| Titre : |
Syntheses and biological applications of phosphorus dendrimers and dendrons |
| Type de document : |
texte imprimé |
| Auteurs : |
Liang Chen, Auteur ; Anne-Marie Caminade, Directeur de thèse ; Xiangyang Shi, Directeur de thèse |
| Langues : |
Anglais (eng) |
| Tags : |
DENDRIMMER AMPHIPHILIC PHOSPHORUS DENDRONS NANOQUARIES GENE THERAPY NANOMEDICINE |
| Résumé : |
"The aim of this work was to design several families of cationic phosphorus dendrimers and of neutral and cationic dendrons, and to investigate their potential in the field of biology/nanomedicine. Firstly, we revisited the cationic phosphorus dendrimers as a non-viral vector for gene delivery towards cancer therapy. The expression efficiency of genes was detected by fluorescence microscopy, flow cytometry, quantitative real time polymerase chain reaction (rt-qPCR) and Western blot assays. The results reveal that under the optimized conditions, the transfection of pDNA induces the significant p53 protein expression as verified through the resulting cell cycle arrest (regulation of p21 and Cdk4/Cyclin-D1 expression) and Western blotting. Moreover, the cancer gene therapy potential of the polyplexes was finally validated through therapy of a xenografted tumor model after intra-tumoral injection without systemic toxicity. In view of all the results already obtained, undoubtedly the use of cationic phosphorus dendrimers for biology holds great promises for the future. Secondly, the first-in-class Cu(II) and Au(III) metaled phosphorus dendrons (generation 1) bearing 10 Cu(II)Cl2 or [Au(III)Cl2]+ on their surface, and with C11 and C17 linear alkyl chains were synthesized. These dendrons showed significant antiproliferative activity against cancer cell lines such as 4T1 and MCF-7 (breast cancer). The best results concerning the antiproliferative activity to kill cancer cells were obtained with the Au(III) dendron complexes bearing short alkyl chain length. Cell death pathway analysis reveals that the metaled dendrons could alter the cell cycle- and apoptosis-related protein status of cells, resulting in cell cycle S-phase arrest and apoptosis. In particular, Au(III)-complexes induced the caspase-dependent cellular lethality by promoting the translocation of Bax to the mitochondria and the release of Cyto C, whereas the Cu(II)-complexes are weak activators of caspase-3, in line with their moderate antiproliferative activity in cancer cells. Taken together, these studies showed that these first-in-class metaled phosphorus dendrons represent a novel class of anticancer nanodrugs, and their development will open new avenues to tackle cancers. Lastly, we prepared the amphiphilic phosphorus dendron 1-C12G1 bearing a long linear alkyl chain (C12H25), and bearing ten protonated pyrrolidine groups in the surface. 1-C12G1 forms nanomicelles which allow to encapsulate anticancer drug DOX and complex the miR-21 inhibitor. Especially, the encapsulation efficiency of DOX can reach up to 83.60%. Meanwhile, gel retardation assay showed that the miR-21i complexed by 1-C12G1DOX were protected from degradation for up to 12 h and 24 h compared to the naked miR-21i.[...]" |
| Document : |
Thèse de Doctorat |
| Etablissement_delivrance : |
Toulouse 3 en cotutelle avec Donghua University (Shanghai, Chine) |
| Date_soutenance : |
31/08/2020 |
| Ecole_doctorale : |
Sciences de la Matière (SdM) (Toulouse) |
| Domaine : |
Chimie Macromoléculaire et Supramoléculaire |
| En ligne : |
http://thesesups.ups-tlse.fr/4944/ |
Syntheses and biological applications of phosphorus dendrimers and dendrons [texte imprimé] / Liang Chen, Auteur ; Anne-Marie Caminade, Directeur de thèse ; Xiangyang Shi, Directeur de thèse . - [s.d.]. Langues : Anglais ( eng)
| Tags : |
DENDRIMMER AMPHIPHILIC PHOSPHORUS DENDRONS NANOQUARIES GENE THERAPY NANOMEDICINE |
| Résumé : |
"The aim of this work was to design several families of cationic phosphorus dendrimers and of neutral and cationic dendrons, and to investigate their potential in the field of biology/nanomedicine. Firstly, we revisited the cationic phosphorus dendrimers as a non-viral vector for gene delivery towards cancer therapy. The expression efficiency of genes was detected by fluorescence microscopy, flow cytometry, quantitative real time polymerase chain reaction (rt-qPCR) and Western blot assays. The results reveal that under the optimized conditions, the transfection of pDNA induces the significant p53 protein expression as verified through the resulting cell cycle arrest (regulation of p21 and Cdk4/Cyclin-D1 expression) and Western blotting. Moreover, the cancer gene therapy potential of the polyplexes was finally validated through therapy of a xenografted tumor model after intra-tumoral injection without systemic toxicity. In view of all the results already obtained, undoubtedly the use of cationic phosphorus dendrimers for biology holds great promises for the future. Secondly, the first-in-class Cu(II) and Au(III) metaled phosphorus dendrons (generation 1) bearing 10 Cu(II)Cl2 or [Au(III)Cl2]+ on their surface, and with C11 and C17 linear alkyl chains were synthesized. These dendrons showed significant antiproliferative activity against cancer cell lines such as 4T1 and MCF-7 (breast cancer). The best results concerning the antiproliferative activity to kill cancer cells were obtained with the Au(III) dendron complexes bearing short alkyl chain length. Cell death pathway analysis reveals that the metaled dendrons could alter the cell cycle- and apoptosis-related protein status of cells, resulting in cell cycle S-phase arrest and apoptosis. In particular, Au(III)-complexes induced the caspase-dependent cellular lethality by promoting the translocation of Bax to the mitochondria and the release of Cyto C, whereas the Cu(II)-complexes are weak activators of caspase-3, in line with their moderate antiproliferative activity in cancer cells. Taken together, these studies showed that these first-in-class metaled phosphorus dendrons represent a novel class of anticancer nanodrugs, and their development will open new avenues to tackle cancers. Lastly, we prepared the amphiphilic phosphorus dendron 1-C12G1 bearing a long linear alkyl chain (C12H25), and bearing ten protonated pyrrolidine groups in the surface. 1-C12G1 forms nanomicelles which allow to encapsulate anticancer drug DOX and complex the miR-21 inhibitor. Especially, the encapsulation efficiency of DOX can reach up to 83.60%. Meanwhile, gel retardation assay showed that the miR-21i complexed by 1-C12G1DOX were protected from degradation for up to 12 h and 24 h compared to the naked miR-21i.[...]" |
| Document : |
Thèse de Doctorat |
| Etablissement_delivrance : |
Toulouse 3 en cotutelle avec Donghua University (Shanghai, Chine) |
| Date_soutenance : |
31/08/2020 |
| Ecole_doctorale : |
Sciences de la Matière (SdM) (Toulouse) |
| Domaine : |
Chimie Macromoléculaire et Supramoléculaire |
| En ligne : |
http://thesesups.ups-tlse.fr/4944/ |
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