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National Chung Hsing University Institutional Repository - NCHUIR > 工學院 > 化學工程學系所 > 依資料類型分類 > 碩博士論文 >  開發具抗癌藥物傳輸與核磁共振顯影之酸鹼應答高分子自組裝系統於腫瘤診治之應用

Please use this identifier to cite or link to this item: http://nchuir.lib.nchu.edu.tw/handle/309270000/154315

標題: 開發具抗癌藥物傳輸與核磁共振顯影之酸鹼應答高分子自組裝系統於腫瘤診治之應用
Multifunctional and pH-Responsive Polymer Assemblies with Tumor-Targeting and Magnetic Resonance Imaging for Cancer Theranostics
作者: 黃義峰
Huang, Yi-Fong
Contributors: 蔡毓楨
Yu-Chen Tsai
化學工程學系所
關鍵字: 高分子自組裝;藥物載體;核磁造影
Polymer assemblies;Drug Carrier;MRI
日期: 2012
Issue Date: 2013-11-21 10:12:57 (UTC+8)
Publisher: 化學工程學系所
摘要: 於奈米醫學發展中,多功能診治平台受到重視,主要是希望能改善治療效益及診斷精確度。本研究目的是發展具酸鹼應答通道的含脂質高分子奈米粒子系統於腫瘤診治之應用。
第一部份利用poly(acrylic acid)-g-monomethoxy poly(ethylene glycol) (PAAc-g-mPEG)與雙尾碳鏈陽離子脂質didodecyldimethylammonium bromide (DDAB)以靜電作用力於水相中自組裝形成複合奈米粒子。由多角度動/靜態光散射(multiangle-SLS/DLS)結果證實此複合奈米粒子結構為球狀液胞結構。此液胞結構的疏水膜是由AAc/DDAB所構成,而親水性鏈段PEG則分布於液胞內外表面。當溶液pH值由8.9降低至5.0時,因部分AAc單元質子化,導致AAc與DDAB之間的複合被破壞,且使得液胞胞膜的疏水性降低。這也將造成外部水相進入液胞內部而導致液胞的膨潤,其說明液胞膜上有穿膜通道(transmembrane channels)的形成。由體外藥物釋放實驗結果顯示於pH 5.0環境下,被包覆於液胞內部的水溶性抗癌藥物doxorubicin (DOX)可經由穿膜通道而被釋放。綜合實驗結果顯示此具有酸鹼應答穿膜通道之高分子/脂質液胞組裝結構極具發展潛力且應用於藥物傳遞系統。
第二部分是開發多功能性高分子奈米粒子於藥物傳遞及磁振造影(magnetic resonance image, MRI)之應用。高分子奈米粒子主要是由poly(acrylic acid)水膠層以靜電作用力覆蓋於chitosan/supramagnetic iron oxide nanoparticles (SPION) complexes (CSC)表面。正電荷藥物DOX被導入富含解離態AAc單元的水膠層中(利用靜電作用力結合),可進行酸鹼應答控制釋放;而SPION則為磁振造影對比劑。陽離子脂質(1,2-dioleoyl-3-trimethylammonium-propane (DOTAP))被導入於水膠層中形成疏水聚集,並於不同pH值下產生結構變化而調節DOX的釋放速率。具專一標的功能的folate基團被修飾於粒子表面,可針對腫瘤細胞進行有效結合。隨著pH值下降, DOTAP疏水區域且疏水區域位置更加集中,而周遭的質子化AAc區域可作為通道幫助DOX釋放。於磁振造影分析,隨著pH值的下降,粒子內部的SPIONs的聚集受到破壞,造成MRI顯影效果有明顯變化。最後,由細胞攝取及存活率實驗證實,於奈米粒子表面上修飾FA基團有效增加腫瘤細胞的吞噬效果及降低腫瘤細胞的存活率。由上述實驗結果顯示,此高分子奈米粒子具有pH調控藥物釋放及MRI對比的功能,增加診斷及治療腫瘤細胞的能力,導入標的功能的官能基於奈米粒子中可賦予其對腫瘤細胞專一標的能力,進而達到毒殺腫瘤細胞的目的。
The aim of the work is to develop the lipid-containing polymer assemblies from co-association of the cationic lipids and oppositely charged polymer with pH-triggered channels for controlled drug release and magnetic resonance imaging (MRI).
First research represents a facile approach to prepare novel hybrid vesicles via co-assembly of a cationic lipid (didodecyldimethylammonium bromide (DDAB)) with poly(acrylic acid)-g-monomethoxy poly(ethylene glycol) (PAAc-g-PEG). The vesicle structure has a thin PAAc/DDAB hydrophobic membrane encircled by hydrophilic PEG coronas. As the pH of the solution decreased from 8.9 to 5, the unionized AAc-rich transmembrane channels were created near the PEG coronas, due to the partial disruption of the electrostatic binding between the AAc residues and DDAB molecules. It has been found that a significantly increased drug release (60 %) at pH 5 as compared to the release of DOX (12 %) at pH 7.4. Therefore, it suggests that these formed channels facilitated the release of encapsulated drug, doxorubicin (DOX) at pH 5.0 in comparison with that at pH 7.4 due to the size of the channel similar to that of DOX. Such pH-triggered change in the membrane morphology is beneficial to control intracellular drug release within acidic endosomal and lysosomal compartments.
In second research, the nanogel-caged nanoparticles were further developed to deliver DOX and superparamagnetic iron oxide nanopaticles (SPION). The nanogel-caged nanoparticles comprise a chitosan/SPION complexes (CSC) enclosed by the poly(acrylic acid) (PAAc) gel layer. The addition of cationic lipids, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) into the PAAc gel layer via electrostatic interaction was capable of regulating the release rate of loaded DOX molecules via the structural rearrangement of lipid domains upon external pH change. DOX was incorporated into the PAAc gel layer via electronic interaction while the SPIONs were loaded into the core of particles as contrast agents. We have demonstrated that MRI images exhibited the significant difference of imaging contrast while experiencing pH change, due to the disruption of CSC aggregates. To provide the ability of the specific targeting to cancer cell, the folate moieties were conjugated onto the surface of the nanogel-caged nanoparticles. The enhanced cellular uptake of folate-conjugated nanoparticles by HeLa cells was observed by flow cytometry, laser confocal scanning microscopy, and MRI. The folate conjugated SPION/DOX loaded nanoparticles showed sharp contrast enhancement, higher cellular uptake and cytotoxicity, in comparison to folate free nanoparticles, due to folate receptor mediated endocytosis. These tumor-targeting multifunctional nanoparticles exhibited pH-controllable drug release and MRI contrast, thereby making targeted cancer therapy and diagnosis possible.
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