, des AuNPs-DTDTPA, des TiONts-AuNPs-PEG 3000 et des TiONts-AuNPs-PEG 3000 -DTX est évaluée sur les cellules PC-3
, 5 nM, 1 nM, 5 nM, 10 nM, 20 nM, 50 nM, 100 nM, 200 nM et 500 nM) est utilisée pour évaluer la molécule libre et les TiONts-AuNPs-PEG 3000 -DTX. Pour une concentration fixée en DTX, la quantité engagée des TiONts-AuNPs-PEG 3000 (sans DTX) (courbe verte) correspond à la quantité de TiONts-AuNPs-PEG 3000 présents sur les TiONts-AuNPs-PEG 3000 -DTX (courbe orange), Quant à la quantité engagée des AuNPs-DTDTPA (courbe bleu), elle correspond à la quantité de nanoparticules d'or modifiées présentes sur les TiONts-AuNPs-PEG 3000 -DTX
, montrent que les AuNPs-DTDTPA et les TiONts-AuNPs-PEG 3000 ne présentent pas de cytotoxicité sur la gamme étudiée à savoir de 4,1.10 -3 à 4,1 ?g.mL -1 de TiONts-AuNPs-PEG 3000 et 3.10 -3 à 3 ?g.mL -1 d'AuNPs-DTDTPA (à savoir que 100 nM de DTX correspond à une quantité de 0,2 ?g de nanohybride par puits soit 1,0 ?g.mL -1 , rapport établi par ATG) (Figure 167)
, 2 nM) et avec la littérature [270]. Néanmoins, l'IC 50 du DTX diffère de celle obtenue dans le chapitre 3 (IC 50 : 20 nM) alors que le lot de DTX utilisé est le même (Figure 144) Ceci pourrait alors confirmer l'hypothèse d'un problème survenu lors de la culture cellulaire PC-3 pour ces expériences en fonction de la longueur de la chaîne de PEG. L'efficacité plus importante du nanohybride TiONts-AuNPs-PEG 3000 -DTX (IC 50 = 82 nM) par rapport au nanohybride TiONts-PEG 3000 -DTX (dit de génération 1, chapitre 2) (IC 50 = 360 nM), atteste d'un meilleur accès du DTX aux microtubles. Ces dernières étant dans la cellule, cela semble traduire une meilleure internalisation des TiONts-AuNPs-PEG 3000 -DTX dans les cellules, par rapport aux TiONts-PEG 3000 -DTX de génération 1. Ces nanohybrides étant mieux dispersés, plus stables en suspension, avec de surcroît un potentiel zêta à pH 7,4 moins négatif (-7 mV vs. -20 mV), tout ceci n'est pas surprenant et devrait favoriser l'internalisation cellulaire (? Chapitre 1. ? I.3.4. et ? III.). Finalement ces résultats très concluants car même si la cytotoxicité du nanohybride TiONts-AuNPs-PEG 3000 -DTX est plus faible que le DTX seul, le DTX garde une activité cytotoxique lorsqu'il est greffé sur le nanohybride
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, Actuellement, les injections systémiques de médicaments atteignent faiblement les sites tumoraux et de fortes doses sont alors administrées provoquant des effets secondaires parfois lourds. Les possibilités offertes par les applications en médecine des nanoparticules permettent de nouvelles stratégies pour vectoriser des substances actives dans les cellules malades. Ces travaux de thèse portent sur le cancer de la prostate qui
, TiONts) sont synthétisés par voie hydrothermale et présentent une longueur moyenne de 170 nm, un diamètre extérieur de 10 nm et une cavité interne accessible de 4 nm. Leur morphologie tubulaire permet aux TiONts d'être internalisés plus facilement dans les cellules, sans induire de cytotoxicité
, le DOTA, radiomarqué avec l' 111 In) pour suivre la biodistribution des tubes par SPECT/CT. La surface des TiONts a été préalablement fonctionnalisée par l'APTES et le poly(éthylène) glycol (PEG3000) pour rendre les TiONts stables et biocompatibles Afin d'évaluer l'efficacité de ce nanohybride, des tests in vitro ont montré que l'association entre les TiONts et le DTX permettait de maintenir une activité cytotoxique sur des lignées cellulaires de prostate (cellules 22Rv1 et PC-3) alors que les TiONts sans le DTX n'étaient pas toxiques. Les études in vivo ont montré, sur des souris Swiss nude mâles, que plus de 70% des nanovecteurs étaient retenus dans la tumeur, après injection IT, après 7 jours. De plus, un retard de croissance tumorale pour les souris ayant reçu le nanohybride avec la radiothérapie (RT) est observé, par rapport aux souris ayant reçues seulement le DTX, largement utilisé pour inhiber les tumeurs de prostate et un agent chélatant Après cette étude, d'autres molécules organiques ont été greffées avec succès à la surface des TiONts pour améliorer la stabilité colloïdale et la biocompatibilité des nanotubes : AHAMTES, catéchols (LDOPA, DHCA et NDOPA), phosphonates (PHA, ALD et un polymère hétérobifonctionnel de type phosphonate : (HO)2-(O)P-PEG-NH2). De plus
, elles-mêmes modifiées par le DTDTPA, ont été couplées avec les TiONts en présence ou non de DTX. Cette nouvelle combinaison a pour objectif le maintien des AuNPs, par les TiONts, dans la tumeur afin d'améliorer l'effet de la RT. Grâce aux AuNPs modifiées par le DTDTPA, le nanohybride est également détectable par imagerie X et par SPECT/CT. Les résultats in vitro ont démontré l'activité cytotoxique de l'édifice final