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研究生： 許世彬
Hsu, Shih-Pin
論文名稱： 合成與性質鑑定由修飾過的聚天門冬氨酸衍生物構成的可環境應答微胞和聚陰離子奈米微胞
Synthesis and Characterization of Environment-Responsiveness Micelles and Polyanionic Nano-Micelles Constituted of Modified Poly (Aspartic Acid)s Derivatives
指導教授： 朱一民
Chu, I-Ming
口試委員: 胡孝光教授
劉繼賢副教授
駱俊良助理教授
張榮語教授
朱一民教授
學位類別： 博士
Doctor
系所名稱： 工學院 - 化學工程學系
Department of Chemical Engineering
論文出版年： 2012
畢業學年度： 100
語文別： 英文
論文頁數： 147
中文關鍵詞： 環境應答 、奈米高分子材料 、低溫臨界溶液性質 、polymersomes 、聚天門冬氨酸 、聚陰離子
外文關鍵詞： Environmental response, nano polymer, LCST, polymersome, poly(aspartic acid), polyanionic
相關次數： 點閱：3  下載：0 
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    • 高分子用特殊鏈段修飾使其具備環境應答能力的材料已在生醫領域被廣泛研究。 此外, 在21世紀, 奈米科技的發展跟下一世代的工業生產習習相關,包括製藥工業。這本論文的內容便包括了這兩個主題: (1) Thermo- and pH-responsive Polymersomes of Poly (α, β-N-substituted-DL-aspartamide)s 和 (2) Design of polyanionic nanocarriers based on modified poly (aspartic acid)s for oral administration: synthesis and characterization。這本論文也將已發表在每個期刊,跟環境應答和/或奈米高分子材料應用在藥物傳輸領域有關的文章加以分類整理和介紹在本文裏 。 這本論文研究的目的在發掘具有可應用在醫藥領域潛力的新材料與探討材料結構和材料性質間的關係。
    在這篇論文, 一系列新的高分子材料, Poly (α, β-N-substituted-DL- aspartamide)s 已成功製備和完成性質鑑定。 這高分子材料同時具備酸鹼和溫度敏感的性質, 而且在不同的溫度和酸鹼條件下有相變化。 兩種一級氨醇以不同比率修飾高分子而製備出一系列具有低溫臨界溶液性質的共聚合物,在水相中所測得的溫度範圍為53℃-28℃。 此外, 當溶液pH值低於中性時, 高分子溶液的低溫臨界溶液溫度會隨著溶液pH值降低而逐漸降低。由兩性高分子所形成的構形在掃瞄式電子顯微鏡和穿透式電子顯微鏡觀察下為具備外殼和中空核結構的polymersomes, 其直徑為0.5-1μm。
    另一系列poly (sodium aspartate-g-hexadecyl aspartate) (Na-PASP-g-C16-PASP)材料已經由聚天門冬氨酸的部份酯化而製備完成, 為具有兩性且帶負電荷的聚合物。 合成出的聚陰離子可在磷酸根緩衝溶液中自我組裝成不受pH影響的奈米微胞。聚陰離子具有不會聚集和不受黏液阻礙而可加速通過腸黏液的特性。 從強酸到鹼性溶液, 高分子的粒徑變化穩定, 意謂着微胞可穩定的從胃到小腸被傳送, 直到通過小腸黏液層到達小腸上皮細胞前。 兩性且可在水相中自我組裝成奈米微胞的特性可用來包水性, 油性和兩性的藥物。 而且, 奈米微胞 (100nm以下)可增加小腸吸收率和促進生體可用率。

    Polymers modified with specific segments equipped polymers with environmental-response ability that have been studied extensively in biomedical fields. Furthermore, the nanotechnology is associated with the development of next- generation industry in the 21st century including pharmaceutical industry. In this paper, two topics are included, (1) Thermo- and pH- responsive Polymersomes of Poly (α, β-N-substituted-DL-aspartamide)s and (2) Design of polyanionic nanocarriers based on modified poly (aspartic acid)s for oral administration: synthesis and characterization. The related papers about environment-responsive and/or nano-polymeric materials which have potentials for applying in medicine that have being published in each journal are also categorized and introduced in this paper. The purpose of this research is to find novel materials for medicine and study the relationship between structure and property comprehensively.
    In this study, a series of novel polymers, poly (α, β-N-substituted-DL- aspartamide)s were successfully synthesized and characterized. The poly (α, β-N-substituted-DL-aspartamide)s showed pH and temperature responsiveness and had phase transitions at different pHs and temperatures. Different ratios of these two amino alcohols were used to modify the polymer to produce a series of copolymers with lower critical solution temperatures (LCSTs) ranging from 53°C to 28℃ when dispersed in aqueous media. Moreover, the LCSTs of the polymers decreased as the pH decreased below neutral. The morphology of the particles formed by these amphiphilic polymers was observed using SEM and TEM, and the particles were found to be polymersomes with shell and hollow core structures and diameters of 0.5–1 um.
    Another series of partially esterified poly (aspartic acid)s was produced to afford an amphiphilic polyanion, poly (sodium aspartate-g-hexadecyl aspartate) (Na-PASP-g- C16-PASP). The synthesized polyanion could be self-assembled into the nano-scaled micelles and be independent of pH in phosphoric buffer solutions. The polyanionic property can prevent the micelles from being congregated and hindered by mucin as well as facilitate the micelles passing through the mucus of the small intestine. The stability of size transition at different pH levels, from strong acid to alkaline, proved that the micelles could stably transport from the stomach to intestinal lumen prior to arriving in the epithelium of the small intestine. The characteristics of amphiphilic and self-assembled nanomicelles can be utilized to encapsulate the hydrophilic, hydrophobic and even amphiphilic drugs. Furthermore, the nano-dimension (under 100 nm) can be promised to enhance the absorption of the small intestine to improve bioavailability.

    Chinese abstract...........................................i English abstract.........................................iii Acknowledge............................................... v Catalogue.................................................vi Figures catalogue.........................................ix Tables catalogue.........................................xiv 1、Literature Review.......................................1 1-1 Introduction of L-Aspartic acid........................1 1-2 Introduction of poly (aspartic acid)...................1 1-2-1 Introduction of nano-micelles of PEG-P (Asp (CDDP))..3 1-2-2 Camptothecine loaded in micelles composed of poly (ethylene glycol-poly (benzyl aspartate) block copolymers..6 1-2-3 NK105, a PTX-incorporating micellar nanoparticle formulation................................................8 1-2-4 Introduction of nano-micelles of poly (ethylene glycol)–poly (aspartate–hydrazone–adriamycin) (PEG–p (Asp–Hyd–ADR)) & Folate–PEG–P (Asp-Hyd-ADR).............9 1-2-5 Introduction of poly (ethylene glycol)-poly(aspartate hydrazide DOX/WOR) block copolymers.......................14 1-2-6 Introduction of PEG-p (Asp-Hyd-LEV-PTX) and PEG-p(Asp-Hyd-4AB-PTX)..............................................15 1-2-7 Iron hydroxide nanoparticles coated with poly(ethyleneglycol)-poly(aspartic acid) block copolymer as novel magnetic resonance contrast agents for in vivo cancer imaging...................................................17 1-2-8 Introduction of poly(aspartic acid)-g-C18 nanoparticles containing iron oxide nanocrystals and doxorubicin for simultaneous cancer diagnosis and therapy.19 1-2-9 Introduction of PEG-graft-α, β-poly [(N-amino acidyl)-aspartamide]-CDDP (FA-PEG-g- PAAsp-CDDP)..................20 1-2-10 Protamine sulfate/poly(L-aspartic acid) polyionic complexes self-assembled via electrostatic attractions for combined delivery of drug and gene........................22 1-3 Introduction of poly[α, β-(N-2-hydroxyethyl-DL-aspartamide)].............................................23 1-3-1 Folate-mediated targeting of PHEA conjugates of gemcitabine...............................................25 1-3-2 Methotrexate Esters of Poly (Ethylene oxide)-Block-Poly(2-Hydroxyethyl-L-Aspartamide)........................28 1-3-3 Macromolecular prodrugs: Synthesis of polymer- gemfibrozil conjugates....................................30 1-3-4 Macromolecular prodrugs: Synthesis and characterization polymer–estradiol conjugate.............31 1-3-5 Synthesis and biopharmaceutical characterisation of new poly (hydroxyl ethyl aspartamide) copolymers as drug carriers..................................................33 1-3-6 Tamoxifen-Loaded Polymeric Micelles: Preparation, Physico-Chemical Characterization and In Vitro Evaluation Studies...................................................35 1-3-7 Polyhydroxyethylaspartamide-based micelles for ocular drug delivery.............................................37 1-3-8 Water-Soluble Macromolecular Platinum Conjugates Derived from 1, 2- Dihydroxyl-Functionalized Carrier Polymers..................................................40 1-3-9 Macromolecular Co-Conjugates of Methotrexate and Ferrocene in the Chemotherapy of Cancer...................42 1-3-10 Glycosilated Macromolecular Conjugates of Antiviral Drugs with a Polyaspartamide..............................45 1-3-11 Porphyrin-containing polyaspartamide gadolinium complexes as potential magnetic resonance imaging contrast agents....................................................50 1-3-12 pDNA/poly (L-lysine) Polyplexes Functionalized with a pH-Sensitive Charge-Conversional Poly (aspartamide) Derivative for Controlled Gene Delivery to Human Umbilical Vein Endothelial Cells....................................54 1-3-13 pH-dependent self-assembling behavior of imidazole-containing polyaspartamide derivatives...............................................58 1-3-14 pH-Sensitive Hydrogel Based On A Novel Photocross-Linkable Copolymer........................................61 Reference.................................................65 2、Thermo- and pH- responsive Polymersomes of Poly (α,β-N-substituted-DL-aspartamide)s..............................70 Abstract..................................................71 Introduction..............................................72 Experiment................................................74 Results and discussion....................................78 Conclusion................................................95 Reference.................................................96 Supplementary............................................103 3、Design of polyanionic nanocarriers based on modified poly (aspartic acid)s for oral administration: synthesis and characterization.....................................106 Abstract.................................................107 Introduction.............................................108 Experiment...............................................110 Results and Discussion...................................116 Conclusion...............................................129 Supplementary............................................131 Reference................................................145

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