PAMAM Dendrimer Based Targeted Nano-Carrier for Bio-Imaging and Therapeutic agents: synthesis, characterization and application in vitro and in vivo.

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研究生：	Shewaye Lakew Mekuria Shewaye - Lakew Mekuria
論文名稱：	PAMAM Dendrimer Based Targeted Nano-Carrier for Bio-Imaging and Therapeutic agents: synthesis, characterization and application in vitro and in vivo. PAMAM Dendrimer Based Targeted Nano-Carrier for Bio-Imaging and Therapeutic agents: synthesis, characterization and application in vitro and in vivo.
指導教授：	蔡協致 Hsieh-Chih Tsai
口試委員:	廖愛禾 Ai-Ho Liao 朱一民 I-Ming Chu 朱智謙 Chih-Chien Chu 賴瑞陽 Jui-Yang Lai
學位類別：	博士 Doctor
系所名稱：	應用科技學院 - 應用科技研究所 Graduate Institute of Applied Science and Technology
論文出版年：	2016
畢業學年度：	104
語文別：	英文
論文頁數：	182
中文關鍵詞：	PAMAM dendrimer 、IL6 、RGD peptide 、DOX 、HeLa cells 、Endocytosis 、Drug delivery 、Bioimaging agent 、Gadolinium oxide (Gd2O3) 、slongitudinal relaxation 、RAW 264.7 cells 、in vivo 、MR imaging
外文關鍵詞：	PAMAM dendrimer, IL6, RGD peptide, DOX, HeLa cells, Endocytosis, Drug delivery, Bioimaging agent, Gadolinium oxide (Gd2O3), slongitudinal relaxation, RAW 264.7 cells, in vivo, MR imaging
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上一筆

過去數十年裡，設計適合藥物傳遞系統已成為治療癌症的主流。奈米科技領域中，樹枝狀高分子為新型奈米藥物載體，擁有球型及高分枝結構且具備固定分子量，內核可包覆抗癌藥物；外部分支可經改質接上其它功能性分子或藥物，應用於生醫領域中，如藥物標的性載體、顯影劑，可用來增加藥物及顯影劑之傳遞效率。而PAMAM Dendrimer表面接上配體(ligand)可和癌細胞特有的受體配對，達到主動標的、高傳遞效率和不會傷害到正常細胞。
本篇論文提到三個主題:第一部分為白細胞介素(IL-6)藉由EDC/NHS和陰離子G4.5鍵結並探討它的光學特性，再由傅立葉紅外線光譜儀(FT-IR)、二維核磁共振(2D-NMR)、穿透式電子顯微鏡(TEM)和廣角X射線散射(WAXS)鑑定。此外G4.5經過IL6改質後，增加G4.5螢光特性，且在UV-Vis下產生blue shift。由細胞吞噬、共軛焦顯微鏡和流式細胞儀，觀察高分子和子宮頸癌細胞(Hela cell)的生物特性，結果顯示改質後的G4.5細胞吞噬能力較佳，並且具有體外生醫影像探針功能。
第二部分為G4.5由IL-6抗體和RGD胜肽兩種配體修飾，再以物理性包覆抗癌藥物Doxorubicin，由共軛焦顯微鏡和流式細胞儀觀察Hela cell吞噬能力。IC50值證明G4.5/IL6不僅是藥物包覆率較高，且藥物釋放率也較佳，表示G4.5/IL6毒性高於G4.5/RGD，此外細胞毒性也可從晚期細胞凋亡(late apoptosis)和壞死(necrosis)觀察，由上述現象可知G4.5/IL6更適合做為藥物釋放標的載體。
第三部分為多功能G4.5-Gd2O3-PEG NPS作為顯影劑，觀察於磁振造影(MRI)下T1 (positive)和T2 (negative)。G4.5-Gd2O3-PEG相較於含有Gd奈米粒子(Gd-DTPA或Gd-DOTA)，顯示T1縱向的弛緩時間。此外由小鼠巨噬細胞(RAW Cell)做毒性測試，可知G4.5-Gd2O3-PEG NPS生物相容性較佳。G4.5-Gd2O3-PEG相較於Gd-DTPA在7T具有較佳縱向弛緩率53.9mS1M1，大約4.75倍。且G4.5-Gd2O3-PEG在體內大腸、小腸、肝、脾、腎和膀胱T1顯示訊號較強；相對地，T2於腎沒有顯影。上述實驗證實本研究所設計之PAMAM 樹狀高分子可成功應用於藥物傳遞標的及核磁共振之顯影劑。

In the last several decades, researchers have focused on developing suitable drug carrier systems for delivery to carcinogenic cells. Therefore, they primarily highlight the contributions of PAMAM dendrimers to the field of nanotechnology with the intent to aid in exploring dendrimers for targeted drug delivery and bio-imaging agents. PAMAM dendrimers have been studied as potential delivery systems to targeting, imaging, and/or deliver therapeutic agents specifically to diseased tissues because of their globular shape, multiple functionalities at the periphery or in the cavity. Anti-cancer agents may be incorporated into the interior void space or conjugated to the surface of PAMAM to enhance the delivery of cytotoxic drugs. In addition, targeting ligands can also be attached to the dendrimer service to allow active targeting and minimize harm to normal cells.
This dissertation is organized based on three independent sections: the first section investigates that interleukin-6 (IL-6) was conjugated with anionic generation 4.5 (G4.5) poly (amidoamine) (PAMAM) through EDC/NHS coupling chemistry and evaluated for its optical properties in vitro. Conjugation was confirmed using Fourier-transformed infrared spectroscopy (FT-IR) and 2-dimensional nuclear magnetic resonance (2D-NMR), transmission electron microscopy (TEM), and wide-angle X-ray scattering (WAXS). Most interestingly, the intrinsic fluorescence of G4.5 significantly increased after IL-6 conjugation and underwent a blue shift as a result of H-aggregation. Furthermore, the cellular uptake of the conjugates by HeLa cells was significantly enhanced in comparison to free G4.5, as demonstrated by confocal microscopy and flow cytometry. These results indicated that the described system may be a potential bioimaging probe in vitro.
The second section explored that PAMAM dendrimer (G4.5) was conjugated with two targeting moieties, IL-6 and RGD peptide (G4.5-IL6 and G4.5-RGD) followed by doxorubicin anticancer drug was physically loaded to form G4.5-IL6/DOX and G4.5-RGD/DOX complexes, respectively. The cellular internalization and uptake efficiency of was observed and compared by confocal microscopy and flow cytometry using HeLa cells. The lower IC50 value of G4.5-IL6/DOX in comparison to G4.5-RGD/DOX is indication that higher drug loading and faster drug release rate corresponded with greater cytotoxicity. The cytotoxic effect was further verified by increment in late apoptotic/necrotic cells due to delivery of drug through receptor-mediated endocytosis. Based on these results, G4.5-IL6 is a better suited carrier for targeted drug delivery of DOX to cervical cancer cells.
The third section, we report a simple and facile strategy to fabricate a multifunctional G4.5-Gd2O3-PEG NPs and have been investigated as a novel T1 positive contrast and T2 negative contrast agent for magnetic resonance imaging (MRI). G4.5-Gd2O3-PEG nanoparticles shows induced longitudinal relaxation time T1 compared with the related Gd-containing nanoparticles and the clinically using Gd-DTPA or Gd-DOTA. The cytotoxicity study showed that the G4.5-Gd2O3-PEG NPs exhibited better biocompatibility to the RAW 264.7 cells (normal mice cells). G4.5-Gd2O3-PEG nanoparticles showed with improved longitudinal relaxivity r1 of 53.9 mS-1M-1 at 7T, which is around 4.75 times enhancement as that of commercial Gd-DTPA contrasting agent. The in vivo T1 weighted MR imaging study of G4.5-Gd2O3-PEG nanoparticles demonstrated that a considerable signal enhancement in the large and small intestine, liver, spleen, kidney and bladder. In addition, the in vivo T2 weighted MR imaging study showed that the negative contrast in the kidney implies that G4.5-Gd2O3-PEG nanoparticles serve as a dual-modal contrasting agent.
Generally, these research finding provides an alternative way for conniving multifunctional PAMAM dendrimer with targeting ligand as a bio-probe, drug delivery and gadolinium based contrasting agents for MRI.

Contents
中文摘要	i
Abstract	iii
Acknowledgments	vii
List of Figures	xiii
List of Tables	xviii
List of Schemes	xix
List of abbreviations	xx
Backgrounds	1
Chapter Two: Introduction	2
1.	Dendrimer	2
1.1.	Synthesis	4
1.2.1.	Monodispersity	5
1.2.2.	Surface charge/Interior chemistry	5
1.2.3.	Size and shape	6
1.2.4.	Biocompatibility	8
1.3.	Dendrimers as drug carrier	10
1.3.1.	Dendrimer-drug conjugates	10
1.3.2.	Dendrimer-drug encapsulation	11
1.4.	Dendrimers for targeted drug delivery	12
1.4.1.	Peptide targeted drug delivery	15
1.4.2.	Monoclonal antibody-targeted delivery system	15
1.4.3.	FA-targeted delivery system	16
1.4.4.	Glycoprotein targeted drug delivery	17
1.4.5.	Biotinylated targeted drug delivery	17
1.5.	Dendrimers for Biomedical imaging	18
1.5.1.	Dendrimers for optical imaging	19
1.5.2.	Dendrimers for magnetic resonance imaging (MRI)	20
Chapter Three: Research Objectives	23
Chapter Four: Preparation of Self-Assembled Core-Shell Nano Structure of Conjugated Generation 4.5 Poly (amidoamine) Dendrimer and Monoclonal Anti-IL-6 Antibody as Bioimaging Probe	24
1.	Introduction	24
2.1.	Materials	26
2.2.	Synthesis of G4.5/IL-6 conjugate	26
2.3.	Structural characterizations	27
2.4.	Cell culture and in vitro cell-binding experiments	28
2.5.	Competitive assay	29
3.2.	Particle morphology and characterization of G4.5/IL-6 conjugate	36
3.3.	Wide-angle X-ray scattering (WAXS) of G4.5/IL-6 conjugate	38
3.4.	Optical properties of G4.5/IL-6 conjugate	40
3.5.	Internalization of G4.5/IL-6 conjugates by HeLa cells	43
4.	Summary	48
Chapter Five: IL-6 Antibody and RGD Peptide Conjugated Poly (amidoamine) Dendrimer for Targeted Drug Delivery of HeLa Cells	49
1.	Introduction	49
2.	Experimental section	51
2.1.	Materials	51
2.2.	Synthesis of G4.5-RGD and G4.5-IL6 Conjugates	51
2.3.	DOX Loading into G4.5-IL6 and G4.5-RGD Complexes	52
2.4.	Characterization Methods	53
2.5.	In Vitro Drug Release Kinetics	53
2.6.	Toxicity toward HeLa Cells	54
2.7.	In Vitro Cellular Uptake	54
2.8.	Flow Cytometry Analysis	55
2.9.	Cell Apoptosis/Necrosis Analysis	55
2.10.	Statistical Analysis	56
3.	Results and discussion	56
3.1.	Loading of Doxorubicin into Modified Dendrimer Carriers	57
3.2.	In Vitro DOX Release from Dendrimer Complexes	62
3.3.	Cell Uptake of G4.5-RGD/DOX and G4.5-IL6/DOX Conjugates	63
3.4.	In Vitro Cytotoxicity	68
4.	Summary	71
Chapter Six: Gadolinium Oxide Nanoparticles (Gd2O3) Contrasting Agent Encapsulated in PAMAM Dendrimer Template for Enhancing Magnetic Resonance Imaging in Vivo	72
1.	Introduction	72
2.	Materials and Methods	75
2.1.	Materials	75
2.2.	Characterization	75
2.3.	Synthesis of G4.5-Gd2O3 nanoparticles (NPs)	76
2.4.	Preparation of G4.5-PEG conjugates	77
2.5.	Conjugation of G4.5-Gd2O3 NPs with PEG	77
2.6.	MRI In vitro relaxivity studies	77
2.7.	In vitro cytotoxicity assay	78
2.8.	Cell Apoptosis/Necrosis Analysis	78
2.9.	Spectrophotometric determination of free gadolinium ions by Xylenol Orange disodium salt	79
2.11.	In Vivo MR Imaging	79
2.12.	Animal Model	80
2.13.	In vivo biodistribution studies	80
3.	Results and discussion	81
3.1.	Synthesis and Characterization of G4.5-Gd2O3 nanoparticles	81
3.2.	PEGylation of G4.5-Gd2O3 nanoparticle	89
3.3.	Biocompatibility studies of nanoparticles	92
3.4.	Phantom MR imaging and Relaxometric analysis	98
3.5.	In vivo results: T1-T2 weighted MR images	101
Chapter Seven: Conclusions and Recommendations	109
1.	Conclusions	109
2.	Recommendations	111
Chapter Eight: Supporting Information	112

                                

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全文公開日期 2021/07/19 (校內網路)
全文公開日期 2036/07/19 (校外網路)
全文公開日期 2036/07/19 (國家圖書館：臺灣博碩士論文系統)

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