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Title Page

Abstract

Contents

Abbreviations 15

Chapter 1. Introduction 16

1-1. Self-assembly of Peptides 16

1-1-1. Self-assembly 16

1-1-2. Peptides 17

1-2. Biomolecules 19

1-2-1. Biomolecules 19

1-2-2. Tumor-specific biomolecules 21

1-3. Self-assembly of peptides with biomolecules (biomarkers) 23

1-4. Research Outline 28

1-4-1. Objectives of Thesis 28

1-4-2. Outline of Thesis 28

1-5. Reference 29

Chapter 2. HA-incorporated nanostructure of peptide-drug amphiphile for targeted anticancer drug delivery. 33

2-1. Abstract 33

2-2. Introduction 33

2-3. Results and Discussion 36

2-4. Materials and Methods 42

2-5. Conclusions 54

2-6. References 54

Chapter 3. Sequestering ATP inside Mitochondria by Nucleopeptide Assembly Induces Cancer Cell Apoptosis 57

3-1. Abstract 57

3-2. Introduction 58

3-3. Results and Discussion 60

3-4. Materials and Methods 72

3-5. Conclusion 87

3-6. References 87

Chapter 4. In-situ Polymerization using Dynamic Covalent Bond Formation using Mitochondria-targeting Peptides 90

4-1. Abstract 90

4-2. Introduction 90

4-3. Results and Discussion 93

4-4. Methods and Materials 100

4-5. Conclusion 107

4-6. Reference 107

Chapter 5. Self-assembly of Fmoc-based peptides for Enhancing Anticancer Therapy 109

5-1. Abstract 109

5-2. Introduction 109

5-3. Results and Discussion 112

5-4. Methods and Materials 118

5-5. Conclusion 121

5-6. Reference 121

Chapter 6. Summary and Future perspectives 123

List of publications 125

List of Figures

Figure 1.1. Schematic illustration of self-assembly process from building blocks into nanostructures... 16

Figure 1.2. Possible self-assembled structures of peptide amphiphiles (PAs). Amphiphilic peptides may... 17

Figure 1.3. Schematic representation of self-assembled nanostructures and their possible applications.... 18

Figure 1.4. a. Schematic illustration of self-assembly of the FF-MTs (Microtubes-FF, two phenylalanine)... 19

Figure 1.5. Examples of biomolecules such as DNA, RNA, Proteins, Lipid, and carbohydrates 20

Figure 1.6. Schematic representation of the interaction between the receptors on cell membrane and... 21

Figure 1.7. Representative unique characteristics of tumor microenvironments. Reproduced from... 22

Figure 1.8. Scheme representation for the preparation of HMCP (HSA-MnO₂-Ce6&Pt) nanoparticles... 23

Figure 1.9. (a-b) Schematic illustration of in-situ self-assembled near-infrared (NIR) peptide probe... 24

Figure 1.10. a. Schematic illustration of self-assembly of pentapeptide AmpF with morphological... 26

Figure 1.11. Schematic representation of intracellular enzyme-instructed self-assembly (EISA) to treat... 27

Figure 1.12. Representative illustration of thesis "Self-assembly of peptides with biomolecules for... 28

Figure 2.1. Schematic representation of (A) transformable self-assembly of the HA-KCK-CPT... 35

Figure 2.2. TEM images of self-assembled nanostructures of KCK-CPT (A and B) and HA-KCK-CPT... 37

Figure 2.3. (A-D) Confocal laser scanning microscope (CLSM)-merged images of in vitro cellular... 39

Figure 2.4. CLSM images of colocalization of HA-KCK-CPT in SCC-7 cells after (A) 1 h, (B) 4 h and... 41

Figure 2.5. Characterization of KCK peptide a. HPLC analysis b. ESI-MS analysis of KCK peptide 43

Figure 2.6. Synthetic scheme of CPT derivatives 44

Figure 2.7. NMR spectra of Camptothecin-4-nitrophenyl carbonate (2). 45

Figure 2.8. NMR spectra of Camptothecin-(4-pyridyldisulfanyl)ethyl carbonate(3). 46

Figure 2.9. Characterization of KCK-CPT a. HPLC analysis b. ESI-MS analysis of KCK-CPT prodrug 47

Figure 2.10. Fluorescence emission spectrum change of KCK-CPT in 1 mM DMSO and aqueous... 47

Figure 2.11. Self-assembled nanostructures of KCK-CPT. A-B) curved sheet nanostructure of 400 μM... 48

Figure 2.12. Colloidal stability studies of HA-KCK-CPT by A-B) hydrodynamic diameter... 49

Figure 2.13. Hydrodynamic diameter distribution of HA-KCK-CPT with different concentrations. A)... 50

Figure 2.14. GSH induced CPT release profile from HA-KCK-CPT. A) drug release percentage versus... 51

Figure 2.15. CLSM images of SCC-7 cells treated by HA-KCK-CPT in the (A) presence of methyl-β-... 53

Figure 3.1. a) Chemical structure of the mitochondria-targeting nucleopeptide (MNP), fluorophore... 59

Figure 3.2. Self-assembly behavior of the MNP/ADP, MNP/ATP, and MNP/ADP-ATP complexes. a-... 62

Figure 3.3. a) Interaction energies and b-c) binding configurations of the MNP/ADP and MNP/ATP... 64

Figure 3.4. a) Mitochondrial localization of the MNP-NBD/ADP complex with mitotracker deep red... 66

Figure 3.5. CLSM images of HeLa cells treated by MNP-NBD/ADP complex (50 μM) in the different... 67

Figure 3.6. Mitochondrial damage a-b) Mitochondrial damage visualizing with a) ROS generation in... 69

Figure 3.7. a-c) FACS analysis of a) control (non-treated), b) MNP and c) MNP/ADP complex treated... 71

Figure 3.8. Synthetic scheme of MNP, AcNP and MNP2 via solid phase peptide synthesis (SPPS). 73

Figure 3.9. Characterization of mitochondria-penetrating nucleopeptides (MNP), acetyl protected... 74

Figure 3.10. Synthetic scheme of NBD-NH₂ 75

Figure 3.11. Synthetic scheme of MNP-NBD 76

Figure 3.12. Characterization of MNP-NBD a) mass spectra MNP-NBD and b) HPLC purity trace of... 76

Figure 3.13. TEM images of a) MNP itself and b) MNP-NBD itself 78

Figure 3.14. Self-assembly behavior of control molecules (AcNP) a) photo of AcNP, and AcNP/ADP... 78

Figure 3.15. a) Radial distribution function (g(r) between phosphate (Q), ribose (N), and adenine (S)... 80

Figure 3.16. Final configuration of a) MNP/ADP complexes and d) MNP/ATP complexes after 40 ns;... 81

Figure 3.17. a) Radial distribution function (g(r) between arginine groups and thymine group for... 81

Figure 3.18. All-atom (AA) and coarse-grained (CG) models of a) ADP, b) ATP, and c) MNP. Gray, blue,... 82

Figure 3.19. Configuration of a) MNP/ADP complexes and b) MNP/ATP complex assemblies after 500... 82

Figure 3.20. a) Snapshot and b) radial number density of MNP/ADP complex nanoparticle after 500 ns.... 83

Figure 3.21. Cytotoxicity of MNP toward Hela (cancer) and IMR90 (Normal) cell lines for 2 days incubation. 84

Figure 3.22. Cytotoxicity of a) AcNP and AcNP/ADP complex, b) NBD-labelled MNP (MNP-NBD)... 84

Figure 4.1. a. Chemical structure of Di-B, Di-A and Di-c and their nanostructures from polymerization... 92

Figure 4.2. TEM images of polymerizable peptides (Di-A, Di-B and Di-C) under different conditions... 95

Figure 4.3. a. Gel Permeation Chromatography (GPC) of polymerized Di-A, Di-B and Di-C prepared... 96

Figure 4.4. TEM images of a. Di-A, b. Di-B and c. Di-C under agitation (stirring) in 0.1 M pH 8.5 buffer... 96

Figure 4.5. a. Mitochondrial localization of Ac-B-NBD peptides at 50 μM for 6 h incubation toward... 98

Figure 4.6. Mitochondrial damage visualized by a. TMRM staining b. MitoSOX by Di-A, Di-B and Di-... 99

Figure 4.7. Chemical structures and their mass spectrum of Di-B and Di-C 101

Figure 4.8. Chemical structures and their mass spectrum of control molecules, Ac-A, Ac-B and Ac-C 101

Figure 4.9. Synthetic procedure of trityl-protected 1,3-dimercapto benzoic acid. 102

Figure 4.10. Characterization of Fmoc-Lys(NBD)-OH by a. NMR and b. MALDI-TOF/TOF spectrum 104

Figure 4.11. Mass spectrum of Ac-B-NBD 105

Figure 5.1. a. chemical structures of Fmoc-based peptides (Fmoc-A, Fmoc-B and Fmoc-C) b.... 111

Figure 5.2. Molecular structures of Fmoc-based peptides and their mass spectra of a. Fmoc-A, b. Fmoc-... 112

Figure 5.3. TEM images of a. Fmoc-A, b. Fmoc-B and c. Fmoc-C at 400 μM in aqueous solution at 37 ℃. 113

Figure 3.4. a. Illustration of cellular internalization of Fmoc-B-NBD b. confocal images of time-... 114

Figure 5.5. Cytotoxicity of Fmoc-A, Fmoc-B and Fmoc-C toward HeLa and Hek293 cell lines for 2... 115

Figure 5.6. Mitochondrial ROS generation by MitoSOX staining by Fmoc-A, B and C 50 μM for 2h... 116

Figure 5.7. Mitochondrial damage by TMRM staining by Fmoc-A, B and C 50 μM for 2h incubation... 117

Figure 5.8. Chemical structure and Mass spectrum of Fmoc-B-NBD 119

초록보기

Self-assembly is one of the supramolecular process happening in biological systems and facile generation of multiplexed nanostructures with building blocks through noncovalent interaction. In nature, there are a rich variety of supramolecular molecules such as lipid bilayers of cell membrane, proteins, deoxyribonucleic acid (DNA), and microtubules. Especially, peptide is widely used as building blocks for self-assembly due to its diversity and biocompatibility. In water condition, amphiphilic peptides can form nanostructures with functional properties. These self-assembled nanostructures are used for diverse applications such as drug delivery, hydrogels, and tissue engineering.

Biomolecules are large polyanionic molecules such as proteins, carbohydrates, enzymes, and nucleic acids, as well as small molecules such as amino acids, lipids, primary metabolites, secondary metabolites, and natural products. Biomolecules as called as biological molecules play an important role for living organisms because those biomolecules are involved in cell divisions, survive, metabolism, and morphogenesis. For application study, biomolecules-assisted self-assembly is an interesting field using stimuli-responsive moiety, targeting moiety, and recognizing moiety.

In this dissertation, self-assembly of peptides with biomolecules will be addressed with four chapters. Different biomolecules are used for self-assembly of peptides to develop anticancer therapy. In first chapter, hyaluronic acid (HA), biopolymers, is used for self-assembly and interaction with CD44 receptors on cancer cells membrane. Peptide-drug amphiphile and HA complexation provide higher efficacy for anticancer therapy. In chapter 3, adenosine triphosphate (ATP), energy source produced inside mitochondria, is used to damage the mitochondria of cancer cells through large-assembly with nucleopeptide which is selectively able to interact with ATP. In chapter 4, hydrogen peroxide (H₂O₂) and higher pH in mitochondria of cancer cells assist disulfide formation of peptides to make oligomers and polymers. Mitochondria-penetrating peptides with polymerizable moiety self-assemble and polymerize into specific nanostructures leading to mitochondrial damage. Last chapter deals with self-assembly of Fmoc-modified mitochondria-penetrating peptides to treat cancers. These strategies can be one of cancer therapies with selectively kill cancer cells via self-assembly with biomolecules (biomarkers).

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