Structure adjustable synthesis of hollowmesoporous silica nanoparticles and its surface modification for anti cancer drugdelivery

– DECLARATION The work was carried out at the Department of Biomaterials & Bioengineering - Institute of Applied Materials Science (IAMS) - Vietnam Academy of Science and Technology (VAST) in Ho Chi Minh City I hereby declare that this is my research work under the scientific guidance of Assoc.Prof.Dr Nguyen Dai Hai The research contents and results presented in this thesis are honest and completely based on my research results The results of this study have not been published on any thesis of the same level Ho Chi Minh, December 30th 2022 NGUYEN THI NGOC HOI ii ACKNOWLEDGEMENTS First of all, I would like to express my most profound gratitude to my supervisor Assoc Prof., PhD Nguyen Dai Hai - Vice Director of the Institute of Applied Materials Science, and Head of Department of Biomaterials and Bioengineering He has given me the delightful lessons, inspiration, constant motivation and enthusiasm that have surely encouraged and helped me to overpass the difficulties encountered, and exerted great aids for my accomplishment of this thesis research Secondly, my sincere gratitude also goes to the enthusiastic help and favorable supports during my PhD course from Graduate University of Science and Technology (GUST) and the Institute of Applied Materials Science (IAMS) Vietnam Academy of Science and Technology (VAST) Furthermore, it is impossible not to mention the valuable support from MSc Nguyen Dinh Tien Dung and BS Truong Thi Ngoc Hang They contributed great help during the experiments at IAMS Last but not least, I am grateful to have my family and friends, who always encourage and support all over time that makes my thesis experience more meaningful Ho Chi Minh, December 30th 2022 NGUYEN THI NGOC HOI iii TABLE OF CONTENTS Page DECLARATION i ACKNOWLEDGEMENTS ii TABLE OF CONTENTS iii LIST OF ABBREVIATIONS vii LIST OF FIGURES ix LIST OF DIAGRAMS xiv LIST OF TABLES xv INTRODUCTION CHAPTER LITERATURE REVIEW 1.1 Overview of cancer and cancer treatment 1.1.1 Overview of cancer 1.1.2 Common cancer treatment therapies 1.2 Nanomaterials in cancer treatment 1.2.1 Nanomaterials in anti-cancer drug delivery applications 1.2.2 Silica nanomaterials in anti-cancer drug delivery applications 1.3 Recent progress of nano silica particle applications in drug delivery 11 1.3.1 International research 11 1.3.2 National research 13 1.4 Hollow mesoporous silica nanoparticles (HMSN) 14 1.4.1 Structure of HMSN 14 1.4.2 Synthesis methods of HMSN 15 1.4.3 Reaction mechanisms in the synthesis of HMSN by silica based hardtemplate method 22 1.4.4 Modular factors in HMSN fabrication 27 1.4.5 Modifications of HMSN 36 1.4.6 Multiple-Drug Loading HMSN 41 CHAPTER MATERIALS AND EXPERIMENTAL METHODS 44 2.1 Materials 44 iv 2.1.1 Chemicals 44 2.1.2 Equipments 45 2.2 Synthesis Methods 46 2.2.1 Synthesis of HMSN 46 2.2.2 The effect of PEG on the mesoporous shell thickness of HMSN 49 2.2.3 The effect of non-ionic surfactants on the mesopore diameter of HMSN 51 2.2.4 Surface Modification Method of HMSNs with Pluronics 53 2.2.5 The effect of Pluronics on dual-drugs delivery characteristics of HMSNPlu 56 2.3 Physicochemical Analysis Methods 57 2.4 Drug loading and in vitro release study 58 2.5 Cell culture and MTT assay 59 2.6 Statistical analysis 59 CHAPTER A MODIFIED HARD-TEMPLATE METHOD FOR HOLLOW MESOPOROUS SILICA NANOPARTICLES SYNTHESIS WITH SUITABLE PARTICLE SIZE AND SHORTENED SYNTHETIC TIME 61 3.1 Synthesis of silica hard-template 61 3.2 Etching over time of silica hard-template in the synthesis of HMSN 62 3.3 Characterizations of synthesized HMSN 63 3.4 Cytotoxicity of synthesized HMSN 66 3.5 Summary 67 CHAPTER SIMPLY AND EFFECTIVELY CONTROL THE SHELL THICKNESS OF HOLLOW MESOPOROUS SILICA NANOPARTICLES BY POLYETHYLENE GLYCOL FOR DRUG DELIVERY APPLICATIONS 69 4.1 Effect of PEG molecular weight on the mesoporous shell thickness of dSiO2@MSN 69 4.2 Effect of PEG weight percentage on the mesoporous shell thickness of dSiO2@MSN 71 v 4.3 Characterizations of the synthesized HMSNs 74 4.3.1 Drug loading and in vitro drug release study of the synthesized HMSN 77 4.4 Cytotoxicity of the synthesized HMSN 79 4.5 Summary 80 CHAPTER NON-IONIC SURFACTANTS AS CO-TEMPLATES TO CONTROL THE MESOPORE DIAMETER OF HOLLOW MESOPOROUS SILICA NANOPARTICLES FOR DRUG DELIVERY APPLICATIONS 81 5.1 Preparation of mixed micelles of non-ionic surfactants with CTAB 81 5.2 Effect of non-ionic surfactants on the mesoporous shell thickness of dSiO2@MSN 83 5.3 Effect of non-ionic surfactants on the mesopore diameter of dSiO2@MSN 85 5.4 Characterizations of the synthesized HMSNs 87 5.5 Drug loading and in vitro drug release study of the synthesized HMSNs 89 5.6 Cytotoxicity of the synthesized HMSNs 90 5.7 Summary 91 CHAPTER SURFACE MODIFICATION OF HOLLOW MESOPOROUS SILICA NANOPARTICLES WITH PLURONICS FOR DUAL DRUGS DELIVERY 93 6.1 Activation Pluronic with NPC 93 6.2 Amination of HMSNs’ surface 94 6.3 Modification of HMSNs’ surface with Pluronics via amine intermediate 96 6.4 Dual-drug loading capacity and in vitro release behavior of HMSN-Plu 99 6.5 In vitro drug release behavior of HMSN-Plu 100 6.6 Cytotoxicity of HMSN-Plu 103 6.7 Characterizations of HMSN-F127 104 6.8 Cancer cell killing ability of DOX.QUE@HMSN-Plu 108 6.9 Summary 109 CONCLUSIONS AND FUTURE PERSPECTIVES 111 vi Conclusion 111 Novelty of the thesis 112 Future perspective 112 LIST OF PUBLICATIONS 114 REFERENCES 115 vii LIST OF ABBREVIATIONS APTES BET BJH BTES C18TMS CMC CTAB CTAC DI DLC DLE DLS DOX dSiO2 EDX EPR FDA FE-SEM FT-IR GPC HMSN HPLC MCM-41 MCM-48 MCM-50 MDR MON MSN PAA PBS PEG PEO PPO PMMA (3-Aminopropyl)triethoxysilane Brunauer-Emmett-Teller Barret Joyner and Halenda Bis (triethoxysilylpropyl) disulfide n-octadecyltrimethoxysilan Critical micelle concentration Cetyltrimethylammonium Bromide Cetyltrimethylammonium Chloride Deioned water Drug loading capacity Drug loading efficiency Dynamic Light Scattering Doxorubicin dense Silicone dioxide Energy Dispersive X-ray Enhanced Permeability and Retention Food and Drug Administration Field Emission Scanning Electron Microscope Fourier Transform Infrared Gel Permeation Chromatography Hollow Mesoporous Silica Nanoparticles High Performance Liquid Chromatography Mobil Composition of Matter No 41 Mobil Composition of Matter No 48 Mobil Composition of Matter No 50 Multidrug Resistance Mesoporous Organosilica Nanoparticle Mesoporous Silica Nanoparticles Poly (Acrylic Acid) Phosphate Buffered Saline Polyethylene Glycol Poly(Ethylene Oxide) Poly(Propylene Oxide) Polymethylmethacrylate viii PS PVP QUE RB SBA-15 SEM TGA TEA TEM TEOS XRD Polystyrene Polyvinylpyrolidone Quercetin Rose Bengal Santa Barbara Amorphous-15 Scanning electron microscope Thermogravimetric analysis Triethanolamine Transmission electron microscopy Tetraethyl orthosilicate X-ray Diffraction Zeta potential of dSiO2 Zeta potential of HMSN Zeta potential of HMSN-NH2 Zeta potential of HMSN-L64 Zeta potential of HMSN-F68 Zeta potential of HMSN-F127 TGA graph of HMSN TGA graph of HMSN-L64 TGA graph of HMSN-F68 TGA graph of HMSN-F127 EDX pattern of HMSN EDX pattern of HNSM-NH2 Isotherm Linear Plot of HMSN BJH Adsorption dV/dD Pore Volume of HMSN Isotherm Linear Plot of HMSN-NH2 BJH Adsorption dV/dD Pore Volume of HMSN-NH2 H-NMR spectrum of NPC-L64-OH H-NMR spectrum of NPC-F68-OH H-NMR spectrum of NPC-F127-OH