作为药物载体的两亲性共聚物合成及性质研究
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摘要
两亲性共聚物在结构上可以划分出亲水部分和疏水部分。由于这种独特的化学结构,在水性介质中能形成具有球形内核-外壳结构的共聚物胶束,疏水部分构成内核,亲水部分形成外壳。在大分子药物、难溶性药物和基因治疗药物载体给药方面具有独特的优势。
为深入探讨两亲性共聚物及其载药纳米粒子的特性,本文分别以聚天冬氨酸和明胶作为亲水段,通过接枝共聚反应,合成了两亲性聚(天冬氨酸-co-乳酸)接枝共聚物和两亲性明胶-聚乳酸接枝共聚物;此外,又将它们与二棕榈酰磷脂酰乙醇胺(DPPE)反应,合成了两种新型两亲性接枝共聚物——聚(天冬氨酸-co-乳酸)-二棕榈酰磷脂酰乙醇胺接枝共聚物和明胶-聚乳酸-二棕榈酰磷脂酰乙醇胺接枝共聚物。用红外光谱(FT-IR)和核磁共振谱(NMR)表征了两亲性共聚物的结构和组成。荧光光谱分析表明,两种两亲性共聚物均具有较低的临界胶束浓度(CMC)值。动态光散射(DLS)和透射电子显微镜(TEM)结果表明,胶束粒径均一并呈现球形形态。
为了解两亲性共聚物与药物包合作用的规律和机理,以阿霉素(DOX)、环孢素A(CsA)和紫杉醇(PTX)三种药物作为模型。针对不同药物,采用纳米沉淀法、双乳法和乳化溶剂蒸发法,制备了包载药物的两亲性共聚物载药纳米粒子。利用紫外光谱或高效液相色谱研究了包载条件对药物包封率(EE)、载药量(LC)和粒径的影响,测定了药物的体外释放行为。研究了载药纳米粒子的细胞毒性,结果表明载药纳米粒子的杀伤细胞能力与浓度成正比,并且与单纯药物对细胞的杀伤程度相当。
It is well known that amphiphilic polymers consist of hydrophilic part and hydrophobic part in the structure. Due to this unique chemical structure, it can form a core-shell structure of polymer micelles in aqueous medium. The hydrophobic part forms the core and the hydrophilic part forms shell. They have unique advantages in macromolecular drugs, low water-solubility drugs and gene therapy as drug carriers.
In order to study the characteristics of amphiphilic polymers and drug-loaded nanoparticles(NPs), we used PAsp and gelatin as hydrophilic segment through copolymerizatinreaction, synthesized amphiphilic poly (L-aspartic acid co-L-lactide) grafted polymer and amphiphilic gelatin-polylactide grafted polymer. Then, we used 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine(DPPE) to synthesize two novel amphiphilic polymers that were poly(L-aspartic acid co-L-lactide)-1,2-dipalmitoyl-sn- glycero-3-phosphoethanolamine and gelatin-polylactide-1,2-dipalmitoyl-sn-glycero-3- phosphorethanolamine. The amphiphilic polymers were characterized by FT-IR and NMR. The fluorescence experiments showed that amphiphilic polymers have a very low critical micelle concentration (CMC).The dynamic light scatter (DLS) and transmission electron microscopy (TEM) experiments indicated that the nanoparticles had uniform particle size and were apt to a spherical shape.
To understand the molecular interaction mechanism of inclusion complex between amphiphilic polymers and the medicine, Doxorubicin hydrochloride(DOX), cyclosporin A(CsA) and paclitaxel (PTX) were chosen as model drug to study their vitro drug release behavior from nanoparticles. Drug-loaded nanoparticles were prepared by nanoprecipitation, double emulsion and emulsification solvent evaporation methods, respectively. Different factors which influence on particular size,encapsulation efficiency(EE) and drug-loaded content(LC) were investigated, and in vitro released characteristics were investigated by ultraviolet spectrum(UV) or high performance liquid chromatography (HPLC). We studied the cytotoxicity of the DOX-loaded NPs and PTX-loaded NPs. The results showed that the ability of killer cells of the drug-loaded nanoparticles was proportional to the concentration, the drug-loaded nanoparticles was the same on killer cells withthe drugs.
为深入探讨两亲性共聚物及其载药纳米粒子的特性,本文分别以聚天冬氨酸和明胶作为亲水段,通过接枝共聚反应,合成了两亲性聚(天冬氨酸-co-乳酸)接枝共聚物和两亲性明胶-聚乳酸接枝共聚物;此外,又将它们与二棕榈酰磷脂酰乙醇胺(DPPE)反应,合成了两种新型两亲性接枝共聚物——聚(天冬氨酸-co-乳酸)-二棕榈酰磷脂酰乙醇胺接枝共聚物和明胶-聚乳酸-二棕榈酰磷脂酰乙醇胺接枝共聚物。用红外光谱(FT-IR)和核磁共振谱(NMR)表征了两亲性共聚物的结构和组成。荧光光谱分析表明,两种两亲性共聚物均具有较低的临界胶束浓度(CMC)值。动态光散射(DLS)和透射电子显微镜(TEM)结果表明,胶束粒径均一并呈现球形形态。
为了解两亲性共聚物与药物包合作用的规律和机理,以阿霉素(DOX)、环孢素A(CsA)和紫杉醇(PTX)三种药物作为模型。针对不同药物,采用纳米沉淀法、双乳法和乳化溶剂蒸发法,制备了包载药物的两亲性共聚物载药纳米粒子。利用紫外光谱或高效液相色谱研究了包载条件对药物包封率(EE)、载药量(LC)和粒径的影响,测定了药物的体外释放行为。研究了载药纳米粒子的细胞毒性,结果表明载药纳米粒子的杀伤细胞能力与浓度成正比,并且与单纯药物对细胞的杀伤程度相当。
It is well known that amphiphilic polymers consist of hydrophilic part and hydrophobic part in the structure. Due to this unique chemical structure, it can form a core-shell structure of polymer micelles in aqueous medium. The hydrophobic part forms the core and the hydrophilic part forms shell. They have unique advantages in macromolecular drugs, low water-solubility drugs and gene therapy as drug carriers.
In order to study the characteristics of amphiphilic polymers and drug-loaded nanoparticles(NPs), we used PAsp and gelatin as hydrophilic segment through copolymerizatinreaction, synthesized amphiphilic poly (L-aspartic acid co-L-lactide) grafted polymer and amphiphilic gelatin-polylactide grafted polymer. Then, we used 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine(DPPE) to synthesize two novel amphiphilic polymers that were poly(L-aspartic acid co-L-lactide)-1,2-dipalmitoyl-sn- glycero-3-phosphoethanolamine and gelatin-polylactide-1,2-dipalmitoyl-sn-glycero-3- phosphorethanolamine. The amphiphilic polymers were characterized by FT-IR and NMR. The fluorescence experiments showed that amphiphilic polymers have a very low critical micelle concentration (CMC).The dynamic light scatter (DLS) and transmission electron microscopy (TEM) experiments indicated that the nanoparticles had uniform particle size and were apt to a spherical shape.
To understand the molecular interaction mechanism of inclusion complex between amphiphilic polymers and the medicine, Doxorubicin hydrochloride(DOX), cyclosporin A(CsA) and paclitaxel (PTX) were chosen as model drug to study their vitro drug release behavior from nanoparticles. Drug-loaded nanoparticles were prepared by nanoprecipitation, double emulsion and emulsification solvent evaporation methods, respectively. Different factors which influence on particular size,encapsulation efficiency(EE) and drug-loaded content(LC) were investigated, and in vitro released characteristics were investigated by ultraviolet spectrum(UV) or high performance liquid chromatography (HPLC). We studied the cytotoxicity of the DOX-loaded NPs and PTX-loaded NPs. The results showed that the ability of killer cells of the drug-loaded nanoparticles was proportional to the concentration, the drug-loaded nanoparticles was the same on killer cells withthe drugs.
引文
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