环境响应性可逆交联的药物控释载体的设计与合成
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摘要
两亲性聚合物通过自组装形成的纳米组装体是理想的运载疏水性抗癌药物的载体之一。但是,纳米组装体注射到体内后,容易因稀释或与体内的其它物质相互作用发生解离而使药物提前释放,肿瘤靶向效率低,治疗效果差。对纳米载体进行交联可以提高其稳定性。然而,稳定交联的纳米载体在到达病灶部位后,药物难于释放出来,造成低药效。
本论文设计合成了四种新型两亲性“智能”高分子纳米药物载体用于抗癌药物阿霉素(doxorubicin, DOX)和紫杉醇(Paclitaxel, PTX)的触发释放。这些载体通过交联提高了稳定性,但是由于该交联剂可在肿瘤细胞内强还原性环境或肿瘤组织和内涵体内低pH环境下降解,把药物快速释放出来,从而达到安全高效运载药物的目的。主要工作包括如下四部分：
1.设计开发了基于双硫键交联的葡聚糖纳米粒子,用于抗癌药物阿霉素的触发释放。交联后的纳米粒子稳定性增强,对高度稀释和高的盐浓度都能保持稳定。体外实验表明交联的载阿霉素的纳米粒子(DS=80)对阿霉素的释放具有还原响应性：在10 mM PB中经过11小时后释放出10%的阿霉素,但在10 mM DTT存在条件下(模拟细胞内还原环境),11小时后释放出90%的阿霉素。MTT结果表明交联的载阿霉素的纳米粒子与未交联的载阿霉素的纳米粒子具有相近的药效。激光共聚焦显微镜(CLSM)观察结果表明,该纳米粒子将阿霉素快速运载并释放到Hela细胞核内。该葡聚糖纳米粒子制备简单,具有良好的生物相容性、降解性、高载药效率、高效细胞内药物释放等多重功能性,在癌症治疗领域具有广阔的应用前景。
2.成功地合成了具有不同硫辛酸取代度的两种不同分子量的聚乙烯醇衍生物,并制备了交联的纳米粒子。交联后的纳米粒子稳定性增强。PVA86-89-LA(DS=16)交联的载阿霉素的纳米粒子对阿霉素的释放具有还原响应性。以Hela细胞为研究对象的荧光显微镜观察结果表明,交联的载阿霉素的纳米粒子可以非常有效的释放出阿霉素到细胞里。细胞毒性结果表明交联的载阿霉素的纳米粒子保持了高药效。
3.合成了一系列聚己内酯-聚乙烯亚胺-聚乙二醇(PCL-PEI-PEG)共聚物,并制备了相应的聚合物的胶束,这些胶束可在水溶液中通过3,3'-二硫代二丙酸(DTDPA)交联而得到界面交联的胶束。交联后的胶束稳定性增强。DTDPA交联的载阿霉素的胶束经过12小时后,释放出少于20%的阿霉素,但在10 mM DTT存在条件下,经过12小时后阿霉素几乎定量释放出来。CLSM观察结果证明了DTDPA交联的载阿霉素的胶束可以快速从内涵体中逃逸出来,在细胞质中解交联并释放出阿霉素。
4.制备了一系列乌头酸酐(CAA)界面交联的共聚物聚己内酯-聚乙烯亚胺-聚乙二醇(PCL-PEI-PEG)的胶束用于抗癌药物紫杉醇的触发释放。CAA交联的胶束对高度稀释和生理盐浓度都能保持稳定。体外释放实验表明CAA交联的载紫杉醇的胶束对紫杉醇的释放具有良好的pH响应性。
Nanosized particles formed by self-assembly of amphiphilic copolymer are one of most ideal nano-carriers for hydrophobic antitumor drugs. However, these nano-carriers after in vivo administration may subject to dissociation and premature drug release due to extensive dilution and interactions with biomolecules, resulting in diminished tumor-targetability. Their stability may be enhanced by cross-linking. It should be noted, nevertheless, that stably crosslinked nano-carriers though arriving at the disease site may not be able to efficiently release drug, leading to low drug efficacy.
In this thesis, four novel types of amphiphilic "intelligent" nano-carriers for triggered release of anti-cancer drugs including doxorubicin (DOX) and paclitaxel (PTX) were designed and evaluated in vitro. The stability of these nano-carriers was markedly enhanced through cross-linking. However, because the crosslinker can be reversed under the reductive environments encountered in cancer cells or mildly acidic environments in endosome, drugs are efficiently released inside cells, resulting in safe and efficient drug delivery. The thesis includes following four parts:
Part I:Disulfide-crosslinked dextran nanoparticles were designed for triggered release of doxorubicin, an antitumor drug. The crosslinked nanoparticles were stable against large volume dilution and concentrated salt condition. In vitro release studies showed reduction-responsive release of doxorubicin. For example, only 10% DOX was released from dextran-lipoic acid with a substitution degree (DS), after 11 hours in 10 mM PB. However,90% DOX was released in 11 hours in the presence of 10 mM DTT (mimicking the intracelullar reductive environment) under otherwise the same conditions. MTT assays displayed that DOX loaded crosslinked nanoparticles had a similar drug efficacy to the non-crosslinked counterparts. The intracellular trafficking of DOX in HeLa cells using confocal laser scanning microscopy (CLSM) revealed that DOX-loaded crosslinked nanoparticles efficiently delivered and released DOX into the cell nucleus. These novel nano-vehicles yet simple display unprecedented multi-functionalities, such as biocompatibility, degradability, high drug loading and efficient drug release inside cells, which render them superb for tumor-targeted delivery of anticancer drugs.
Part II:Crosslinked nanoparticles were prepared from polyvinyl alcohol-lipoic acid derivatives. These crosslinked nanoparticles showed enhanced stability. The release studies revealed reduction-sensitive DOX release from DOX-loaded crosslinked nanoparticles. The intracellular release of DOX from the crosslinked nanoparticles followed by CLSM using Hela cells showed that DOX-loaded crosslinked nanoparticles efficiently delivered and released DOX into the cells. Toxicity studies demonstrated that DOX loaded crosslinked nanoparticles had a similar drug efficacy to the non-crosslinked counterparts.
Part III:Micelles based on poly(ε-caprolactone)-polyethylenimine-poly(ethylene glycol) (PCL-PEI-PEG) copolymers were prepared and crosslinked at the interface using 3,3'-dithiodipropionic acid (DTDPA) as a crosslinker under aqueous conditions. The resulting crosslinked micelles had improved stability The DOX release from DTDPA crosslinked PCL-PEI-PEG2 micelles was less than 20% in 12 h. However, in the presence of 10 mM DTT under otherwise the same conditions., DOX was released nearly quantitatively in 12 h CLSM observations showed fast endosomal escape and rapid de-crosslinking of micelles in the cytoplasm, resulting in efficient intracellular DOX release.
Part IV:cis-aconitic acid anhydride(CAA) crosslinked PCL-PEI-PEG micelles were prepared and used for triggered release of paclitaxel. CAA-crosslinked micelles were stable against large volume dilution and physical salt condition. The in vitro release studies revealed that PTX release from CAA crosslinked PCL-PEI-PEG2 micelles were pH-dependant.
本论文设计合成了四种新型两亲性“智能”高分子纳米药物载体用于抗癌药物阿霉素(doxorubicin, DOX)和紫杉醇(Paclitaxel, PTX)的触发释放。这些载体通过交联提高了稳定性,但是由于该交联剂可在肿瘤细胞内强还原性环境或肿瘤组织和内涵体内低pH环境下降解,把药物快速释放出来,从而达到安全高效运载药物的目的。主要工作包括如下四部分：
1.设计开发了基于双硫键交联的葡聚糖纳米粒子,用于抗癌药物阿霉素的触发释放。交联后的纳米粒子稳定性增强,对高度稀释和高的盐浓度都能保持稳定。体外实验表明交联的载阿霉素的纳米粒子(DS=80)对阿霉素的释放具有还原响应性：在10 mM PB中经过11小时后释放出10%的阿霉素,但在10 mM DTT存在条件下(模拟细胞内还原环境),11小时后释放出90%的阿霉素。MTT结果表明交联的载阿霉素的纳米粒子与未交联的载阿霉素的纳米粒子具有相近的药效。激光共聚焦显微镜(CLSM)观察结果表明,该纳米粒子将阿霉素快速运载并释放到Hela细胞核内。该葡聚糖纳米粒子制备简单,具有良好的生物相容性、降解性、高载药效率、高效细胞内药物释放等多重功能性,在癌症治疗领域具有广阔的应用前景。
2.成功地合成了具有不同硫辛酸取代度的两种不同分子量的聚乙烯醇衍生物,并制备了交联的纳米粒子。交联后的纳米粒子稳定性增强。PVA86-89-LA(DS=16)交联的载阿霉素的纳米粒子对阿霉素的释放具有还原响应性。以Hela细胞为研究对象的荧光显微镜观察结果表明,交联的载阿霉素的纳米粒子可以非常有效的释放出阿霉素到细胞里。细胞毒性结果表明交联的载阿霉素的纳米粒子保持了高药效。
3.合成了一系列聚己内酯-聚乙烯亚胺-聚乙二醇(PCL-PEI-PEG)共聚物,并制备了相应的聚合物的胶束,这些胶束可在水溶液中通过3,3'-二硫代二丙酸(DTDPA)交联而得到界面交联的胶束。交联后的胶束稳定性增强。DTDPA交联的载阿霉素的胶束经过12小时后,释放出少于20%的阿霉素,但在10 mM DTT存在条件下,经过12小时后阿霉素几乎定量释放出来。CLSM观察结果证明了DTDPA交联的载阿霉素的胶束可以快速从内涵体中逃逸出来,在细胞质中解交联并释放出阿霉素。
4.制备了一系列乌头酸酐(CAA)界面交联的共聚物聚己内酯-聚乙烯亚胺-聚乙二醇(PCL-PEI-PEG)的胶束用于抗癌药物紫杉醇的触发释放。CAA交联的胶束对高度稀释和生理盐浓度都能保持稳定。体外释放实验表明CAA交联的载紫杉醇的胶束对紫杉醇的释放具有良好的pH响应性。
Nanosized particles formed by self-assembly of amphiphilic copolymer are one of most ideal nano-carriers for hydrophobic antitumor drugs. However, these nano-carriers after in vivo administration may subject to dissociation and premature drug release due to extensive dilution and interactions with biomolecules, resulting in diminished tumor-targetability. Their stability may be enhanced by cross-linking. It should be noted, nevertheless, that stably crosslinked nano-carriers though arriving at the disease site may not be able to efficiently release drug, leading to low drug efficacy.
In this thesis, four novel types of amphiphilic "intelligent" nano-carriers for triggered release of anti-cancer drugs including doxorubicin (DOX) and paclitaxel (PTX) were designed and evaluated in vitro. The stability of these nano-carriers was markedly enhanced through cross-linking. However, because the crosslinker can be reversed under the reductive environments encountered in cancer cells or mildly acidic environments in endosome, drugs are efficiently released inside cells, resulting in safe and efficient drug delivery. The thesis includes following four parts:
Part I:Disulfide-crosslinked dextran nanoparticles were designed for triggered release of doxorubicin, an antitumor drug. The crosslinked nanoparticles were stable against large volume dilution and concentrated salt condition. In vitro release studies showed reduction-responsive release of doxorubicin. For example, only 10% DOX was released from dextran-lipoic acid with a substitution degree (DS), after 11 hours in 10 mM PB. However,90% DOX was released in 11 hours in the presence of 10 mM DTT (mimicking the intracelullar reductive environment) under otherwise the same conditions. MTT assays displayed that DOX loaded crosslinked nanoparticles had a similar drug efficacy to the non-crosslinked counterparts. The intracellular trafficking of DOX in HeLa cells using confocal laser scanning microscopy (CLSM) revealed that DOX-loaded crosslinked nanoparticles efficiently delivered and released DOX into the cell nucleus. These novel nano-vehicles yet simple display unprecedented multi-functionalities, such as biocompatibility, degradability, high drug loading and efficient drug release inside cells, which render them superb for tumor-targeted delivery of anticancer drugs.
Part II:Crosslinked nanoparticles were prepared from polyvinyl alcohol-lipoic acid derivatives. These crosslinked nanoparticles showed enhanced stability. The release studies revealed reduction-sensitive DOX release from DOX-loaded crosslinked nanoparticles. The intracellular release of DOX from the crosslinked nanoparticles followed by CLSM using Hela cells showed that DOX-loaded crosslinked nanoparticles efficiently delivered and released DOX into the cells. Toxicity studies demonstrated that DOX loaded crosslinked nanoparticles had a similar drug efficacy to the non-crosslinked counterparts.
Part III:Micelles based on poly(ε-caprolactone)-polyethylenimine-poly(ethylene glycol) (PCL-PEI-PEG) copolymers were prepared and crosslinked at the interface using 3,3'-dithiodipropionic acid (DTDPA) as a crosslinker under aqueous conditions. The resulting crosslinked micelles had improved stability The DOX release from DTDPA crosslinked PCL-PEI-PEG2 micelles was less than 20% in 12 h. However, in the presence of 10 mM DTT under otherwise the same conditions., DOX was released nearly quantitatively in 12 h CLSM observations showed fast endosomal escape and rapid de-crosslinking of micelles in the cytoplasm, resulting in efficient intracellular DOX release.
Part IV:cis-aconitic acid anhydride(CAA) crosslinked PCL-PEI-PEG micelles were prepared and used for triggered release of paclitaxel. CAA-crosslinked micelles were stable against large volume dilution and physical salt condition. The in vitro release studies revealed that PTX release from CAA crosslinked PCL-PEI-PEG2 micelles were pH-dependant.
引文
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