製備脂多醣-去唾液酸醣蛋白受體-聚乳酸共聚物標靶奈米粒子用於肝纖維化動物模型

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姓名

黃靜如(Ching-Ju Huang) 查詢紙本館藏

畢業系所

生醫科學與工程學系

論文名稱

製備脂多醣-去唾液酸醣蛋白受體-聚乳酸共聚物標靶奈米粒子用於肝纖維化動物模型
(Fabrication of Asialoglycoprotein Receptor-Targeted Lipopolysaccharides-Encapsulated PLGA Nanoparticles for Establishment of Liver Fibrosis Animal Models)

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摘要(中)

血清神經肽Y (NPY) 是經由中樞神經元和周圍神經元所分泌的一種抑制性神經傳遞物質，它的改變可能會導致睡眠障礙等情緒疾病，γ-氨基丁酸（GABA）是一種抑制性神經傳導物質可以提高哺乳動物中樞神經系統的交感神經或副交感神經活動，因此被廣泛用於減輕憂鬱、焦慮。然而，合成GABA在體內半衰期短、吸收效率低使得其在藥物製劑中的可用性較差，而透過長期/規律的日常飲食攝取GABA更為有效。
在這項研究中，我們透過發芽過程中液化澱粉芽孢桿菌（B.amyloliquefaciens）(fermented rice)在台灣水稻中產出富含GABA的水稻，並證明接種解澱粉芽孢桿菌（fermented rice）的水稻不但可以正常生長更可提高發芽率。基於洞板試驗相關的研究，我們的數據顯示接受發酵米治療8天的小鼠血清NPY水平以及低頭次數與沒有GABA的小鼠相比顯著增加2倍（P < 0.01），除此之外透過使用GABA 受體拮抗劑或迷走神經切斷術分別去除胃腸道GABAB 受體或迷走神經時，這種fermented rice 誘導的功效急劇消失。這些結果證明發酵米在抗焦慮應用中的潛力，並證實了 GABA 誘導的抗焦慮活性可能的介質。
除此之外我的另一主要研究與奈米粒子息息相關，肝纖維化被認為是大多數肝臟疾病的開始，因此肝纖維化動物模型是開發大多數肝臟疾病治療策略的基石。儘管在過去幾十年中，肝毒性物質的運用和/或膽管結紮已被廣泛用於體內模型，但它們因耗時、高死亡率和不穩定而受到嚴重阻礙，這表明一個安全且有效的動物模型中誘導方法在目前是肝纖維化的防治亟待解決的問題。
在這項研究中，我們開發了去唾液酸醣蛋白受體（ASGPR）聚乳酸共聚物標靶奈米粒子靶向脂多醣（LPS）奈米粒子，稱為ALPND，用於建立肝纖維化動物模型。 ALPND 的特徵為球形奈米結構，尺寸為 182.9 ± 8.89 nm，表面電荷為 -8.3 ± 1.48 mV。奈米顆粒表面配備的抗 ASGPR 抗體，交聯效率為 95.03%，使 ALPND 具有肝細胞特異性結合能力。與遊離 LPS 相比，ALPND 可以提供類似的誘導肝臟發炎和纖維化的能力，但與裸露藥物相比具有更高的肝臟靶向性。此外，與遊離LPS相比，ALPND對肝臟以外的器官的毒性較小，這表明ALPND在體內不會引起脫靶效應。鑑於PLGA提供的上述功效以及生物相容性和藥物釋放可控性等其他優點，我們預期所開發的ALPND非常適合在臨床前研究中建立肝纖維化動物模型。

摘要(英)

hanges in neuropeptide Y (NPY) levels in the bloodstream can lead to sleep disturbances, disruptions in circadian rhythms, and potentially contribute to emotional disorders. γ-Aminobutyric acid (GABA) is an inhibitory neurotransmitter and has been widely used for reduction of depression, anxiety, and/or psychological stress since it can raise the total or parasympathetic nerve activities in the mammalian central nervous system. In this study, we successfully produced GABA-enriched rice by inoculating grain seeds of Taiwanese rice with Bacillus amyloliquefaciens (B. amyloliquefaciens) during germination, and demonstrated that the B. amyloliquefaciens-inoculated rice (fermented rice) can grow with a normal root/sprout length but significantly increased germination ratio compared to the rice without B. amyloliquefaciens treatment. Based on the animal study in association with the hole board test, our data showed that the level of serum NPY as well as the number of head-dips of the mice treated with the fermented rice for 8 days significantly enhanced 2 folds (P < 0.01) compared to the mice without GABA, but such fermented rice-induced efficacies dramatically vanished as their gastrointestinal GABAB receptor and/or vagus nerves were removed through use of GABA receptor antagonist or vagotomy, respectively. These results manifested the potential of the fermented rice on anxiolytic applications and unveiled likely mediators for GABA-induced anxiolytic activity.
In addition, my other main research is closely related to nanoparticles. Liver fibrosis is generally considered as the beginning of most liver diseases and therefore a liver fibrosis animal model is the cornerstone for the development of therapeutic strategies for most of hepatic diseases. Although administrations of hepatotoxic substances and/or bile duct ligation have been widely used to build up the in vivo model over the last decades, they are seriously hindered with time consuming, high mortality, and instability, indicating that an effective and safe approach for induction of liver fibrosis is still urgently needed nowadays. In this study, we have developed asialoglycoprotein receptor (ASGPR)-target lipopolysaccharide (LPS)-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles named ALPNDs for establishing animal models of liver fibrosis. The ALPNDs are characterized as a spherical nanostructure with size of 182.9 ± 8.89 nm and surface charge of −8.3 ± 1.48 mV. The anti-ASGPR-antibodies equipped on the nanoparticles surface with crosslinking efficiency of 95.03% allow the ALPNDs to be hepatocytic binding specific. In comparison to free LPS, the ALPNDs can induce higher aspartate aminotransferase and total bilirubin concentrations in plasma, reduce blood flow rate, and increase vascular resistance in liver, kidney, and collateral shunting vasculature. Based on the histological and RNA-seq analyses, the ALPNDs can provide similar capability on inductions of hepatic inflammation and fibrosis compared to free LPS, but possess higher liver targetability compared to the naked drug. In addition, the ALPNDs are less toxicity in organs other than liver in comparison to free LPS, demonstrating that the ALPNDs did not elicit off-target effects in vivo. Given aforementioned efficacies with other merits such as biocompatibility and drug release controllability provided by PLGA, we anticipate that the developed ALPND is highly applicable for establishing animal models of liver fibrosis in the pre-clinical study.

關鍵字(中)

★ 去唾液酸醣蛋白受體
★ 脂多醣
★ 肝纖維化
★ 肝纖維化動物模型

關鍵字(英)

★ γ-aminobutyric acid
★ PLGA nanoparticles
★ Liver fibrosis
★ Fermented rice

論文目次

Contents
Abstract in Chinese i
Abstract iii
Acknowledgment v
Contents vi
List of figures x
Chapter 1 Literature Review 1
1.1 Microbiome and Microbiota 1
1.2 Gut-Brain Axis GBA 1
1.3 The relationship between Neuropeptide Y (NPY) and anxiety disorders 3
1.4 Endophytic bacteria 4
1.5 Nanomedicine 5
1.6 Nanoparticles for Drug Delivery 5
1.7 Nano drug carriers 6
1.8 Polymer biomedical materials 9
1.9 PLGA nanoparticles 10
1.10 Bacteria in Nanoparticle Synthesis 10
1.11 Liver fibrosis 10
1.12 Animal models of liver fibrosis 11
Chapter 2 Research Framework and Research diagram 13
2.1 Research Topic 1: 13
2.2 Research Topic 2: 21
Chapter 3 Bacillus amyloliquefaciens-Inoculated GABA-Rich Rice Upregulate Neuropeptide Y to Relieve Psychological Stress through Mediations of GABAB Receptor and Vagus Nerves 29
3.1 Abstract 29
3.3 Materials and methods 31
3.3.1 Bacterial culture 31
3.3.2.Fermented rice production, cultivation and characterization 32
3.3.3 Ethical statement for animal study 32
3.3.4 Vagotomy 33
3.3.5 Hole-Board Test (HBT) 33
3.3.6 Administration and effect of fermented rice on mice 33
3.3.7 Assessment of the effects of GABAB receptor on NPY expression and behaviors of fermented rice -fed mice 34
3.3.8 Assessment of the effects of vagus nerves on NPY expression and behaviors of fermented rice-fed mice 34
3.3.9 Statistical analysis. 35
3.4 Results 35
3.4.1 Effects of B. amyloliquefaciens on Rice Germination and GABA Productions 35
3.4.2 Effects of fermented rice on NPY expression and behavioral changes of mice 37
3.4.3 Effects of GABAB Receptor on NPY Expression and Behavioral Changes of fermented rice-fed Mice 39
3.4.4 Effects of Vagus Nerves on NPY Expression and Behavioral Changes of fermented rice-fed Mice 41
3.5 Discussion 43
Chapter 4 Synthesis, Characterization, and Biological Verification of Asialoglycoprotein Receptor-Targeted Lipopolysaccharides-Encapsulated PLGA Nanoparticles for Establishment of Liver Fibrosis Animal Models 46
4.1 Abstract 46
4.2 Introduction 48
4.3 Materials and methods 51
4.3.1 Fabrication, surface modification, and characterization of the ALPNDs 51
4.3.2 Assessment of drug release efficiency of the ALPNDs 52
4.3.3 Cell culture 53
4.2.4 Evaluation of the proinflammatory capability of the ALPNDs in vitro 53
4.3.5 Assessment of cytotoxicity of the ALPNDs in vitro 54
4.3.6 Animal model and assay 54
4.3.7 Evaluation of effect of ALPNDs on hemodynamics and toxicity in vivo 54
4.3.8 Assessment of liver fibrosis degree in vivo after treatment with ALPNDs 56
4.3.9 Histological study 57
4.3.10 NGS Library construction and sequencing 57
4.3.11 Sequencing data analysis 58
4.3.12 Statistical Analysis 58
4.4 Results and discussion 59
4.4.1 Characterization of the ALPNDs 59
4.4.2 Efficiency of LPS release 59
4.4.3 Effectiveness of the ALPNDs on cellular inflammation 60
4.4.4 Cytotoxicity of the ALPNDs in vitro 61
4.4.5 Effect of ALPNDs on rat system 63
4.4.5 Effect of the ALPNDs on systemic hemodynamics 65
4.4.6 Effect of ALPNDs on liver fibrosis & RNA-sequencing analysis 67
4.4.7 Analyses of protein expressions of inflammation and fibrosis markers in liver 70
4.4.8 In vivo systematic toxicity analyses 72
3.5 Conclusions 74
References 75

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指導教授

李宇翔

審核日期

2024-6-26

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