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Title Page

Abstract

Contents

1. Introduction 13

2. Experimental 18

2.1. Materials 18

2.2. Preparation of CP-loaded HA 19

2.3. Preparation of injectable hydrogel containing HA 20

2.4. Rheological properties of hydrogel 21

2.5. Injectability test of injectable formulations 22

2.6. Preparation of fluorescence labeled HA-CP 23

2.7. Preparation of fluorescence labeled PCLA 24

2.8. In vitro CP release and degradation of hydrogel 25

2.9. Synovial fibroblast isolation 26

2.10. In vitro cytotoxicity of hydrogel 27

2.11. Monitoring localization of CP from hydrogel 28

2.12. In vitro evaluation of pro-inflammatory cytokine level 29

2.13. In vivo CP release and degradation of hydrogel 30

2.14. Preparation of rat collagen-induced arthritis (CIA) model 31

2.15. In vivo therapeutic effects of PLP and PCP in CIA model 32

2.16. Histological assay 33

2.17. In vivo quantification of pro-inflammatory cytokines 34

2.18. Statistical analysis 35

3. Results & Discussion 36

3.1. Preparation and characterization of injectable formulations 36

3.2. In vitro CP release and degradation of hydrogel 40

3.3. In vitro evaluation of anti-inflammatory effect of CP from hydrogel 42

3.4. In vivo persistence of hydrogels in articular knee joint 46

3.5. Evaluation of inflammation relief via monitoring CIA model 48

3.6. Histological analysis of articular joint tissue 50

3.7. In vivo evaluation of pro-inflammatory cytokine level 52

4. Conclusion 54

References 58

List of Publications 62

List of Presentations 63

List of Tables

Table S1. Primers used for real-time PCR. 56

Table S2. Characterization of HA and HA-CP by using elemental analysis (EA). 57

Table S3. Characterization of PCLA 57

List of Figures

Figure 1. Schematic image for PCLA+HA-CP (PCP) as an injectable in-situ forming hydrogel formulation for sustained release of CP from the hydrogel. 17

Figure 2. Characterization of hydrogel formulations. Gelation time of (a) PCLA, (b) PCLA+HA, (c) PLP, and (d) PCP. (e) Viscosity-versus-temperature curves, (f) rheological characterization of storage modulus and loss modulus, and (g) phase... 38

Figure 3. Characterization of injectability of hydrogel formulations. (a) photo images of PCP loaded to syringe and pushing 30 s, (b) Plot of loading force on plunger required to expel 100 μl of PCLA, PCLA+HA, PLP, and PCP formulations with... 39

Figure 4. (a) In vitro fluorescence images of hydrogel degradation [green image (F-CP), violet image (IR-HA), red image (R-PCLA)]. (b) F-CP release percentage at each time and (c) accumulated F-CP release amount from PLP and PCP. 41

Figure 5. Viability of (a) RAW 264.7 cells and (d) rat synovial cells treated without a CP, with CP single, PLP and PCP for 1, 4, and 7 days (#p 〉 0.99).[이미지참조] 43

Figure 6. Confocal images of the binding of F-CP to the RAW 264.7 cells and synovial cells and the regulation of p65 activity by F-CP observed 1, 4, and 7 days after treatment without F-CP and with F-CP-single, F-PLP, and F-PCP.... 44

Figure 7. Quantification of extracellular (a) TNF-α and (b) IL-6 in cell media and gene expression level of (c) Tnfa and (d) Il6 of RAW 264.7 cells treated without a... 45

Figure 8. (a) In vivo distribution of F-CP and degradation of hydrogels in articular knee [green image (F-CP)), violet image (IR-HA), red image (R-PCLA)]. Plots of remained fluorescence of (b) F-CP, (c) IR-HA, and (d) R-PCLA. 47

Figure 9. (a) Hind paw photographs, (b) articular index (AI) score, (c) ankle circumference, and (d) body weight of CIA rats during the 6 weeks after they received intra-articular injection without a drug, with CP, PLP, and PCP at 1, 3, and 6... 49

Figure 10. (a) Histological assay with H&E staining and (b) thickness of articular cartilage determined using H&E staining images. (c) Safranin-O staining and (d) GAG positive area determined using SO staining images. Joint tissues were stained at at 1, 3, and 6... 51

Figure 11. Pro-inflammatory cytokines (a) TNF-α and (b) IL-6 in rat blood specimens quantified by ELISA. Relative gene expression level of (c) Tnfa and (d)... 53

Figure S1. ¹H-NMR spectra of (a) HA, (b) HA-CP, and (c) PCLA. 55

초록보기

 Rheumatoid arthritis (RA) is an autoimmune disease that involves a systemic inflammatory reaction and causes symptoms mainly in joint tissues. Because RA is a chronic disease, patients require chronic medication. A sustained-release drug delivery system can reduce the frequency of drug administrations, which is more convenient for patients. Cyclic phage-display-derived inhibitory peptide is an antagonist of toll-like receptor 4 and was developed based on machine learning technology. It reduces the levels of inflammatory factors and exhibits treatment effects in vitro and in vivo; however, this peptide is unstable and thus has a short half-life due. This study was conducted to develop an injectable hydrogel formulation for controlled release of the peptide to stably act at the target site. To achieve sustained release, the peptide was bound to a carboxyl group in each monomer of hyaluronic acid and mixed with methoxy polyethylene glycol-b-[poly(ε-caprolactone)-ran-poly(lactide)] (PCLA) to prepare a peptide-conjugated PCLA hydrogel (PCP). PCP injected into the joint cavity underwent a sol-gel transition at physiological temperature and formed a depot. Peptide release continued for a longer period from PCP than from peptide-loaded PCLA hydrogel (PLP) prepared by simply mixing the peptide. As a result, PCP inhibited the expression of inflammatory cytokines for a longer period than that by the drug alone and PLP in vitro. Injection of PCP into the joint cavity of collagen-induced arthritis rats exhibited superior therapeutic effects based on reduced RA symptoms, cartilage regeneration, and suppressed pro-inflammatory cytokine levels. Thus, Intra-articular injection of PCP can be effective for treating RA by maintaining the therapeutic concentration of the drug for an extended period.

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