ENCAPSULATION OF PLATINUM BASED DERIVATIVES WITHIN CARBON NANOTUBES INVESTIGATIONS ON CONTROLLED RELEASE AND IN VIVO BIODISTRIBUTION

ENCAPSULATION OF PLATINUM-BASED DERIVATIVES WITHIN CARBON NANOTUBES: INVESTIGATIONS ON CONTROLLED RELEASE AND IN VIVO BIODISTRIBUTION LI JIAN (B.S., Shanghai Jiao Tong University) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2012 DECLARATION I hereby declare that this thesis is my original work and it has been written by me in its entirety. I have duly acknowledged all the sources of information which have been used in the thesis. This thesis has also not been submitted for any degree in any university previously. ___________________________ LI JIAN 29 DEC 2012 Acknowledgements This dissertation would not have been possible without the guidance and the help of several individuals who in one way or another contributed and extended their valuable assistance in the preparation and completion of this study. First and foremost, I would like to express my sincere gratitude to my supervisor, Prof PASTORIN Giorgia, Associate Professor, Department of Pharmacy, National University of Singapore, for the continuous support of my Ph.D. study and research, for her patience, encouragement, enthusiasm, constructive comments, and immense knowledge. Besides my supervisor, I would like to thank Prof ANG Wee Han, Assistant Professor, Department of Chemistry, National University of Singapore, for kindly providing platinum(IV) compounds, and Prof RAMAPRABHU Sundara, Indian Institute of Technology, Madras, India, for providing ultrapure multi-walled carbon nanotubes for my research. My warmest thanks also go to Prof HO Chi Lui, Prof LEONG Tai Wei, and Prof YAN Bing, for taking time to be my Ph.D. examiners. I am deeply grateful to Mr CHONG Ping Lee and Ms LOY Gek Luan, Department of Biology, National University of Singapore, for guidance on transmission electron microscopy; Ms LENG Lee Eng and Ms TAN Tsze Yin, Department of Chemistry, National University of Singapore, for helping perform thermogravimetric analysis and inductively coupled plasma optical emission spectrometry; Dr AL-HADDAWI Muthafar, Institute of Molecular and Cell Biology, Singapore, for offering the consultation on histopathological analysis. i I would like to thank the Department of Pharmacy, National University of Singapore, for granting me the scholarship that allowed me to pursue this study, and for providing the premises and equipments for me to conduct the experiments. I would also like to thank Prof CHUI Wai Keung (Head of the Department), Prof CHAN Sui Yung (former Head of the Department), and all other faculty members of Department for their cooperation whenever I needed. I would like to express my sincere gratitude to the colleagues and fellows in my laboratory and department. They are Ms CHAN Wei Ling, Dr CHEONG Siew Lee, Ms CHEW Ying Ying, Mr CHIN Chee Fei, Mr GOH Min-Wei, Mr HU Jun, Mr Johannes Murti Jaya, Ms LIM Wan Min, Ms LYE Pey Pey, Dr MANDEL Alex, Ms NAM Wan Chern, Ms Napsiah Binte Suyod, Dr NAYAK Tapas Ranjan, Ms NG Sek Eng, Ms Nor Hazliza Binte Mohamad, Ms OH Tang Booy, Ms PANT Aakanksha, Dr PRIYANKAR Paira, Dr REN Yupeng, Mr SHAO Yi-Ming, Dr TIAN Quan, Mr VENKATA Sudheer Makam, Mr VENKATESAN Gopalakrishnan, Mr WIRATAMA CHANDRA Gary, Ms YAP Siew Qi, Ms YONG Sock Leng, Ms YOONG Sia Lee, and Ms ZHAO Chunyan. Last but not the least, I would like to thank my family for giving birth to me at the first place and offering understanding, encouragement, and support throughout my life. ii Table of Contents Acknowledgements i Table of Contents .iii Summary xi List of Tables xiv List of Figures . xv List of Illustrations . xviii List of Abbreviation . xix List of Publications and Conference Presentations . xxvii Chapter Introduction 1.1 1.2 Nanotechnology and nanomaterials . 1.1.1 Overview of nanotechnology . 1.1.2 Nanotechnology in medicine 1.1.3 Nanotechnology in drug delivery . Carbon nanotubes . 1.2.1 Background and general applications of carbon nanotubes . 1.2.2 Carbon nanotubes in drug delivery . 1.2.2.1 CNT-based drug delivery system through chemistry attachment . 10 1.2.2.2 CNT-based drug delivery system through π-π stacking interactions 13 1.2.2.3 CNT-based drug delivery system through incorporation into inner cavity 17 1.3 The biocompatibility of carbon nanotubes in drug delivery 22 1.3.1 Toxicity issues of carbon nanotubes towards biological systems . 22 1.3.1.1 Purity of carbon nanotubes . 23 iii 1.3.1.2 Toxicity reports on carbon nanotubes . 26 1.3.1.2.1 In vitro toxicity study on carbon nanotubes . 26 1.3.1.2.2 In vivo toxicity study on carbon nanotubes . 26 1.3.1.2.3 systems Elimination of carbon nanotubes from biological . 28 1.3.1.2.4 Correlation between toxicity and administrated dose as well as exposure time 30 1.3.1.3 Toxicity-related factors of carbon nanotubes 31 1.3.2 1.3.1.3.1 Metal impurities . 31 1.3.1.3.2 Carbon nanotubes’ structure 32 1.3.1.3.3 Carbon nanotubes’ length 33 1.3.1.3.4 Carbon nanotubes’ aspect ratio 34 1.3.1.3.5 Carbon nanotubes’ diameter 35 1.3.1.3.6 Carbon nanotubes’ surface properties 36 1.3.1.3.7 Carbon nanotubes’ charge 37 Biocompatibility improvement of carbon nanotubes . 37 1.3.2.1 Non-covalent coating 38 1.3.2.2 Covalent binding . 41 1.4 Conclusion . 46 Chapter Hypothesis and Objectives . 47 2.1 Thesis rationale and hypothesis . 47 2.2 Objectives . 48 Chapter Carbon Nanotubes for Incorporation, Storage and Release of Cisplatin 51 3.1 3.2 Introduction 51 3.1.1 Anticancer drug cisplatin 51 3.1.2 Rationale of nano-extraction and nano-condensation . 53 3.1.3 Selective washing of CNTs with guest molecules 56 Hypothesis and objectives 57 iv 3.3 Materials and methods . 58 3.3.1 Chemicals and reagents 58 3.3.2 Instruments . 58 3.3.3 Methods 59 3.3.3.1 Entrapment of CDDP within MWCNTs via nano-extraction and nano-condensation methods . 59 3.3.3.1.1 Dispersibility test of carbon nanotubes 59 3.3.3.1.2 Solubility test of CDDP . 59 3.3.3.1.3 Screening of “washing solvent” . 60 3.3.3.1.4 Encapsulation of CDDP in MWCNTs . 60 3.3.3.1.4.1 Nano-extraction method . 60 3.3.3.1.4.2 Nano-condensation method 61 3.3.3.2 Characterization of MWCNT-CDDP . 61 3.3.3.2.1 Transmission Electron Microscopy (TEM) . 61 3.3.3.2.2 Quantification of encapsulated CDDP using TGA and ICP-OES . 62 3.3.3.3 In vitro release of CDDP from MWCNT-CDDP complex . 62 3.4 Results and discussion . 63 3.4.1 Dispersibility of carbon nanotubes . 63 3.4.2 Solubility of CDDP 65 3.4.3 Screening of “washing solvent” for selective cleaning of MWCNT-CDDP . 66 3.4.4 Characterization of MWCNT-CDDP . 67 3.4.4.1 TEM imaging of MWCNT-CDDP . 67 3.4.4.2 Quantification of CDDP entrapped within MWCNTs using TGA and ICP-OES 71 3.4.4.3 SEM-EDX characterization of MWCNT-CDDP 74 3.4.5 In vitro release of CDDP from MWCNT-CDDP in neutral and weakly acidic conditions . 75 v 3.5 Conclusion . 77 Chapter Carbon Nano-bottles Capped by Gold Nanoparticles for Controlled Release and Enhanced Cytotoxic Effect of Cisplatin . 78 4.1 Introduction 78 4.1.1 “Carbon nano-bottle” structure for drug storage 78 4.1.2 Use of gold nanoparticles as “caps” . 81 4.2 Hypothesis and objectives 84 4.3 Materials and methods . 84 4.3.1 Chemicals and reagents 84 4.3.2 Instruments . 85 4.3.3 Methods 85 4.3.3.1 Functionalization of AuNPs with 1-octadecanethiol 85 4.3.3.2 Capping MWCNT-CDDP with ODT-f-AuNPs 86 4.3.3.3 In vitro release of CDDP from capped MWCNT-CDDP 87 4.3.3.4 Cell viability assays of CDDP, pristine MWCNTs, uncapped MWCNT-CDDP, and capped MWCNT-CDDP on MCF-7cells . 87 4.4 4.3.3.4.1 Cell culture 87 4.3.3.4.2 MTT cell viability assay 88 Results and discussion . 90 4.4.1 Synthesis of capped MWCNTs loaded with CDDP . 90 4.4.2 In vitro release of CDDP from capped MWCNT-CDDP . 96 4.4.3 Cell viability assay on MCF-7 cells treated with capped and uncapped MWCNT-CDDP samples . 98 4.5 Conclusion . 102 Chapter Covalent Capping of Carbon Nano-bottles with Gold Nanoparticles for Selective Release in Tumor Cells . 103 5.1 Introduction 103 5.1.1 Chemical modification of carbon nanotubes 103 5.1.2 Biologically cleavable bonds for drug delivery 108 vi 5.1.2.1 The use of hydrazone bond in drug delivery 109 5.1.2.2 The use of disulfide bond in drug delivery . 110 5.1.2.3 The use of ester bond in drug delivery 112 5.2 Hypothesis and objectives 113 5.3 Materials and methods . 114 5.3.1 Chemicals and reagents 114 5.3.2 Instruments . 115 5.3.3 Methods 115 5.3.3.1 Functionalization of multi-walled carbon nanotubes (MWCNTs) . 115 5.3.3.1.1 Oxidation of MWCNTs . 115 5.3.3.1.2 Synthesis of f-MWCNT-1 116 5.3.3.1.3 Synthesis of f-MWCNT-2 116 5.3.3.2 Functionalization of AuNPs 117 5.3.3.2.1 Reaction with 4-(2-(2-(2-mercaptoethoxy)ethoxy) ethoxy)benzaldehyde 117 5.3.3.2.2 Reaction with 9-mercapto-1-nonanol 118 5.3.3.3 Preparation of AuNP-capped nano-bottles assembled via chemical bonds 119 5.3.3.3.1 AuNP-capped nano-bottles assembled via hydrazone bond . 119 5.3.3.3.2 bond AuNP-capped nano-bottles assembled via ester . 119 5.3.3.3.3 bond AuNP-capped nano-bottles assembled via disulfide . 120 5.3.3.4 In vitro release of CDDP from covalently capped MWCNTCDDP nano-bottles . 122 5.3.3.5 Cell viability assays of covalently capped nano-bottles . 122 5.3.3.5.1 Cell culture 122 5.3.3.5.2 Lactate Dehydrogenase (LDH) assay 123 vii 5.3.3.6 Statistical analysis . 125 5.4 Results and discussion . 125 5.4.1 Synthesis of covalently capped MWCNT-CDDP nano-bottles 125 5.4.2 In vitro release from covalently capped nano-bottles . 130 5.4.3 Cytotoxicity of CDDP, f-MWCNT-CDDP-3, MWCNTox-CDDP, and blank nano-bottles to HCT-116 and IMR-90 . 134 5.5 Conclusion . 136 Chapter Platinum(IV) Prodrugs Entrapped within Multi-walled Carbon Nanotubes: Selective Release by Chemical Reduction and Hydrophobicity Reversal 138 6.1 Introduction 138 6.2 Hypothesis and objectives 142 6.3 Materials and methods . 142 6.3.1 Chemicals and reagents 142 6.3.2 Instruments . 143 6.3.3 Methods 143 6.3.3.1 Encapsulation of cis,cis,trans-Pt(NH3)2Cl2(CO2C6H5)2 (compound 6.1) in MWCNTs via nano-extraction method . 143 6.3.3.1.1 Solubility test of compound 6.1 . 143 6.3.3.1.2 Encapsulation of compound 6.1 in MWCNTs via nano-extraction method . 144 6.3.3.2 Reactivity of platinum complexes 144 6.3.3.2.1 Reactivity with DDTC . 144 6.3.3.2.2 Analysis of Pt-dGMP adduct formation 145 6.3.3.3 Controlled release of platinum from MWCNT-Pt(IV) complex 146 6.3.3.3.1 Release from MWCNT-Pt(IV) complex . 146 6.3.3.3.2 Pt(IV) Binding to DNA target upon release from MWCNT . 146 6.3.3.4 Platinum uptake in A2780 ovarian carcinoma cells 146 6.4 Results and discussion . 148 viii Appendices 297. 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Advanced Drug Delivery Reviews, 2012. 64(15): 1700-1705. 225 Appendices Appendices Appendix I UV-vis spectra of nm bare (left) and functionalized (right) AuNPs. UV-vis spectra analysis confirmed the successful surface functionalization of AuNPs with ODT, by showing an increase in SPR λmax (i.e. a red shift) from 528 nm (for nm bare AuNPs) to 532 nm (for ODT-f-AuNPs). 226 Appendices Appendix II FT-IR spectra of (a) ODT and (b) ODT-f-AuNPs. The IR spectrum of ODT-f-AuNPs resembled the spectrum of ODT closely. This suggests that ODT molecules were successfully attached to the AuNPs. The IR vibrational bands at approximately 1,260 cm-1 corresponded to CH2-S wagging, while the weak intensity peaks at approximately 2,380 cm-1 could be attributed to S-H stretching. The absence of the peaks at 2,380 cm-1 in the spectrum of ODT-f-AuNPs supported the idea that ODT molecules were attached to the AuNPs via the formation of Au-S bond, which resulted in the dissociation of S-H bond and hence the loss of S-H stretching vibration peak. S-S vibration, eventually located in the 450~550 cm-1 region, is not relevant in IR spectra. 227 Appendices Appendix III Serum immunological indicator levels of the control mice and the MWCNT/Pt-based drug exposed mice at h, h, and 24 h post- exposure. (a) IL-1β levels; (b) IL-6 levels; (c) TNF-α. Data are represent as Mean ± SD (n=3). 228 [...]... purpose, the interest of this thesis is focused on the use of a particular type of nanomaterial, namely carbon nanotubes (CNTs), as a vehicle for drug delivery, based on the great progress of research on carbon nanotubes in the fields of chemistry and biology 1.2 Carbon nanotubes 1.2.1 Background and general applications of carbon nanotubes Carbon nanotubes have received considerable attention since their... Samples preparation 163 7.3.4.1.1 Synthesis of MWCNTOX and MWCNTTEG 163 7.3.4.1.2 Entrapment of CDDP in MWCNTOX and MWCNTTEG via nano-extraction 165 7.3.4.1.3 Entrapment of Pt(IV) compound 6.1 in MWCNTOX and MWCNTTEG via nano-extraction 165 7.3.4.2 In vivo injection of Pt-MWCNT complexes in mice 166 7.3.4.3 Determination of platinum content in the organs, serum, and urine ... List of Figures Figure 1.1 Schematic illustration of (a) single-walled carbon nanotube, and (b) multiwalled carbon nanotube 7 Figure 3.1 Structure of cisplatin 51 Figure 3.2 Schematic illustration of nano-extraction and nano-condensation 54 Figure 3.3 Scheme of the selective filling of carbon nanotubes 56 Figure 3.4 TEM image of CDDP 68 Figure 3.5 TEM images of ultrapure... distribution of cisplatin and Pt(IV) complex in vivo, cisplatin and Pt(IV) complex were entrapped within various MWCNTs (i.e pristine, carboxylated, amidated), and then injected intravenously into mice The results showed that the distribution of elemental platinum in organs remarkably altered when they were delivered through MWCNTs, and the extent of accumulation was correlated with functionalities onto... Pastorin, G., Thin Films of Functionalized Multiwalled Carbon Nanotubes as Suitable Scaffold Materials for Stem Cells Proliferation and Bone Formation Acs Nano, 2010 4(12): p 7717-7725 Oral and Poster Presentations: 1 Li, J., Yap, S Q., Yoong, S L., Nayak, T R., Chandra, G W., Ang, W H., Pastorin, G., Carbon Nanotube Bottles for Incorporation, Release and Enhanced Cytotoxic Effect of Cisplatin AAPS-NUS... a carbon nanotube bottle” structure Cisplatin was incorporated into MWCNTs via nano-extraction and/ or nano-condensation methods to obtain a MWCNT-CDDP complex, and the open ends of MWCNTs were subsequently capped with functionalized gold nanoparticles (AuNPs) on the basis of physical interaction High loading of cisplatin was achieved in both uncapped and capped MWCNT-CDDP nano-bottles In comparison... cleavable bond linked carbon nano-bottle”: the drug release is activated by the dissociation of cleavable linkage 114 Scheme 5.4 Synthetic procedure of the samples 117 Scheme 5.5 Functionalization of gold nanoparticles 118 Scheme 5.6 Preparation of covalently capped MWCNT-CDDP nano-bottles 121 Scheme 6.1 Design concept on based on hydrophobic entrapment of platinum( IV) prodrug within. .. diagnostic and imaging techniques for quick identification of diseases and accurate location of cancer tumors On the basis of proteins and other biomarkers that are left behind by cancer cells, sensor test chips containing thousands of nanowires are designed for the detection and diagnosis of cancer in the early stages from a few drops of a patient’s blood [50, 51] Gold nanoparticles (AuNPs) linked with... Yoong, S L., Pastorin, G., Ang, W H., Platinum( IV) prodrugs entrapped within multiwalled carbon nanotubes: Selective release by chemical reduction and hydrophobicity reversal Chemical Science, 2012 3(6): p 2083-2087 2 Li, J., Yap, S Q., Yoong, S L., Nayak, T R., Chandra, G W., Ang, W H., Pastorin, G., et al., Carbon nanotube bottles for incorporation, release and enhanced cytotoxic effect of cisplatin... CDDP alone, MWCNT-CDDP, MWCNTOX-CDDP, and MWCNTTEG-CDDP in mice 170 7.4.2.2 Biodistribution of elemental platinum from administration of Pt(IV) compound 6.1 alone, MWCNT-Pt(IV), MWCNTOX-Pt(IV), and MWCNTTEG-Pt(IV) in mice 174 7.4.2.2.1 Increased platinum levels in vivo through MWCNTOX or MWCNTTEG 174 7.4.2.2.2 Variations in distribution tendency of Pt(IV) compound 6.1 through MWCNTOX . ENCAPSULATION OF PLATINUM-BASED DERIVATIVES WITHIN CARBON NANOTUBES: INVESTIGATIONS ON CONTROLLED RELEASE AND IN VIVO BIODISTRIBUTION LI JIAN (B.S., Shanghai Jiao Tong University). of carbon nanotubes towards biological systems . 22 1.3.1.1 Purity of carbon nanotubes 23 iv 1.3.1.2 Toxicity reports on carbon nanotubes 26 1.3.1.2.1 In vitro toxicity study on carbon. carbon nanotubes 26 1.3.1.2.2 In vivo toxicity study on carbon nanotubes 26 1.3.1.2.3 Elimination of carbon nanotubes from biological systems 28 1.3.1.2.4 Correlation between toxicity and administrated