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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78321完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 沈麗娟(Li-Jiuan Shen) | |
| dc.contributor.author | Shan-Yuan Fu | en |
| dc.contributor.author | 傅善圓 | zh_TW |
| dc.date.accessioned | 2021-07-11T14:51:06Z | - |
| dc.date.available | 2025-08-10 | |
| dc.date.copyright | 2020-09-10 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-04 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78321 | - |
| dc.description.abstract | 發炎性腸道疾病(inflammatory bowel disease, IBD)是一種持續性及反覆性的腸胃道發炎疾病，由於罹病率與發生率逐年上升、病人生活品質低，且需終生服藥，使發炎性腸道疾病亟需被重視。與發炎相關細胞素如腫瘤壞死因子-α(tumor necrosis factor, TNF-α)是由浸潤至固有層(lamina propria)的免疫細胞分泌，並於發炎性腸道疾病中扮演重要的角色。英利昔單抗(infliximab, IFX) 是第一個被食品藥物管理局(Food and Drug Administration, FDA)核准用於治療發炎性腸道疾病的抗TNF-α單株抗體，在臨床試驗中顯示其有效性。然而，由於需經由血管給藥，而產生的安全的疑慮需被考量，如增加病人感染風險、腫瘤風險、輸注時之反應等。以口服方式給予IFX似乎較佳，然而腸道生理障蔽將可能阻擋局部遞送至IBD病灶。肝素結合凝血附著素c (heparin-binding haemagglutinin adhesin C, HBHAc)在過去的研究中指出可協助大分子藥物胞內與穿胞遞送之載體。因此本研究欲探討HBHAc是否能夠增加IFX於腸道生理障蔽的穿透效果。 以兩步驟化學合成方式將HBHAc與IFX鍵結(IFX-HBHAc)，第一步驟反應為3-(2-吡啶基二硫代)丙酸N-羥基琥珀醯亞胺酯(succinimidyl 3-(2-pyridyldithio) propionate, SPDP)上的N-羥基琥珀醯亞胺酯基團(N-hydroxysuccinimide, NHS)與IFX上的一級胺反應，而第二步驟為經半胱氨酸修飾的HBHAc取代IFX-SPDP上的2-吡啶基二硫代(2-pyridyldithio)基團。IFX-HBHAc 被合成並有1.6與2.6個HBHAc修飾的IFX(IFX-HBHAc(1.6)與IFX-HBHAc(2.6))，IFX-HBHAc(1.6)與IFX-HBHAc(2.6)中和TNF-α的活性(TNF-α neutralizing activity)與未修飾的IFX相比，保留了78.3% ± 22.9% 以及 79.6% ± 14.9%。化學鍵結反應所產生的混和物以粒徑篩析層析法(size exclusion chromatography, SEC)純化。螢光異硫氰酸鹽(fluorescein isothiocyanate, FITC)先鍵結於IFX再合成出經FITC修飾之IFX-HBHAc以進行內吞與穿胞實驗，相同莫耳濃度的經FITC修飾之IFX-HBHAc與IFX具有相似的任意螢光強度。以人類結腸腺癌細胞Caco-2細胞進行細胞內吞實驗，在劑量依賴性細胞內吞實驗(dose-dependent cellular uptake study)中，將FITC標定的IFX與IFX-HBHAc以10至100 nM的濃度給藥一小時；在時間依賴性細胞內吞實驗(time-dependent cellular uptake study)中，Caco-2細胞與濃度30 nM 的經FITC標定IFX與IFX-HBHAc培養1-4小時。與IFX相比，IFX-HBHAc具較高的細胞內吞量，且呈現劑量與時間依賴性。以Caco-2細胞建構的transwell system可以用來評估藥物的穿胞能力，經培養14-21天後，transwell system的跨上皮電阻值(transepithelial electrical resistance)皆可到達900 Ω*cm2以上，以模擬體外腸道生理障蔽。將經FITC 標定的抗體加入上室並計算下室累計螢光強度(accumulated fluorescence intensity)，經過穿胞試驗6小時後，IFX-HBHAc的累計螢光強度隨時間增加有上升的趨勢且穿過至下室的螢光比例為34.8 ± 5.4 %，另於穿胞試驗24小時後，經8倍濃縮下室培養基以酵素免疫測定法(enzyme-linked immunosorbent assay)測定濃度，IFX-HBHAc(1.6)與IFX-HBHAc(2.6)組別所測到的濃度相較IFX組別高出2.5與3.2倍。除此之外，經過穿胞試驗24小時後，評估經4.5倍濃縮下室培養基的中和TNF-α的活性，IFX-HBHAc(1.6)與IFX-HBHAc(2.6)的細胞存活率顯著高於沒有給予抗體的組別(36.6 ± 4.2 %與38.4 ± 6.1 % v.s. 27.7 ± 2.5 %, p<0.001)，顯示其保留了中和TNF-α的活性。 在本研究中，具有中和TNF-α活性的IFX-HBHAc成功以化學鍵結方式形成與純化，在體外試驗中，HBHAc可將IFX送入腸道上皮細胞以及穿過腸道障壁，穿過後亦保有中和TNF-α的活性。這些結果顯示HBHAc具有協助單株抗體藥物克服腸道生理障蔽的潛力，當治療性單株抗體藥物應用於IBD的口服遞送時，應在動物中有進一步的研究。 | zh_TW |
| dc.description.abstract | Inflammatory bowel disease (IBD) is characterized by chronic and relapsing inflammation in gastrointestinal (GI) tract. The rising prevalence and incidence rate, low quality of life, and life-long treatment drive the burden of IBD. Inflammatory-related cytokines such as tumor necrosis factor-α (TNF-α) are produced by immune cells invading to laminar propria and play an important role in IBD. Infliximab (IFX) is the first anti-TNF-α monoclonal antibody approved from FDA to treat IBD and showed efficacy in clinical trials. However, due to the intravascular administration, the safety issue such as increased risk of infection, malignancy, and infusion reaction should be concerned. Oral administration seems a more favorable pathway to deliver IFX, while the physiological intestinal barrier would hinder the local delivery to IBD diseased tissues. HBHAc has shown the potential to be a macromolecular carrier for intracellular and transcytosis delivery in the previous studies. Thus, we would like to test if HBHAc can enhance the permeability of IFX through the intestinal barrier. HBHAc modified IFX (IFX-HBHAc) was synthesized with two steps chemical conjugation. Step 1 reaction is that the N-hydroxysuccinimide ester group on succinimidyl 3-(2-pyridyldithio) propionate (SPDP) conjugated to the primary amino group on IFX. Step 2 reaction is that the 2-pyridyldithio (P2S) group on IFX-SPDP was displaced by cysteine-modified HBHAc. IFX-HBHAc was synthesized with 1.6 and 2.6 HBHAc modification (IFX-HBHAc(1.6) and IFX-HBHAc(2.6)). The TNF-α neutralizing activity of IFX-HBHAc(1.6) and IFX-HBHAc(2.6) reserved 78.3% ± 22.9% and 79.6% ± 14.9% potency compared to unmodified IFX. The impurity produced after chemical conjugation was removed by size exclusion chromatography (SEC). FITC was first labeled on IFX to synthesize FITC labeded IFX-HBHAc for cellular uptake and transcytosis study. The arbitrary fluorescence intensity of FITC-IFX-HBHAc was similar to FITC-IFX at the same molarity. The cellular uptake study was accessed in human colon adenocarcinoma, Caco-2 cells. In dose-dependent cellular uptake study, FITC labeled IFX and IFX-HBHAc was dosed at the concentration of 10 to 100 nM for 1 hour. In time-dependent cellular uptake study, Caco-2 cells were incubated with FITC labeled IFX and IFX-HBHAc for 1 to 4 hours at the concentration of 30 nM. IFX-HBHAc showed the higher internalization compared to IFX in the dose- and time-dependent manner. Caco-2 transwell system was established for the transcytosis study. Transepithelial electrical resistance (TEER) value can reach above 900 Ω*cm2 after incubation for 14 to 21 days, suitable for mimicking the intestinal barrier in vitro. The FITC labeled IFX and IFX-HBHAc was added to the apical chamber and the accumulated fluorescence intensity in the basolateral chamber was calculated after transcytosis for 6 hours. The accumulated fluorescence intensity of IFX-HBHAc increased with time and proportion from apical to basolateral chamber was 34.8 ± 5.4 %. After transcytosis for 24 hours, the concentration of 8X concentrate from the basolateral chamber was measured by enzyme-linked immunosorbent assay (ELISA) kit. The concentration of IFX-HBHAc(1.6) and IFX-HBHAc(2.6) was 2.5 and 3.2-fold higher than IFX. Moreover, after transcytosis for 24 hours, the TNF-α neutralizing activity of 4.5X conditioned concentrate from the basolateral chamber was estimated. The cell viability of IFX-HBHAc(1.6) and IFX-HBHAc(2.6) was significantly higher than the group without dosing antibody (36.6 ± 4.2 % and 38.4 ± 6.1 % v.s. 27.7 ± 2.5 %, p<0.001), suggesting the TNF-α neutralizing activity was reserved. In summary, IFX-HBHAc with TNF-α neutralizing activity was successfully synthesized through chemical conjugation and purified. HBHAc can deliver the IFX to internalize into the epithelial cells and cross the intestinal barrier with the reservation of TNF-α neutralizing activity in vitro. These results suggested the potential of HBHAc as a monoclonal antibody carrier to overcome the physiological intestinal barrier. The study should be further investigated in animals when the therapeutic monoclonal antibody is applied in oral treatment to IBD. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T14:51:06Z (GMT). No. of bitstreams: 1 U0001-0408202016464300.pdf: 2820708 bytes, checksum: 35e0b651d1017e67592e79f271af655c (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | Contents 摘要 I Abstract III List of Schemes and Figures IX List of Tables XI List of Abbreviations XII Chapter I : Introduction 1 1-1 General overview of inflammatory bowel disease (IBD) 1 1-2 Mechanisms and limitations of anti-tumor necrosis factor-α (TNF-α) monoclonal antibodies 2 1-3 Obstacles and approaches for oral delivery of protein drugs 4 1-4 Development of heparin-binding haemagglutinin adhesin C (HBHAc) 6 Chapter II : Aim and Objectives 8 Chapter III : Materials and Methods 9 3-1 Materials 9 3-1-1 Preparation of FITC labeled antibodies and IFX-HBHAc 9 3-1-2 The TNF-α neutralizing activity assay 10 3-1-3 Cell culture 10 3-1-4 Transcytosis study 11 3-2 Cell culture 11 3-3 Conjugation of FITC labeled IFX 11 3-4 Synthesis of IFX-HBHAc and FITC labeled IFX-HBHAc 12 3-4-1 Step 1 reaction 13 3-4-2 Step 2 reaction 13 3-4-3 Purification of IFX-HBHAc after chemical conjugation 14 3-5 Construction of the TNF-α neutralizing activity assay 15 3-5-1 The optimal concentration of actinomycin D and TNF-α in TNF-α neutralizing activity assay 15 3-5-2 The TNF-α neutralizing activity of IFX-HBHAc 16 3-6 Cellular uptake of IFX and IFX-HBHAc 16 3-6-1 Dose-dependent cellular uptake study 17 3-6-2 Time-dependent cellular uptake study 17 3-7 Transcytosis assay for IFX-HBHAc 18 3-7-1 Construction of Caco-2 transwell system 18 3-7-2 The quantity of IFX and IFX-HBHAc after transcytosis for 6 hours 18 3-7-3 The quantity of IFX and IFX-HBHAc after transcytosis for 24 hours 19 3-7-4 The TNF-α neutralizing activity of IFX-HBHAc after transcytosis for 24 hours 20 3-8 Statistics analysis 20 Chapter IV : Results 21 4-1 Synthesis of FITC labeled IFX-HBHAc 21 4-1-1 Conjugation of FITC labeled IFX and IFX-HBHAc 21 4-1-2 Purification and characterization of FITC-IFX-HBHAc 21 4-2 Synthesis of IFX-HBHAc 22 4-2-1 Conjugation of IFX-HBHAc 22 4-2-2 Purification and characterization of IFX-HBHAc 23 4-3 TNF-α neutralizing activity assay for IFX-HBHAc 23 4-3-1 The optimized concentration of actinomycin D and TNF-α for TNF-α neutralizing activity assay 23 4-3-2 The TNF-α neutralizing activity of IFX with HBHAc modification 24 4-4 Cellular uptake of FITC labeled IFX and IFX-HBHAc 24 4-4-1 Dose-dependent cellular uptake study 24 4-4-2 Time-dependent cellular uptake study 25 4-5 Transcytosis assay for IFX-HBHAc 25 4-5-1 Well-established Caco-2 transwell system 25 4-5-2 The quantity of FITC labeled IFX and IFX-HBHAc after transcytosis for 6 hours 25 4-5-3 The quantity of IFX and IFX-HBHAc after transcytosis for 24 hours 26 4-5-4 The TNF-α neutralizing activity of IFX-HBHAc after transcytosis for 24 hours 27 Chapter V : Discussion 28 5-1 The intracellular and transcytosis delivery of IFX-HBHAc and IFX 28 5-1-1 Cellular uptake of IFX-HBHAc and IFX 28 5-1-2 Transcytosis of IFX-HBHAc and IFX 29 5-1-3 The potential transcytosis mechanism of IFX-HBHAc 31 5-2 Chemical conjugation of IFX-HBHAc 32 5-3 in vitro bioactivity assays of anti-TNF-α monoclonal antibodies 35 Chapter VI : Conclusion and Future prospective 38 References 68 | |
| dc.language.iso | en | |
| dc.subject | 化學合成 | zh_TW |
| dc.subject | 細胞穿透胜肽 | zh_TW |
| dc.subject | 英利昔單抗 | zh_TW |
| dc.subject | 發炎性腸道疾病 | zh_TW |
| dc.subject | 穿胞 | zh_TW |
| dc.subject | Infliximab | en |
| dc.subject | inflammatory bowel disease | en |
| dc.subject | chemical conjugation | en |
| dc.subject | transcytosis | en |
| dc.subject | cell-penetrating peptide | en |
| dc.title | 經胜肽修飾之治療性單株抗體作為發炎性腸道疾病口服治療之研究 | zh_TW |
| dc.title | Study a peptide modified therapeutic monoclonal antibody as an oral treatment to inflammatory bowel disease | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 梁碧惠(Pi-Hui Liang),楊家榮(Chia-Ron Yang) | |
| dc.subject.keyword | 英利昔單抗,發炎性腸道疾病,化學合成,穿胞,細胞穿透胜肽, | zh_TW |
| dc.subject.keyword | Infliximab,inflammatory bowel disease,chemical conjugation,transcytosis,cell-penetrating peptide, | en |
| dc.relation.page | 84 | |
| dc.identifier.doi | 10.6342/NTU202002392 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2020-08-05 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| dc.date.embargo-lift | 2025-08-10 | - |
| 顯示於系所單位： | 藥學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| U0001-0408202016464300.pdf 未授權公開取用 | 2.75 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。