Development of Novel Crosslinked Polymeric Materials for Drug Delivery System
- Abstract
- Crosslinked polymeric materials such as micelles and hydrogels are widely studied in the development of a drug delivery system with high efficacy. The behavior of the materials in delivering drug molecules under physiological conditions could be governed by finely designing the chemical structures of the crosslinkers.
In this dissertation, on-demand drug delivery systems were developed by employing novel crosslinked polymeric materials. The study covers several cases as follows:
- Systematic investigation to the effects of near-infrared light exposure on polymeric micelles of poly(ethylene glycol)-block-poly(styrene-alt-maleic anhydride) loaded with indocyanine green.
- Diselenide core cross-linked micelles of poly(ethylene oxide)-b-poly(glycidyl methacrylate) prepared through alkyne-azide click chemistry as a near-infrared controlled drug delivery system.
- Tunable porosity of covalently crosslinked alginate-based hydrogels and its significance in drug release behavior.
The covalent bond between polymer backbones and the crosslinkers were proceeded via “click chemistry” reactions such as Diels-Alder, alkyne-azide, and norbonene-tetrazine. These types of reactions were selected owing to their simple and facile process. As for the polymers, the biocompatibility aspect was considered; thus the following polymers were employed: poly(ethylene glycol)-block-poly(styrene-alt-maleic anhydride) (PEG-b-PSMA), poly(ethylene oxide)-block-poly(glycidyl methacrylate) (PEO-b-PGMA), and a carbohydrate-based natural polymer i.e. alginate. In the first study, fundamental aspects governing drug release behavior in polymeric micelles were investigated i.e. the cleavage of crosslinker and the degradation of the polymer chain. In the second study, a release responsive drug delivery system was developed. The release of drug from its carrier could be effectively controlled using near-infrared (NIR) light as a safe and non-invasive technique. In the third study, alginate-based hydrogel was developed for a specific targeted drug delivery system. Fundamental factors affecting drug release behavior were investigated systematically as well as the potential for long and steady therapy.
Several analysis and characterization techniques were used in this dissertation which is proton nuclear magnetic resonance (1H NMR) spectroscopy, Fourier transforms infrared (FTIR) spectroscopy, ultraviolet-visible (UV-Vis) spectroscopy, dynamic light scattering (DLS), gel permeation chromatography (GPC), scanning electron microscopy (SEM), and transmission electron microscopy (TEM).
In conclusion, the studies demonstrated that in preparing polymer-based drug delivery materials, crosslinkers played an essential role. NIR-light responsive micelles of PEG-b-PSMA and PEO-b-PGMA were successfully prepared using diselenide (Se-Se) crosslinkers. In case of hydrogels, the morphology was governed by the type and amount of crosslinkers. Alginate-norbonene crosslinked by disulfide-tetrazine resulted in a porous structure hydrogel, while alginate-furfuryl amine crosslinked by disulfide-maleimide resulted in non-porous hydrogels. In addition, the degradation of the polymer chain itself should be taken into account. The systematic investigation showed that the hydrophilic part of the PEG-b-PSMA and PEO-b-PGMA underwent a slow degradation under NIR light irradiation in the presence of indocyanine green. Likewise, the alginate polymer chain was also seemed to self-degraded over immersion in buffer solution for more than 30 days.
마이셀, 하이드로겔 등 가교결합 고분자 물질은 효능이 높은 약물전달 시스템 개발에 폭넓게 연구되고 있다. 생리학적 조건 하에서 약물 분자를 전달할 때 물질의 거동은 가교제의 화학적 구조를 정교하게 설계함으로써 통제될 수 있다.
본 논문에서는 새로운 가교구조 고분자 소재를 차용하여 온디맨드 약물 전달 시스템을 개발하였다.
본 연구는 다음과 같은 몇 가지 경우를 다룬다.
- Indocyanine green 을 탑재한 poly(ethylene glycol)-block-poly(styrene-alt-maleic anhydride)의 고분자 마이셀에 근적외선 광 조사가 미치는 영향에 대한 체계적인 조사
- alkyne-azide click chemistry 를 통해 준비된 poly(ethylene oxide)-b-poly(glycidyl methacrylate)의 근적외선 제어 약물전달 시스템으로 제조된 Diselenide core cross-linked 마이셀
- 공유결합된 알지네이트 기반 하이드로겔의 조절 가능한 다공성 및 약물 방출 거동에 대한 중요성
선형 고분자 구조와 가교제 사이의 공유결합은 Diels-Alder, alkyne-azide, norbonene-tetrazine 등의 “click chemistry” 반응을 통해 진행되었다. 이러한 종류의 반응은 간단하고 쉬운 과정 때문에 선택되었다.
고분자의 경우 생체적합성 측면을 고려하여,
Poly(ethylene glycol)-block-poly(styrene-alt-maleic anhydride) (PEG-b-PSMA), Poly(ethylene oxide)-block-poly(glycidyl methacrylate) (PEO-b-PGMA), 알지네이트와 같은 탄수화물 기반 천연 고분자들이 차용되었다. 첫 번째 연구에서는 고분자 마이셀의 약물 방출 거동을 결정하는 근본적인 측면, 즉 가교제의 분해와 고분자 사슬의 분해를 연구했다. 두 번째 연구에서는, 방출 응답 약물 전달 시스템이 개발되었다. 캐리어로부터의 약물의 방출은 안전하고 비침습적인 기술로 근적외선(NIR) 빛을 사용하여 효과적으로 제어할 수 있다. 세 번째 연구에서는 특정 표적 약물 전달 시스템을 위해 알지네이트 기반 하이드로겔이 개발되었다. 약물 방출 행동에 영향을 미치는 근본적인 요인과 장기적이고 꾸준한 치료 가능성을 체계적으로 조사하였다.
양성자 핵자기공명(1H NMR) 분광학, 푸리에 변환 적외선(FTIR) 분광학, 자외선-가시성(UV-Vis) 분광학, 동적광 산란(DLS), 젤 투과 크로마토그래피(GPC), 주사전자 현미경(SEM), 투과전자 현미경(TEM) 등 여러 분석 및 특성화 기법이 본 논문에서 사용되었다.
결론적으로, 그 연구는 폴리머 기반의 약물 전달 물질을 준비하는 데 있어서 가교제가 필수적인 역할을 했다는 것을 증명했다. PEG-b-PSMA와 PEO-b-PGMA의 NIR 광 응답 마이셀은 Diselenide (Se-Se) 크로스링커를 사용하여 성공적으로 준비되었다. 하이드로겔의 경우, 표면 형태는 가교제의 종류와 양에 의해 결정되었다. Disulfide-tetrazine에 의한 Alginate-norbonene 가교결합이 다공성 구조 하이드로겔을, Disulfide-maleimide에 의한 Alginate-furfuryl amine 가교결합이 비다공성 하이드로겔을 형성시켰다. 또한 고분자 사슬 자체의 분해도 고려해야 한다. 체계적 조사 결과 PEG-b-PSMA와 PEO-b-PGMA의 친수성 부위는 Indocyanine green이 존재하는 상태에서 NIR 광 조사로 느린 성능 저하를 나타냈다. 마찬가지로, 완충용액에 30일 이상 액침된 알지네이트 고분자 사슬도 자가 분해되는 것으로 판단된다.
- Issued Date
- 2021
- Awarded Date
- 2021. 2
- Type
- Dissertation
- Publisher
- 부경대학교
- Affiliation
- Pukyong National University Graduate School
- Department
- 대학원 융합디스플레이공학과
- Advisor
- Kwon Taek Lim
- Table Of Contents
- Chapter 1: General Introduction 1
1.1. Polymeric Materials in Drug Delivery System 1
Figure 1. Various delivery strategies in drug delivery system [4]. 2
1.1.1. Polymeric Micelles 2
Figure 2. (a) typical micelle [6] and (b) polymeric micelle structure [7]. 3
1.1.2. Hydrogels 4
Figure 3. Multistage structure of hydrogels [4]. 4
1.2. Crosslinking Polymeric Materials 5
1.2.1. Click Chemistry reactions 6
Figure 4. Reactions which match with click chemistry criteria [17]. 7
1.2.2. On-demand Cleavage of Crosslinkers 7
Chapter 2: Systematic Investigation to The Effects of Near-Infrared Light Exposure on Polymeric Micelles of Poly(Ethylene Glycol)-Block-Poly(Stryene-Alt-Maleic Anhydride) Loaded With Indocyanine Green 9
2.1. Introduction 9
2.2. Experiment 13
Scheme 1. Synthesis of block copolymer PEG-b-PSMF, diselenide-containing crosslinker, and PEG-b-PSMF CCL micelles. 18
2.3. Results and Discussion 21
Figure 5. ESI-MS spectra of 3,3′-diselanediyldipropionic acid. 21
Figure 6. 1H NMR of (a) PEG-b-PSMF block copolymer, (b) CCL, (c) Non-CCL micelles in D2O. The asterisk symbol (*) represents the solvent peaks. 22
Figure 7. UV-Vis spectra of Free ICG, CCL micelles/ICG and Non-CCL micelles/ICG. 24
Figure 8. DLS profile of (a) CCL Micelles and (b) Non-CCL micelles before and after NIR exposure. 25
Figure 9. Effect of NIR exposure to temperature change 26
Figure 10. UV-Vis spectra of Non-CCL micelles/ICG after NIR and DCM extracted solution. 27
Figure 11. GPC chromatogram of (a) PEG-b-PSMF before and after NIR exposure, and (b) PEG 5 kDa before and after NIR exposure, inset is degradation profile of PEG as a function of time after NIR exposure. 28
Figure 12. FTIR spectra of PEG-b-PSMF (a) before the NIR exposure, (b) 12 h, (c) 36 h, (d) 72 h, (e) 120 h after NIR exposure. 30
Figure 13. 1H NMR spectra of (a) small esters and (b) amides before and after NIR exposure in the presence of ICG. 31
Figure 14. TEM images of CCL Micelles and Non-CCL micelles (a,d) before NIR, 32
(b,e) 6h after NIR, and (d,f) 36h after NIR, respectively. 32
Figure 15. Schematic illustration on the effect of NIR exposure to CCL and Non-CCL micelles loaded with ICG. 33
2.4. Conclusion 34
Chapter 3: Diselenide Core Cross-Linked Micelles of Poly(Ethylene Oxide)-B-Poly (Glycidyl Methacrylate) Prepared Through Alkyne-Acide Click Chemistry As a Near-Infrared Controlled Drug Delivery System 35
3.1. Introduction 35
Scheme 2. Near-infrared (NIR)-controlled drug release. 37
3.2. Experiment 38
3.3. Results and Discussion 44
Scheme 3. Preparation of diselenide CCL micelles. 45
Figure 16. 1H NMR (top) and 13C NMR (bottom) of diselenide cross-linker. 46
Figure 17. GPC chromatogram of PEO-Br, PEO-b-PGMA and PEO-b-PGMA-N3. 47
Figure 18. FTIR spectra of (a) PEO, (b) PEO-Br macroinitiator, (c) PEO-b-PGMA block copolymer (d) PEO-b-PGMA-N3, and (e) CCL micelles of PEO-b-PGMA. 48
Figure 19. 1H NMR of (a) PEO-Br macroinitiator, (b) PEO-b-PGMA block copolymer, (c) PEO-b-PGMA-N3, and (d) diselenide CCL micelle of PEO-b-PGMA. 50
Figure 20. A graph of fluorescence intensity ratio versus polymer solution concentrations to determine the critical micelles concentration (CMC). 51
Figure 21. TEM images of (a) non-CCL micelles and (b) CCL micelles. 52
A. 52
Figure 22. The hydrodynamic diameter of CCL micelles and non-CCL micelles measured using DLS. 53
Figure 23. Profiles of temperature alteration of PBS, free ICG, CCL micelles, and CCL/ICG micelles as exposed by NIR light. 54
Figure 24. DOX release profile (cumulative) from CCL/ICG/DOX micelles with and without NIR irradiation in pH of 7.4 and 5. 55
3.4. Conclusion 56
Chapter 4: Tunable Porosity of Covalently Crosslinked Alginate-Based Hydrogels and Its Significance in Drug Release Behavior 57
4.1. Introduction 57
4.2. Experiment 61
Scheme 4. Preparation of hydrogel A and hydrogel B 62
Figure 25. (a) 1H-NMR and (b) 13C-NMR of Tz-acid; (c) 1H-NMR and (d) 13C-NMR of 4-AM-GA 64
Figure 26. Gelation process of (a) hydrogels A1, A2, A3, and A4, as well as (b) hydrogels B1 and B4 66
Table 1. Feed ratio and gelation time of the hydrogel samples. 68
4.3. Results and Discussion 69
Figure 27. 1H-NMR spectra of the crosslinkers (a) disulfide-tetrazine (S-Tz) and (b) disulfide-maleimide (S-Ma) 70
Figure 28. 1H-NMR spectra of the alginate precursor (Alg), alginate-norbornene (Alg-Nb), and alginate-furfuryl amine (Alg-FA) 72
Figure 29. FTIR spectra of alginate, Alg-Nb, Alg-FA, hydrogel A, and hydrogel B 73
Figure 30. SEM images of hydrogels A1, A2, A3, and A4 (cross-sectional view) 74
Figure 31. SEM images of the surface of hydrogels A1, A2, A3, and A4 75
Figure 32. Photograph of hydrogel A containing N2 bubbles 75
Figure 33. SEM images of hydrogels A1, A4, B1, and B4 in micro (top images, 50 µm) and sub-micro (bottom images, 2 µm) scales 77
Figure 34. Photograph of hydrogels A1, A4, and B1 during drug release measurements 78
Table 2. Drug loading capacity and drug release of the hydrogels after 10 days. 79
Figure 35. Cumulative DOX release profiles of alginate hydrogels (a) within 10 days and (b) after the addition of DTT (A1, A4 and B1) and (c) over 35 days without the addition of DTT (A1 and A4); error bars represent standard deviation 82
4.4. Conclusion 83
Chapter 5: Conclusions 84
5.1. Summary 84
5.2. Outlook 87
References 88
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