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研究生：	莊子玄 Chuang, Tzu-Hsuan
論文名稱：	發展同時搭載鐵鉑奈米粒子和丙酮特安皮質醇的新型藥物傳遞系統並評估在蟹足腫上的協同治療效果 To develop a novel drug delivery system to carry both FePt nanoparticles and Triamcinolone acetonide and evaluate the synergistic effect of keloid treatment
指導教授：	吳炳慶 Wu, Ping-Ching
學位類別：	碩士 Master
系所名稱：	工學院 - 生物醫學工程學系 Department of BioMedical Engineering
論文出版年：	2020
畢業學年度：	108
語文別：	英文
論文頁數：	79
中文關鍵詞：	蟹足腫細胞、鐵鉑奈米粒子、輻射療法、輻射增敏劑、聚乳酸-甘醇酸共聚物、滲透和留滯作用、丙酮特安皮質醇、協同作用
外文關鍵詞：	Keloid fibroblast(KF), iron-platinum nanoparticles (FePt NPs), radiation therapy, radiation sensitizer, poly(lactic-co-glycolic acid)PLGA, permeability and retention (EPR) effect, triamcinolone acetonide(TAC), synergistic-function
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蟹足腫是一種由於傷口癒合不正常而引起的纖維化增生。其疤痕會生長超過原始傷口的範圍，不斷生長，很少隨時間消退，並且其在有色個體中最常見。雖然它是良性的，沒有惡性潛能，但是蟹足腫造成的外觀毀損會給病人相當大的身心不利影響。當前，仍然沒有能夠立即、完全和永久去除蟹足腫並恢復皮膚功能的治療方法。臨床上存在多種治療蟹足腫的方法，但這些方法都有其自身的優劣勢；然而，副作用和經常復發的風險仍然很高。因此，現今研究主要專注於改善原有的蟹足腫的治療方法或尋找新藥物。
近年來，奈米材料的發展已大大改善了臨床應用中的診斷和治療。鐵鉑奈米粒子（FePt NPs）已被開發用於生物醫學應用中，因為它具有超順磁性，抗氧化性和極高化學穩定性等優異特性。而鐵鉑奈米粒子的高原子序數（Z）金屬性能讓它在X射線的放射線照射下，可作為臨床具有潛能的輻射增敏劑。另外，聚乳酸-甘醇酸共聚物（PLGA）對人體具有非常低的毒性，可以應用於生物醫學中的奈米藥物傳輸載體。而其奈米尺寸的聚乳酸-甘醇酸共聚物作為載體可以通過高強度的滲透和留滯作用（EPR），迅速在組織內擴散和積累。具體而言，我們打算借助奈米的藥物遞送功能，徹底改變蟹足腫是治療策略。
這項研究的目的是利用聚乳酸-甘醇酸共聚物（PLGA）做為奈米藥物載體同時搭載第一線臨床類固醇藥物丙酮特安皮質醇（TAC）和輻射增敏劑鐵鉑金屬粒子，並測試其在蟹足腫上的治療效果。我們認為輻射增敏的鐵鉑奈米粒子可以增強放射治療的功效，而皮質類固醇，丙酮特安皮質醇，可以抑制蟹足腫細胞的發炎環境。因此，FePt-PLGA-TAC NPs將有機會是減少藥物劑量和並發症發生率的理想策略。
在這項研究中，我們首先證明了在顯微鏡下，FePt-PLGA-TAC NPs形成了均勻而圓形的顆粒。粒子的大小為219.7±50.8 nm，表面電位為-24.38 ± 0.85 mV。TAC的包覆效率為63.75 ± 0.50 ％，高於先前的PLGA-TAC NPs。而在蟹足腫細胞中的測試中，
FePt-PLGA-TAC NPs的放射增敏作用，使其中細胞存活率在72 h時降至10 ％，並顯著喪失了增殖能力。我們還觀察到，我們的FePt-PLGA-TAC NPs結合低輻射劑量，具有通過FePt NPs和TAC藥物之間的協同功能調節炎症反應的良好能力。重要的是，在奈米藥物的處理下，作為蟹足腫細胞中的I型膠原蛋白標誌其表現量也明顯下降。由於目前缺乏合適的動物模型，我們尚不能在動物層級上驗證FePt-PLGA-TAC NPs在蟹足腫治療上的功效。然而，從上述的細胞實驗結果，FePt-PLGA-TAC NPs將來依舊有潛力作為蟹足腫治療的藥物。

Keloids are the fibroproliferative disorders of the skin that result from an abnormal wound healing response. Keloids can grow beyond the original borders of the wound, continue to grow, rarely regress, and are the most common in pigmented individuals. Although benign and with no malignant potential, disfigurement from keloids leads to considerable physical and psychological adverse effects. Currently, there are still no specific therapeutics that can instantly, completely, and permanently remove keloids and restore the function of the skin. A wide range of therapeutic options exist for the treatment of keloids, all of which have their strengths; however, a high risk of side-effects and frequent recurrence remains. Therefore, the present study aimed to identify improved therapeutic approaches to drugs for the treatment of keloids.
In recent years, the development of nanomaterials has substantially improved diagnosis and treatment in clinical applications. Iron-platinum nanoparticles (FePt NPs) have been developed in biomedical applications due to their superior characteristics, including super-paramagnetism, resistance to oxidation, and high chemical stability. The high atomic number (Z) metallic property of FePt NPs under X-ray based radiotherapy beams can be a potential radiation sensitizer in clinical applications. Additionally, poly(lactic-co-glycolic acid) (PLGA) as a nanocarrier is considered to produce minimal systemic toxicity when used for biomedical applications. Owing to the nano-size, PLGA NPs as a carrier can rapidly spread and accumulate within tissues through the enhanced permeability and retention (EPR) effect. Specifically, we intend to revolutionize the strategy of keloid treatment through the use of advance of the nano-based drug delivery features.
The purpose of this study is to develop a synergistic-functional FePt polymer nanoparticle with first-line steroid drug Triamcinolone acetonide (TAC) with the poly lactic-co-glycolic acid (PLGA). We assume that radiation-sensitive FePt NPs can enhance the efficacy of radiation therapy and that corticosteroid TAC can inhibit the inflammatory environment of keloid fibroblasts(KF). Thus, FePt-PLGA-TAC NPs might be an ideal strategy to reduce the prescribed dose and the incidence of complications.
In this study, we first demonstrated that FePt-PLGA-TAC NPs formed uniform and round particles under the microscope. The particles were 219.7 ± 50.8 nm in size, and the zeta potential was -24.38 ± 0.85 mV. The encapsulation efficiency of TAC was 63.75 ± 0.50 %, which is greater than that of other common PLGA NPs. A test in KF cells using FePt-PLGA-TAC NPs enhanced the radio-sensitizing effects on KF, whose of cell viability was lowered to 10 % at 72 h, and dramatically decreased the proliferative ability. We also observed that our FePt-PLGA-TAC NPs combined with low radiation dosage had better ability to regulate the inflammatory reaction due to the synergistic function between FePt NPs and TAC drugs. Importantly, the hallmark of collagen type I expression in keloids was also expressed lower under the NPs treatment. Due to the absence of a suitable animal model, we still cannot prove the efficacy of FePt-PLGA-TAC NPs in keloid therapy. However, from these cell studies, we expect that FePt-PLGA-TAC NPs will be a promising agent for keloid treatment in the future.

Content
摘要	I
Abstract	III
致謝	V
Content	VII
List of tables	X
List of figures	X
Chapter 1 Introduction	1
1.	The current problem of keloid treatment	1
1.1	Definition of Keloid Scar	1
1.2	Normal wound healing and scar formation	1
1.3	The pathogenesis of keloid	2
1.3.1	The TGF-β ⁄Smad signaling pathway	2
1.3.2	The IL-6 signaling pathway	3
1.3.3	The NF-κß signaling pathway	3
1.3.4	The Extracellular matrix(ECM)	4
1.4	The Problem of Clinical Treatment	4
1.4.1 Steroid therapy in keloid disease	5
1.4.2	Radiation therapy for keloid	5
1.5	The main limitation of therapeutic development of Keloid	6
1.6	Radiation therapy	7
1.6.1	Radiosensitizers	7
1.6.2	FePt nanoparticles	8
1.7	Polymeric nanoparticles delivery system	8
1.7.1	Drug delivery system	8
1.7.2	PLGA nanoparticle	9
1.8	Specific aims	9
Chapter 2 Materials and Methods	11
2.1	Material	11
2.2	Preparation of 12 nm FePt nanoparticles	12
2.3	Ligand Exchange of FePt nanoparticles	12
2.4	Preparation of the TAC loaded into PLGA nanoparticles	12
2.5	Determination of the content of TAC in PLGA nanoparticles	13
2.6	TAC release from PLGA nanoparticles	13
2.7	Preparation of the FePt-conjugated PLGA containing TAC	14
2.8	The physicochemical properties of the nanoparticles	14
2.8.1 The morphology and particle size of the nanoparticles	14
2.8.2	Zeta potential and Fourier transform infrared (FT-IR) spectrometry	15
2.9	Cell Culture	15
2.9.1	Fibroblasts Primary Cell Culture	15
2.9.2	The Cell Count	16
2.10	Preparation of Rhodamine B-Loaded Nanoparticles	16
2.11	Cellular uptake of RhB-loaded PLGA NPs	17
2.12	Cell viability assay	17
2.13	Electronic beam irradiation	17
2.14	Immunocytochemistry to detect Ki67 in the KF	18
2.15	Total ROS measurement in KF	18
2.16	Immunocytochemistry to detect nuclear factor kappa B (NF-κB) activation in KF…	19
2.17	Quantitative Determination of the mRNA expression in Collagen I of KF	20
2.18	Keloid explants are embedded in the collagen matrix	20
2.19	Apoptosis and Ki-67 Detection on Ex-vivo model by Immunohistochemistry..	21
2.20	Data Analysis and Statistical Evaluation	21
Chapter 3 Results	22
3.1	Synthesis and characterization of the FePt-PLGA-TAC NPs	22
3.1.1	Synthesis and characterization of the FePt NPs	22
3.1.2	The size and shape of the distributions	22
3.1.3	The zeta potential and the FTIR spectra	22
3.2	Determination of TAC concentrations and drug release in FePt-PLGA-TAC NPs…	23
3.3	KF demonstrated cancel-like characteristic and resistance to radiotherapy compared to NF	24
3.4	The cytotoxicity of PLGA-TAC NPs	24
3.5	FePt-PLGA-TAC NPs enhanced the radiation sensitivity in KF	25
3.6	FePt-PLGA-TAC NPs influence the proliferation and cell number of KF	26
3.7	FePt-PLGA-TAC NPs regulate ROS in KF	27
3.8	FePt-PLGA-TAC NPs regulate inflammation in the KF	27
3.9	FePt-PLGA-TAC NPs had negative effects on collagen type I expression in KFs…	28
3.10	Ex vivo organ culturing of Keloid	28
Chapter 4 Discussion	30
4.1	Characterization of the FePt-PLGA-TAC NPs	30
4.2	The Cancer-like properties and radiation resistance in KF	31
4.3	FePt-PLGA-TAC NPs enhanced the radiation sensitivity in KFs	32
4.4	FePt-PLGA-TAC NPs regulate the ROS and inflammation in KF.	33
4.5	FePt-PLGA-TAC NPs reduce collagen production.	34
4.6	The challenge of achieving long-term culture of Keloid organ models	34
Chapter 5 Conclusion	36
Reference	72

List of tables
Table 1. Characteristics of keloids scars[3-6].	39
Table 2. Characterization of nanoparticle	40
Table 3: Characteristics of the individuals used in this study.	41

List of figures
Figure 1. Typical keloid scars.	42
Figure 2. The process of normal wound healing.	42
Figure 3.Scheme for keloid pathogenesis and possible mechanisms.	43
Figure 4. Schematic illustration of the interaction between nanoparticles and ionizing radiation. ROS: reactive oxygen species[55].	43
Figure 5: Schematic illustration of mechanism of synergistic-functional FePt-PLGA-TAC NPs for keloid treatment.	44
Figure 6. Polyol reduction method for the synthesis of FePt-Cys NPs.	44
Figure 7: Emulsion-evaporation method for synthesis of PLGA-TAC NPs.	45
Figure 8. The way to synthesize synergistic-functional FePt-PLGA-TAC NPs.	45
Figure 9. A flow chart for the preparation of primary cell cultures.	46
Figure 10: Schematic representation of the keloid explant culture.	47
Figure 11. The morphology and solubility test of FePt NPs.	48
Figure 12. TEM photomicrograph of (A) empty PLGA nanoparticles (B) PLGA-TAC nanoparticles (C) unmodified FePt nanoparticles (D)FePt-PLGA-TAC nanoparticles.	49
Figure 13. Particle size distribution of FePt-PLGA-TAC NPs was measured by DLS.	50
Figure 14. The surface charge of FePt-PLGA-TAC NPs was determined by zeta potential.	51
Figure 15: FTIR transmittance spectrum of (A) FePt-PLGA-TAC NPs (B) FePt-Cys NPs and (C) empty PLGA only NPs, full wave number from 400-4000 cm-1.	51
Figure 16. The Encapsulating rate of TAC in PLGA-TAC NPs.	52
Figure 17. In vitro drug release profiles of TAC from PLGA-TAC NPs.	53
Figure 18. Uptake kinetics of RhB-loaded PLGA NPs in NskinF and KF.	55
Figure 19. The resistance of ionizing radiation to NskinF、sNskinF and KF.	56
Figure 20. The cytotoxicity of PLGA-TAC NPs and TAC alone in NskinF、sNskinF and KF.	57
Figure 21. The cytotoxicity of FePt-PLGA NPs under radiation in sNskinF and KF.	58
Figure 22: FePt-PLGA-TAC NPs enhanced radio sensitization of KF.	59
Figure 23: Effects of FePt-PLGA-TAC NPs on KF with several doses of irradiation in reducing cell viability over time.	60
Figure 24 Effects of FePt-PLGA-TAC NPs with radiation on viable cell numbers at direct cell counting in KF over time.	61
Figure 25. Effects of FePt-PLGA-TAC NPs with radiation on Ki-67 immunofluorescence staining in KF cells.	62
Figure 26. The quantification of ROS generation over time.	64
Figure 27. Effects of FePt-PLGA-TAC NPs with radiation on inhibition of NF-κB activation in KF cells.	65
Figure 28. Immunofluorescence analysis of collagen type I at Day 7 post FePt-PLGA-TAC NPs with radiation treatment.	67
Figure 29.Quantitative real-time PCR measurments of collagen I mRNA expression levels at 72 h post treatment with FePt-PLGA-TAC NPs with radiation treatment group	69
Figure 30: Cell apoptosis using the TUNNEL assay of the Keloid ex-vivo model	70
Figure 31: Cell proliferation using the Ki-67 marker of Keloid in an ex-vivo model	70
Figure 32. Risk factors of keloid and the mechanism of the synergistic-functional FePt-PLGA-TAC NPs for keloid treatment.	71



                                    

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