Temperature-responsive hydrogel containing hyaluronic acid modified with anti-inflammatory peptide for treating rheumatoid arthritis
- 주제(키워드) Rheumatoid arthritis , thermosensitive hydrogel , intra-articular injection , long-lasting release , hyaluronic acid
- 주제(DDC) 547
- 발행기관 아주대학교
- 지도교수 김문석
- 발행년도 2023
- 학위수여년월 2023. 8
- 학위명 석사
- 학과 및 전공 일반대학원 분자과학기술학과
- 실제URI http://www.dcollection.net/handler/ajou/000000033004
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
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.
more목차
1. Introduction 1
2. Experimental 6
2.1. Materials 6
2.2. Preparation of CP-loaded HA 7
2.3. Preparation of injectable hydrogel containing HA 8
2.4. Rheological properties of hydrogel 9
2.5. Injectability test of injectable formulations 10
2.6. Preparation of fluorescence labeled HA-CP 11
2.7. Preparation of fluorescence labeled PCLA 12
2.8. In vitro CP release and degradation of hydrogel 13
2.9. Synovial fibroblast isolation 14
2.10. In vitro cytotoxicity of hydrogel 15
2.11. Monitoring localization of CP from hydrogel 16
2.12. In vitro evaluation of pro-inflammatory cytokine level 17
2.13. In vivo CP release and degradation of hydrogel 18
2.14. Preparation of rat collagen-induced arthritis (CIA) model 19
2.15. In vivo therapeutic effects of PLP and PCP in CIA model 20
2.16. Histological assay 21
2.17. In vivo quantification of pro-inflammatory cytokines 22
2.18. Statistical analysis 23
3. Results & Discussion 24
3.1. Preparation and characterization of injectable formulations 24
3.2. In vitro CP release and degradation of hydrogel 28
3.3. In vitro evaluation of anti-inflammatory effect of CP from hydrogel 30
3.4. In vivo persistence of hydrogels in articular knee joint 34
3.5. Evaluation of inflammation relief via monitoring CIA model 36
3.6. Histological analysis of articular joint tissue 38
3.7. In vivo evaluation of pro-inflammatory cytokine level 40
4. Conclusion 42
