Amphiphilic and thermoresponsive block copolymers based on hydroxypropyl methyl cellulose as nano-carrier of hydrophobic drugs Aijing Lu To cite this version: Aijing Lu. Amphiphilic and thermoresponsive block copolymers based on hydroxypropyl methyl cellu- lose as nano-carrier of hydrophobic drugs. Material chemistry. Université Montpellier, 2020. English. NNT : 2020MONTS010. tel-03021310 HAL Id: tel-03021310 https://tel.archives-ouvertes.fr/tel-03021310 Submitted on 24 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Délivré par Université de Montpellier Préparée au sein de l’école doctorale Sciences Chimiques Balard ED 459 Et de l’unité de recherche Institut Européen des Membranes (UMR 5635) Spécialité : Chimie et Physicochimie des Matériaux Présentée par Aijing LU Copolymères à blocs amphiphiles et thermosensibles à base d'hydroxypropyl méthyl cellulose comme nano-vecteurs de principes actifs hydrophobes Amphiphilic and thermoresponsive block copolymers based on hydroxypropyl methyl cellulose as nano-carrier of hydrophobic drugs Soutenue le 2 avril, 2020 devant le jury composé de M. André DERATANI, DR, IEM UMR 5635 Invité M. Christophe MINGOTAUD, DR, IMRCP UMR 5623 Rapporteur M. Luc PICTON, Prof., PBS, UMR 6270 Rapporteur M. Mihai BARBOIU, DR, IEM UMR 5635 Président du jury M. Suming LI, DR, IEM UMR 5635 Directeur de Thèse I Table of contents Résumé ......................................................................................................................... I Abstract .................................................................................................................... VII List of Tables ............................................................................................................ XII List of Schemes ....................................................................................................... XIII List of Figures .......................................................................................................... XIV List of abbreviations ................................................................................................ XIX Chapter 1 Introduction .................................................................................................. 1 1.1 Nano-sized drug delivery systems.................................................................... 1 1.2 Polymers in drug delivery systems ................................................................... 3 1.2.1 Polysaccharides .................................................................................... 5 1.2.2 Polyesters ........................................................................................... 16 ® 1.2.3 Poloxamers ....................................................................................... 21 1.2.4 Other polymers in drug delivery systems............................................. 23 1.3 Polymeric nanocarriers .................................................................................. 25 1.3.1 Dendrimers ......................................................................................... 26 1.3.2 Nanoparticles ...................................................................................... 28 1.3.3 Nanogels ............................................................................................. 29 1.3.4 Polymersomes..................................................................................... 30 1.4 Micelles......................................................................................................... 32 1.4.1 Topology ............................................................................................. 33 1.4.2 Stimuli-responsiveness........................................................................ 36 1.4.3 Characterization of micelles ................................................................ 42 1.4.4 Drug encapsulation methods ............................................................... 45 1.5 Hydrophobic anticancer drugs ....................................................................... 48 1.6 Summary and work plan ................................................................................ 50 I References .......................................................................................................... 51 Chapter 2 Synthesis and Self-Assembly of AB2-type Amphiphilic Copolymers from Biobased Hydroxypropyl Methyl Cellulose and Poly(L-lactide) ......................................... 76 2.1. Introduction .................................................................................................. 76 2.2. Materials and Methods ................................................................................. 78 2.2.1 Materials ............................................................................................. 78 2.2.2 Synthesis of alkynyl terminated PLLA ................................................ 79 2.2.3 Enzymatic degradation of HPMC and determination of substitution degree ................................................................................................................. 79 2.2.4 Synthesis of thiol terminated HPMC ................................................... 80 2.2.5 Synthesis of (HPMC)2-PLLA .............................................................. 80 2.2.6 Characterization .................................................................................. 81 2.3. Results and Discussion ................................................................................. 83 2.3.1 Synthesis of amphiphilic block copolymers......................................... 83 2.3.2. Cloud point of (HPMC)2-PLA copolymers ......................................... 90 2.3.3. Self-assembly of (HPMC)2-PLA copolymers ..................................... 92 2.4. Conclusion ................................................................................................... 94 References .......................................................................................................... 95 Chapter 3 Self-Assembled Micelles Prepared from Bio-Based Hydroxypropyl Methyl Cellulose and Polylactide Amphiphilic Block Copolymers for Anti-Tumor Drug Release . 100 3.1 Introduction ................................................................................................. 100 3.2 Materials and Methods ................................................................................ 103 3.2.1 Materials ........................................................................................... 103 3.2.2 Synthesis of amino-terminated PLA .................................................. 103 3.2.3 Synthesis of HPMC-PLA block copolymers ...................................... 104 3.2.4 Characterization ................................................................................ 104 3.2.5 In vitro drug release .......................................................................... 105 3.2.6 MTT assay ........................................................................................ 106 II 3.2.7 Sulforhodamine B (SRB) assay ......................................................... 107 3.3 Results and discussion ................................................................................. 108 3.3.1 Synthesis of amphiphilic block copolymers....................................... 108 3.3.2 Self-assembly of copolymers ............................................................ 114 3.3.3 In vitro drug release .......................................................................... 116 3.3.4 Biocompatibility of HPMC-PLA copolymer micelles........................ 118 3.3.5 Cytotoxic activity of drug-loaded micelles ........................................ 119 3.4 Conclusion .................................................................................................. 120 References ........................................................................................................ 120 Chapter 4. Synthesis and Self-Assembly of Amphiphilic Block Copolymers from Hydroxypropyl Methyl Cellulose and Poly(ε-caprolactone) .............................................. 125 4.1 Introduction ................................................................................................. 126 4.2 Materies and Methods ................................................................................. 128 4.2.1 Materials ........................................................................................... 128 4.2.2 Synthesis of amino terminated PCL .................................................. 128 4.2.3 Synthesis of HPMC-PCL block copolymers ...................................... 129 4.2.4 Characterization ................................................................................ 129 4.2.5 In vitro drug release .......................................................................... 130 4.2.6 MTT assay ........................................................................................ 131 4.3 Results and discussion ................................................................................