíacas (18,5 %). Seis pacientes (40 %) tiveram linfonodos-sentinela bilaterais. Dos 27 linfonodos-sentinela detectados, 11 (40,7 %) foram detectados pelo corante, 9 (33,3%) pela radioatividade e 7 (26 %) pela radioatividade e corante. O índice de detecção intra-operatória com o gamma-probe foi de 90,9 % ( 11 pacientes ). Destes, 7 linfonodos foram azul e quente (31,8 %), 6 linfonodos foram apenas azuis (27,2 %) e 9 linfonodos foram apenas quentes (40,9 %). A sensibilidade, especificidade e valor preditivo negativo para a detecção do linfonodo-sentinela foram 100%, 85,7 % e 100 % respectivamente. Conclusão: A combinação do radiofármaco 99Tc e azul patente é efetiva na detecção do linfonodosentinela em câncer de colo uterino inicial. / Objective: to establish the feasibility of sentinel lymph node identification in patients with stages Ib1 invasive cervical cancer. Material and Methods: 16 consecutive patients with cervical cancer, were scheduled for radical hysterectomy with bilateral pelvic lymphadenectomy, were submitted to sentinel lymph node detection. Eleven patients was injected 1 mCi of technetium-99 (99Tc) into four points of the superficial cervical stroma around the tumor, at the 12, 3, 6 and 9 o’clock positions (sixteen hours before surgery ). On the day of the surgery, the patients were submitted to gamma-probe-guided lymphatic mapping and patent blue dye was injected into the same points as the 99Tc. Five patients were submitted to detection with patent blue only. Results: at least one sentinel lymph node (one to three per patient) was detected in each of the 15 patients (93.7%) in whom a combination of both methods was used. At least one sentinel lymph node was detected in four patients ( 80 % ) with patent blue only. Most sentinel lymph nodes were identified in the obturator (37%), external iliac (22.2%) and interiliac (18.5%) regions. Six patients (40%) had bilateral sentinel lymph nodes. Of the 27 sentinel lymph nodes detected, 11 (40.7%) were identified by the blue-dye technique, 9 (33.3%) by radiation, and 7 (26%) by radiation and by the blue-dye technique. The intraoperative detection rate was 90.9% with gamma-probe only ( 11 patients ). Of these, 7 lymph nodes were blue-stained and hot (31.8), 6 were just blue-stained (27.2%) and 9 were just hot (40.9%). Sensitivity, specificity and the negative predictive value for sentinel lymph node detection were 100%, 85,7% and 100 % respectively. Conclusion: the combination of 99Tc and patent blue dye is effective in the detection of sentinel lymph nodes in early-stage cervical cancer.

Objetivo: determinar a viabilidade da identificação do linfonodo-sentinela em pacientes com câncer invasor de colo uterino estádio Ib1. Material e Métodos: 16 pacientes consecutivas com câncer de colo uterino agendadas para histerectomia radical com linfadenectomia pélvica bilateral realizaram estudo para detecção de linfonodo-sentinela. Onze pacientes injetaram 1 mCi de tecnécio 99 (99Tc) em quatro pontos do estroma superficial do colo uterino ao redor do tumor, às 12, 3, 6 e 9 h ( 16 horas antes da cirurgia ). No dia da cirurgia, as pacientes foram submetidas ao mapeamento linfático com gamma-probe e azul patente injetado nos mesmos pontos que o 99Tc.Cinco pacientes realizaram a detecção apenas com azul patente. Resultados: foi detectado pelo menos um (1 a 3 por paciente) linfonodo-sentinela em cada uma das 15 pacientes (93,7 %) que realizaram a técnica combinada.Foi detectado pelo menos 1 linfonodo-sentinela em 4 pacientes ( 80% )com azul patente apenas. A maioria dos linfonodos-sentinela foi localizada nas regiões: obturadora (37 %), ilíaca externa (22,2 %) e inter-ilíacas (18,5 %). Seis pacientes (40 %) tiveram linfonodos-sentinela bilaterais. Dos 27 linfonodos-sentinela detectados, 11 (40,7 %) foram detectados pelo corante, 9 (33,3%) pela radioatividade e 7 (26 %) pela radioatividade e corante. O índice de detecção intra-operatória com o gamma-probe foi de 90,9 % ( 11 pacientes ). Destes, 7 linfonodos foram azul e quente (31,8 %), 6 linfonodos foram apenas azuis (27,2 %) e 9 linfonodos foram apenas quentes (40,9 %). A sensibilidade, especificidade e valor preditivo negativo para a detecção do linfonodo-sentinela foram 100%, 85,7 % e 100 % respectivamente. Conclusão: A combinação do radiofármaco 99Tc e azul patente é efetiva na detecção do linfonodosentinela em câncer de colo uterino inicial. / Objective: to establish the feasibility of sentinel lymph node identification in patients with stages Ib1 invasive cervical cancer. Material and Methods: 16 consecutive patients with cervical cancer, were scheduled for radical hysterectomy with bilateral pelvic lymphadenectomy, were submitted to sentinel lymph node detection. Eleven patients was injected 1 mCi of technetium-99 (99Tc) into four points of the superficial cervical stroma around the tumor, at the 12, 3, 6 and 9 o’clock positions (sixteen hours before surgery ). On the day of the surgery, the patients were submitted to gamma-probe-guided lymphatic mapping and patent blue dye was injected into the same points as the 99Tc. Five patients were submitted to detection with patent blue only. Results: at least one sentinel lymph node (one to three per patient) was detected in each of the 15 patients (93.7%) in whom a combination of both methods was used. At least one sentinel lymph node was detected in four patients ( 80 % ) with patent blue only. Most sentinel lymph nodes were identified in the obturator (37%), external iliac (22.2%) and interiliac (18.5%) regions. Six patients (40%) had bilateral sentinel lymph nodes. Of the 27 sentinel lymph nodes detected, 11 (40.7%) were identified by the blue-dye technique, 9 (33.3%) by radiation, and 7 (26%) by radiation and by the blue-dye technique. The intraoperative detection rate was 90.9% with gamma-probe only ( 11 patients ). Of these, 7 lymph nodes were blue-stained and hot (31.8), 6 were just blue-stained (27.2%) and 9 were just hot (40.9%). Sensitivity, specificity and the negative predictive value for sentinel lymph node detection were 100%, 85,7% and 100 % respectively. Conclusion: the combination of 99Tc and patent blue dye is effective in the detection of sentinel lymph nodes in early-stage cervical cancer.

Ce travail a consisté à préparer des matériaux silicatés poreux à caractère stimuli-sensible à base de nanoparticules lipidiques solides (SLN) et de tensioactifs magnétiques. Plusieurs systèmes à base de tensioactifs ont été utilisés afin de synthétiser des matériaux silicatés à porosité contrôlée en utilisant des méthodes décrites dans la littérature ou mises au point au laboratoire. De différents caractères stimuli-sensible ont été introduits dans les matériaux silicatés poreux en fonction de système utilisé: les nanoparticules lipidiques solides (SLN) pour les matériaux sensible au pH et les tensioactifs magnétiques pour les matériaux sensible au champ magnétique. Premièrement, les matériaux à base de nanoparticules lipidiques solides (SLN) ont été utilisés pour la vectorisation d’un principe actif, la curcumine. La libération de la curcumine a été contrôlée en fonction de pH. Un revêtement sur la surface silice a été également employé pour mieux contrôler la libération de la curcumine. D’autre part, la sensibilité au champ magnétique a été introduite dans des silices mésoporeuses en utilisant des tensioactifs magnétiques. Leurs propriétés d’auto-assemblage (i.e. micelles, vésicules) ont été mise en évidence. Ainsi, la synthèse de matériaux silicatés poreux à caractère magnétique-sensible a été effectuées en utilisant ces tensioactifs. Enfin, les SLN magnétiques ont été préparés en combinant les SLN avec un tensioactif magnétique, qui ont été servi pour la synthèse de catalyseur à base de la silice méso-macroporeuse dopée en nanoparticules d’oxyde de fer / This work is to prepare stimuli-responsive porous silica materials based on solid lipid nanoparticles (SLN) and magnetic surfactants. To develop this study, several surfactants systems were used to synthesize silica materials with controlled porosity via protocols described in the literature or developed in the laboratory. Different stimuli-responsive characters were introduced in porous silica materials as a function of system used: solid lipid nanoparticles (SLN) for pH-sensitive and magnetic-sensitive surfactants for magnetic silica materials. First, the materials synthesized with solid lipid nanoparticles (SLN) were used for the delivery of an anti-carcinogenic drug, curcumin. A coating method on silica surface was also used to better control the release of curcumin. Secondly, the responsiveness to the magnetic field was introduced in silica materials using the magnetic surfactants. Their self-assembly properties (i.e. micelles, vesicles) were studied and their applications in the synthesis of magnetic porous silica materials were investigated. Finally, the magnetic solid lipid nanoparticles have been prepared by combining SLN with magnetic surfactants, which have been used for the synthesis of meso-macroporous silica catalyst encapsulating iron oxide nanoparticles.

Cette thèse met en évidence l'importance des transporteurs lipidiques et leurs implications pharmaceutiques dans la délivrance de principes actifs de nature différente, par voie orale et/ou par voie cutanée. L'introduction générale de cette thèse donne un aperçu des différents types é en mettant l'accent sur les nanoparticules lipidiques solides ( SLN ) et les nanocapsules lipidiques ( LNC ). Dans la première partie, les SLN chargées avec le propionate de clobétasol ( CP ), ont été développées et formulées en un hydrogel pour une long terme corticothérapie topique. Les études du transport ex vivo ont indiqué que le CP maintenu par la peau était plus élevé pour les SLN gel par rapport au produit commercial. La deuxième partie met l'accent sur les nanocapsules lipidiques ( LNC ). Chapitre 1 de cette partie vise à obtenir des LNC chargées d'un principe actif hydrophile le pentasaccharide, fondaparinux ( F ) à partir de deux microémulsions ( ME ) selon un brevet qui a été déposé. Les résultats obtenus par les LNC préparés de la ME1 contenant les tensio-actifs non ioniques ( Imwitor/Span ) ont été les meilleurs ( 59.87 nm, 48.62 % taux d'encapsulation ). Le chapitre 2 vise à encapsuler le F par la stratégie de l'intéraction cationique pour réaliser une association efficace élevée ( 80-100%). L'impact de cette formulation sur la pharmacocinétique du médicament après administration orale chez le rat a montré une amélioration de la biodisponibilité de F d'une mode dépendante de la dose. Les LNC cationiques chargées en F ont démontré une potentialité thérapeutique intéressante pour l'administration d'un pentasaccharide dérivé de l'héparine par voie orale comme une première preuve de concept comme une solution alternative à l'administration de F.