Psoriasis Therapy with Hyaluronic Acid Nanoparticles and Peripheral CB1R Antagonists
- 주제(키워드) Psoriasis , hyaluronic acid nanoparticles , CB1R antagonists
- 주제(DDC) 547
- 발행기관 아주대학교 일반대학원
- 지도교수 김은하
- 발행년도 2026
- 학위수여년월 2026. 2
- 학위명 석사
- 학과 및 전공 일반대학원 분자과학기술학과
- 실제URI http://www.dcollection.net/handler/ajou/000000035756
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Psoriasis is a chronic relapsing inflammatory skin disease, and current topical agents and cytokine-targeted biologics remain limited by relapse, safety concerns, and cost, underscoring the need for peripherally acting therapies that directly modulate lesional immune cells. Here, we describe two complementary chemistry- based strategies built around hyaluronic acid nanoparticles (HANPs) and cannabinoid receptor 1 (CB1R) antagonists. Hydrophobic modification of hyaluronic acid with bile acid–type moieties afforded self-assembled HANPs, and systematic variation of conjugate structure, substitution level, and polymer molecular weight identified small, stable nanoparticles that preferentially accumulated in psoriasiform skin and attenuated epidermal hyperplasia and inflammatory readouts. In parallel, structure-based virtual screening and hit optimization yielded urea-linked CB1R antagonists with high CB1 potency, CB1- over-CB2 functional selectivity, and physicochemical properties consistent with reduced central nervous system exposure; selected analogues improved psoriasis- like inflammation in an imiquimod-induced mouse model. Together, these HANPs and CB1R antagonists exemplify nanoscale and small-molecule approaches for peripherally oriented control of psoriatic inflammation and provide a basis for future psoriasis therapies beyond conventional systemic biologics. [Keywords: psoriasis, hyaluronic acid nanoparticles, CB1R antagonists]
more목차
1. Introduction 1
1.1 Psoriasis as a chronic immune-mediated skin disease. 1
1.2 Current therapies and unmet needs. 2
1.3 Innate immune cells in psoriatic lesions and targetable receptors. 4
1.4 A new approach to overcome current psoriasis therapy. 4
1.5 HA-based self-assembled nanoparticles as a tunable topical platform. 5
1.6 Cannabinoid Receptor 1 as a target for peripheral inflammatory modulation. 7
1.7 Evolution of CB1R antagonists and rationale for peripheral-selective design. 8
1.8 Overall objective and specific aims of this thesis. 9
2. Results and Discussion 11
2.1 Optimization strategy for HANPs. 11
2.2 Physicochemical characterization of optimized HANPs. 15
2.3 Biological activity of HANPs in vitro. 18
2.4 Anti-psoriatic efficacy of HANPs in vivo. 20
2.5 Transdermal penetration of size-tuned HALN nanoparticles. 26
2.6 Structure–property analysis of bile-acid–modified HANPs. 28
2.7 Virtual screening–driven discovery of compound 1 and analogue expansion to compounds 2– 8. 31
2.8 In vitro CB1/CB2 binding and structural analysis of compounds 1– 8. 34
2.9 In vivo assessment of central CB1R engagement: hypothermia and catalepsy. 35
2.10 In vivo efficacy of CB1R antagonists in IMQ-induced psoriasis-like dermatitis. 37
2.11 Structure-based analysis of CB1R binding modes of compounds 3 and 8. 40
2.12 Structure-guided design of second-generation analogues targeting the Arm 2 hydrophobic pocket. 43
2.13 Functional profiling of second-generation analogues and confirmation of peripheral selectivity. 46
2.14 In vivo CNS liability of second-generation analogues: WIN-induced hypothermia and catalepsy. 47
2.15 Overall structure–activity relationships of urea-type CB1R antagonists. 49
3. Conclusion 54
4. Experimental Section. 55
4.1 General information. 55
4.2 Synthetic procedure of HANPs. 56
4.3 Synthetic procedure of CB1R antagonists. 63
5. References 79
6. Analytical results 81
6.1 DLS result of HANPs 81
6.2 1H NMR and 13C NMR spectra of HANPs. 83
6.3 1H NMR and 13C NMR spectra of CB1R antagonists. 94
6.4 Docking pose of compound 1, 3, 7 and 8. 111
