基于阿霉素纳米粒子靶向药物输送体系的制备及其应用探讨
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摘要
本论文根据药物输送系统的要求，以生物相容材料介孔纳米硅粒子(MSN)、水溶性富勒烯(Fullerene)纳米粒子和嵌段共聚物胶束(P(DEMA-co-APMA)-b-PEGMA)为药物载体，设计与合成了三种多功能化的纳米粒子药物输送系统。本论文的研究集中于多功能化药物输送系统的制备及其应用。研究发现，我们所制备的药物输送系统具有pH值响应、光动力疗法(PDT)和叶酸靶向等功能，期望能为癌症治疗药物输送体系中的设计、合成和癌症治疗等方面的应用提供一些有益的参考。本论文的主要研究内容和结果如下：
(1)设计与合成了以介孔纳米硅粒子(MSN)为药物载体的多功能化抗癌前体药物输送体系。研究表明，具有适当粒径(180nm)的MSN药物输送体系不会出现非特异性的细胞摄入；带有叶酸基的前药纳米粒子DOX-Hydrazone-MSN-FA对叶酸受体(FR)阳性细胞具有靶向功能，叶酸基具有增强纳米粒子被FR阳性细胞内吞噬的效果；药物分子阿霉素(DOX)与载体通过酸敏感的羧酸腙键连接，使得此前体药物输送体系可以稳定于体内循环，而在酸性的环境下（肿瘤或癌细胞内）能快速地释放出游离的阿霉素。
(2)设计与合成了以水溶性富勒烯(Fullerene)纳米粒子为药物载体的多功能化抗癌前体药物输送体系。在此研究中，富勒烯纳米粒子表面上的大量亲水性齐聚乙二醇(OEG)链段、酸敏感羧腙键和酰胺键会导致分子间具有强烈相互作用（如氢键）的前药体系形成聚集体。我们通过优化和控制富勒烯表面上的功能化程度，把富勒烯聚集体的尺寸控制在135nm左右。抗癌药物阿霉素与水溶性富勒烯纳米粒子通过酸敏感羧腙键相连接，主动靶向分子叶酸（FA）通过酰胺化反应与富勒烯纳米粒子结合生成对FR阳性癌细胞具有靶向功能的前药体系。此外，用可以产生单线态氧的富勒烯(Fullerene)纳米粒子为药物载体可以为癌症治疗提供一种具有的双效治疗（化疗和PDT）的方法。
(3)设计与合成了以双pH值响应的嵌段共聚物胶束(P(DEMA-co-APMA)-b-PEGMA)为药物载体的多功能化抗癌药物输送体系。在此项研究中，两嵌段共聚物P(DEMA-co-APMA)-b-PEGMA疏水部分中的碱基腺嘌呤(A)与U-(CH_2)_6-U中的碱基尿嘧啶(U)互补配对形成超分子交联嵌段共聚物。因为同时具有亲疏水性相互转换和非共价交联的特点，所以超分子交联双亲性嵌段共聚物在水溶液可自主装成胶束并且有双pH值响应能力。这种新型的双pH值响应胶束不仅具有与传统共价交联聚合物胶束相似的性质，而且还能在微酸性的环境下快速释放出药物DOX。此外，在双pH值响应胶束表面引入靶向配体叶酸(FA)，即可以实现胶束药物输送系统对FR阳性肿瘤或癌细胞的靶向功能。
综上所述，本研究所制备的多功能化抗癌药物输送体系具有增强治疗癌症药效和减少阿霉素(DOX)毒副作用的效果，可望为今后药物输送体系的研究与开发提供一些依据和技术支持。
The three multi-functional nanoparticle drug delivery systems based on bio-compatibleand water-soluble mesoporous silica nanoparticles, fullerene aggregates and block copolymermicelles (P(DEMA-co-APMA)-b-PEGMA) were designed and synthesized. This thesis ismainly focused on the preparation and application of multi-functional drug delivery systems.This study demonstrates that the multi-functional drug delivery systems have strong responseto mildly acid pH values and are capable of rapidly releasing DOX, active targeting and PDTinside the cells to yield significantly enhanced drug efficacy. We expect to provide someuseful insights for designing and improving the applicability of the multi-functional drugdelivery systems in targeted anticancer prodrug systems. The main contents and results of thisthesis are as follows:
(1) A targeted anticancer prodrug system was fabricated with180nm mesoporoussilica nanoparticles (MSN) as carriers. The anticancer drug doxorubicin (DOX) wasconjugated to the particles through an acid-sensitive carboxylic hydrazone linker which iscleavable under the acidic conditions. Moreover, folic acid (FA) was covalently conjugated tothe particle surface as the targeting ligand for folate receptors (FR) over-expressed in somecancer cells. The in vitro release profiles of DOX from the MSN-based prodrug systemsshowed a strong dependence on the environmental pH values. Thus, with180nm MSN as thecarrier for the prodrug system, good drug loading, selective targeting and sustained release ofdrug molecules within targeted cancer cells can be realized.
(2) A multi-functional anti-cancer prodrug delivery systems based on water-solublefullerene nanoparticles was designed and synthesized. For the synthesis of thefullerene-aggregate-based targeted prodrug, a hydrophilic oligo(ethylene glycol)(OEG) linkerwas first covalently incorporated onto fullerene through fullerenol and succinic acid conjugate.After that, DOXs were conjugated onto the fullerene through the acid-sensitive carboxylichydrazone which is cleavable under acidic conditions. Moreover, an active targeting ligand(folic acid, FA) was also linked onto the fullerene through amidation reaction for targeting theFR-positive cancer cells. The large amounts of hydrophilic OEG linkers, hydrazone groupsand amide groups on the surface of fullerene could lead to strong intermolecular interactions (such as hydrogen bonding), and accordingly the prodrug readily formed aggregates. The sizeof fullerene aggregates was controlled at ca.135nm by optimizing the amounts of theconjugated functional groups. In addition, fullerene aggregates capable of generating singletoxygen1O2can provide a new method of combination therapy (chemotherapy and PDT).
(3) A multi-functional anti-cancer drug delivery system based on dual pH-responsiveblock copolymer micelles (P(DEMA-co-APMA)-b-PEGMA) was designed and synthesized.In the present work, the complementary adenine-uracil (A:U) base pair between A inhydrophobic core of micelles and cross-linker U-(CH_2)_6-U was employed to constructsupramolecular cross-linking block copolymers micelles (P (DEMA-co-APMA)-b-PEGMA).Benefiting from the reversible conversion between hydrophobicity and hydrophilicity in thecore of micelles and noncovalent cross-linking, P(DEMA-co-APMA)-b-PEGMA andU-(CH2)6-U could self-assemble into micelles with dual pH-responsive abilities in aqueoussolution. These novel stimuli-responsive micelles not only exhibited similar properties toconventional micelles from cross-linked micelles, but also rapid dual-pH response to mildacidic stimulus. Moreover, with folic acid as the targeting ligand, the cross-linked micellardrug delivery systems could be preferably internalized by FA-positive cells.
In summary, the multifunctional anticancer drug delivery systems have the effect ofenhanced efficacy and reduced side effects of doxorubicin (DOX) and may provide someuseful insights and alternative approachs for future research and development of new drugdelivery systems.
(1)设计与合成了以介孔纳米硅粒子(MSN)为药物载体的多功能化抗癌前体药物输送体系。研究表明，具有适当粒径(180nm)的MSN药物输送体系不会出现非特异性的细胞摄入；带有叶酸基的前药纳米粒子DOX-Hydrazone-MSN-FA对叶酸受体(FR)阳性细胞具有靶向功能，叶酸基具有增强纳米粒子被FR阳性细胞内吞噬的效果；药物分子阿霉素(DOX)与载体通过酸敏感的羧酸腙键连接，使得此前体药物输送体系可以稳定于体内循环，而在酸性的环境下（肿瘤或癌细胞内）能快速地释放出游离的阿霉素。
(2)设计与合成了以水溶性富勒烯(Fullerene)纳米粒子为药物载体的多功能化抗癌前体药物输送体系。在此研究中，富勒烯纳米粒子表面上的大量亲水性齐聚乙二醇(OEG)链段、酸敏感羧腙键和酰胺键会导致分子间具有强烈相互作用（如氢键）的前药体系形成聚集体。我们通过优化和控制富勒烯表面上的功能化程度，把富勒烯聚集体的尺寸控制在135nm左右。抗癌药物阿霉素与水溶性富勒烯纳米粒子通过酸敏感羧腙键相连接，主动靶向分子叶酸（FA）通过酰胺化反应与富勒烯纳米粒子结合生成对FR阳性癌细胞具有靶向功能的前药体系。此外，用可以产生单线态氧的富勒烯(Fullerene)纳米粒子为药物载体可以为癌症治疗提供一种具有的双效治疗（化疗和PDT）的方法。
(3)设计与合成了以双pH值响应的嵌段共聚物胶束(P(DEMA-co-APMA)-b-PEGMA)为药物载体的多功能化抗癌药物输送体系。在此项研究中，两嵌段共聚物P(DEMA-co-APMA)-b-PEGMA疏水部分中的碱基腺嘌呤(A)与U-(CH_2)_6-U中的碱基尿嘧啶(U)互补配对形成超分子交联嵌段共聚物。因为同时具有亲疏水性相互转换和非共价交联的特点，所以超分子交联双亲性嵌段共聚物在水溶液可自主装成胶束并且有双pH值响应能力。这种新型的双pH值响应胶束不仅具有与传统共价交联聚合物胶束相似的性质，而且还能在微酸性的环境下快速释放出药物DOX。此外，在双pH值响应胶束表面引入靶向配体叶酸(FA)，即可以实现胶束药物输送系统对FR阳性肿瘤或癌细胞的靶向功能。
综上所述，本研究所制备的多功能化抗癌药物输送体系具有增强治疗癌症药效和减少阿霉素(DOX)毒副作用的效果，可望为今后药物输送体系的研究与开发提供一些依据和技术支持。
The three multi-functional nanoparticle drug delivery systems based on bio-compatibleand water-soluble mesoporous silica nanoparticles, fullerene aggregates and block copolymermicelles (P(DEMA-co-APMA)-b-PEGMA) were designed and synthesized. This thesis ismainly focused on the preparation and application of multi-functional drug delivery systems.This study demonstrates that the multi-functional drug delivery systems have strong responseto mildly acid pH values and are capable of rapidly releasing DOX, active targeting and PDTinside the cells to yield significantly enhanced drug efficacy. We expect to provide someuseful insights for designing and improving the applicability of the multi-functional drugdelivery systems in targeted anticancer prodrug systems. The main contents and results of thisthesis are as follows:
(1) A targeted anticancer prodrug system was fabricated with180nm mesoporoussilica nanoparticles (MSN) as carriers. The anticancer drug doxorubicin (DOX) wasconjugated to the particles through an acid-sensitive carboxylic hydrazone linker which iscleavable under the acidic conditions. Moreover, folic acid (FA) was covalently conjugated tothe particle surface as the targeting ligand for folate receptors (FR) over-expressed in somecancer cells. The in vitro release profiles of DOX from the MSN-based prodrug systemsshowed a strong dependence on the environmental pH values. Thus, with180nm MSN as thecarrier for the prodrug system, good drug loading, selective targeting and sustained release ofdrug molecules within targeted cancer cells can be realized.
(2) A multi-functional anti-cancer prodrug delivery systems based on water-solublefullerene nanoparticles was designed and synthesized. For the synthesis of thefullerene-aggregate-based targeted prodrug, a hydrophilic oligo(ethylene glycol)(OEG) linkerwas first covalently incorporated onto fullerene through fullerenol and succinic acid conjugate.After that, DOXs were conjugated onto the fullerene through the acid-sensitive carboxylichydrazone which is cleavable under acidic conditions. Moreover, an active targeting ligand(folic acid, FA) was also linked onto the fullerene through amidation reaction for targeting theFR-positive cancer cells. The large amounts of hydrophilic OEG linkers, hydrazone groupsand amide groups on the surface of fullerene could lead to strong intermolecular interactions (such as hydrogen bonding), and accordingly the prodrug readily formed aggregates. The sizeof fullerene aggregates was controlled at ca.135nm by optimizing the amounts of theconjugated functional groups. In addition, fullerene aggregates capable of generating singletoxygen1O2can provide a new method of combination therapy (chemotherapy and PDT).
(3) A multi-functional anti-cancer drug delivery system based on dual pH-responsiveblock copolymer micelles (P(DEMA-co-APMA)-b-PEGMA) was designed and synthesized.In the present work, the complementary adenine-uracil (A:U) base pair between A inhydrophobic core of micelles and cross-linker U-(CH_2)_6-U was employed to constructsupramolecular cross-linking block copolymers micelles (P (DEMA-co-APMA)-b-PEGMA).Benefiting from the reversible conversion between hydrophobicity and hydrophilicity in thecore of micelles and noncovalent cross-linking, P(DEMA-co-APMA)-b-PEGMA andU-(CH2)6-U could self-assemble into micelles with dual pH-responsive abilities in aqueoussolution. These novel stimuli-responsive micelles not only exhibited similar properties toconventional micelles from cross-linked micelles, but also rapid dual-pH response to mildacidic stimulus. Moreover, with folic acid as the targeting ligand, the cross-linked micellardrug delivery systems could be preferably internalized by FA-positive cells.
In summary, the multifunctional anticancer drug delivery systems have the effect ofenhanced efficacy and reduced side effects of doxorubicin (DOX) and may provide someuseful insights and alternative approachs for future research and development of new drugdelivery systems.
引文
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