中空介孔纳米硅球的表面修饰及其药物控释性能研究
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摘要
中空介孔纳米硅球（Hollow mesoporous nanoparticles, HMS）具有优异的生物相容性，表面羟基可修饰性，良好的单分散性，天生的缓释能力，粒径与孔道大小的可调节性，较大的比表面积以及较高的载药量，因而在生物医用材料领域受到了广泛关注。然而未经修饰的HMS纳米粒子在应用于抗肿瘤药物输送过程中提出的到达靶向目标前药物的“零”释放和到达肿瘤部位之后的控制释放的要求依旧有所欠缺。针对上述在实际应用中中空介孔纳米硅球HMS存在的一些缺陷，本论文主要展开了以下三部分工作：
（1）在中空介孔纳米硅球表面修饰pH敏感两亲性嵌段聚合物，实现了纳米药物载体在肿瘤细胞中的控制释放。首先采用模板法合成了中空介孔纳米硅球，并在其表面通过原子转移自由基聚合（ATRP）成功地接枝了酸性条件可水解的两亲性聚合物poly(PDM-b-PEGMEM)，以实现药物在肿瘤内部偏酸性环境和刺激下可控释放。分别以发红色荧光的Nile Red和Doxorubicin（DOX）为模拟药物，通过荧光分光光度法测试了载体的载药量和输送和释放药物的性能，发现其具有高达80%左右载药效率，以及良好的酸性控释能力。分别以人体正常肝细胞L02和人体肺癌细胞7402为靶向细胞，结果显示所制备的纳米复合物能在肺癌细胞7402中靶向富集并释放药物，而在正常肝细胞L02中不释放。
（2）在中空介孔纳米硅球表面修饰稀土荧光材料并与pH敏感两亲性嵌段共聚物自组装，在实现控制释放的同时，赋予载体细胞荧光成像的功能。首先利用溶胶-凝胶法在中空介孔纳米硅球表面修饰上稀土材料YVO4:Eu3+，并在其表面修饰上长的烷基链（HMS@YVO4:Eu3+@C18），利用疏水基团之间的范德华力，在HMS@YVO_4:Eu~(3+)@C18表面自组装包裹上两亲性嵌段聚合物PMD得到复合纳米粒子HMS@YVO_4:Eu~(3+)@C18@PMD。通过TEM，DLS等表征发现，所得到的纳米粒子具有较小的粒径和良好的单分散性，呈内部中空、外部以介孔二氧化硅和聚合物为壳的核-壳结构。以布洛芬（IBU）为模拟药物，通过紫外分光光度法测算了其载药量高达834mg/g（药物/载体）。另外长烷基链的引入使得载体释放80%的药物时间从50h延长到150h，实现了载体的长效释放；酸性可降解的PMD的包裹实现了载体的药物控制释放；稀土荧光素的引入实现了载体细胞荧光成像的功能。
（3）在中空介孔纳米硅球表面修饰β-环糊精，并与两亲性偶氮聚合物自组装，通过紫外光照下偶氮基团的顺-反异构转变来实现药物的控制释放。首先通过“click”反应将β-环糊精（β-CD）修饰到中空介孔纳米硅球表得到HMS@β-CD，同时设计合成了含有偶氮苯结构的两亲性聚合物PPP（poly(PPHM-co-PEGMEM)）。PPP的偶氮苯基团呈低能态的反式结构时可在水相中通过自组装进入β-CD的环状内腔，而在紫外光照射下则转换为高能态的顺式结构，从β-CD的内腔脱出，该过程具有可逆性，具有潜在的光控释药的应用。通过TEM，DLS等表征发现，所得到的纳米粒子结构规整，粒径分布窄。通过紫外分光光度法证明了载体仅在紫外光照射时释放药物，具有人工控制药物释放的性能。
Due to their excellent biocompatibility, modifiable Si-OH on surface, goodmonodispersity, innate ability of sustained drug release, adjustability of particle and poresize, large specific surface area and high drug loading capacity, hollow mesoporous silicananoparticles (HMS) have received much attention in biomaterials. However, in thepractical application of drug delivery, there are still some defects in satisfying therequirements of “zero” release before carrier reaching target goals and controlled release.To solve the problem above, three part works were discussed below：
(1) We modified the Hollow mesoporous silica nanoparticles with the pH-sensitiveamphiphilic diblock copolymer to achieve the controlled drug release of carrier in cancercells. Firstly, hollow mesoporous silica nanoparticles were synthesized by model method,and an acid-sensitive amphiphilic polymer poly(PDM-b-PEGMEM) was grafted on thesurface of the nanoparticles by atom transfer radical polymerization (ATRP), the preparednanocomposites can achieve controlled drug releaas in acid enviroment of cancer cells. Weuse Nile Red and DOX with red fluorescence as model drugs and use fluorescencespectrophotometry to test the abilities of drug loading and release. The results showed thatthe nanocomposites possess high drug loading efficient about80%and good capacity ofcontrolled-release. Normal human liver cells L02and human lung cancer cells7402wereused as target cells, the results showed that the nanocomposites only release drug in cancercells.
(2) We modified the hollow mesoporous silica nanoparticles with fluorescencerare-earth and self-assemble with pH-sensitive amphiphilic diblock copolymer, thismaterials not only can achieve controlled drug release, but also can used foe cells imaging.Firstly, Fluorescence hollow mesoporous silica nanoparticles were synthesized bymodifying rare-earth via sol-gel process, then the fluorescence nanoparticles weremodified by long alkyl chains and coated with acid-sensitive amphiphilic polymer PMD through hydrophobic van der waals interactions. The results of characterization such asTEM and DLS reveal that the material shows excellent monodisperse sphericalmorphology and narrow size distribution (180nm) withhollow-core@mesoporous-silica-shell@thin-polymer-film structure. We use IBU as themodel drug and the drug loading content of the system is as high as834mg/g(drug/carrier). The time of releasing about80%drug was prolonged from50h to150h bythe effect of modified C18. The loaded drug is selectively released in mildly acidicenvironment by coating pH-sensitive polymer film. Besides, the nanocomposites wassuitable for cell imaging by modify the rare-earth.
(3) Hollow mesoporous silica nanoparticles were modified by β-cyclodextrin andself-assemble with amphiphilic polymers contained azobenzene groups, and this carrierscan release drugs in a control manner under UV-irradiation. β-Cyclodextrin (β-CD) wasmodified on the surface of hollow mesoporous silica nanoparticles by “click” reaction, andan amphiphilic polymer poly(PPHM-co-PEGMEM)(PPP) contain azobenzene groups wassynthesized. The azobenzene groups with lower energy state trans-structure can enter thecavity of β-CD under easily. After UV-irradiation, the structure of PPP would change intohigh energy state cis-structure and emerge from the β-CD cavity. This progress wasreversible and can be used in light-triggered drug release. The results of characterizationsuch as TEM and DLS reveal that the material shows excellent monodisperse sphericalmorphology and narrow size distribution. UV spectrophotometry comfirmed the carrieronly release drug under UV-irradiation. The nanocomposites have the performance withartificial control of drug release.
（1）在中空介孔纳米硅球表面修饰pH敏感两亲性嵌段聚合物，实现了纳米药物载体在肿瘤细胞中的控制释放。首先采用模板法合成了中空介孔纳米硅球，并在其表面通过原子转移自由基聚合（ATRP）成功地接枝了酸性条件可水解的两亲性聚合物poly(PDM-b-PEGMEM)，以实现药物在肿瘤内部偏酸性环境和刺激下可控释放。分别以发红色荧光的Nile Red和Doxorubicin（DOX）为模拟药物，通过荧光分光光度法测试了载体的载药量和输送和释放药物的性能，发现其具有高达80%左右载药效率，以及良好的酸性控释能力。分别以人体正常肝细胞L02和人体肺癌细胞7402为靶向细胞，结果显示所制备的纳米复合物能在肺癌细胞7402中靶向富集并释放药物，而在正常肝细胞L02中不释放。
（2）在中空介孔纳米硅球表面修饰稀土荧光材料并与pH敏感两亲性嵌段共聚物自组装，在实现控制释放的同时，赋予载体细胞荧光成像的功能。首先利用溶胶-凝胶法在中空介孔纳米硅球表面修饰上稀土材料YVO4:Eu3+，并在其表面修饰上长的烷基链（HMS@YVO4:Eu3+@C18），利用疏水基团之间的范德华力，在HMS@YVO_4:Eu~(3+)@C18表面自组装包裹上两亲性嵌段聚合物PMD得到复合纳米粒子HMS@YVO_4:Eu~(3+)@C18@PMD。通过TEM，DLS等表征发现，所得到的纳米粒子具有较小的粒径和良好的单分散性，呈内部中空、外部以介孔二氧化硅和聚合物为壳的核-壳结构。以布洛芬（IBU）为模拟药物，通过紫外分光光度法测算了其载药量高达834mg/g（药物/载体）。另外长烷基链的引入使得载体释放80%的药物时间从50h延长到150h，实现了载体的长效释放；酸性可降解的PMD的包裹实现了载体的药物控制释放；稀土荧光素的引入实现了载体细胞荧光成像的功能。
（3）在中空介孔纳米硅球表面修饰β-环糊精，并与两亲性偶氮聚合物自组装，通过紫外光照下偶氮基团的顺-反异构转变来实现药物的控制释放。首先通过“click”反应将β-环糊精（β-CD）修饰到中空介孔纳米硅球表得到HMS@β-CD，同时设计合成了含有偶氮苯结构的两亲性聚合物PPP（poly(PPHM-co-PEGMEM)）。PPP的偶氮苯基团呈低能态的反式结构时可在水相中通过自组装进入β-CD的环状内腔，而在紫外光照射下则转换为高能态的顺式结构，从β-CD的内腔脱出，该过程具有可逆性，具有潜在的光控释药的应用。通过TEM，DLS等表征发现，所得到的纳米粒子结构规整，粒径分布窄。通过紫外分光光度法证明了载体仅在紫外光照射时释放药物，具有人工控制药物释放的性能。
Due to their excellent biocompatibility, modifiable Si-OH on surface, goodmonodispersity, innate ability of sustained drug release, adjustability of particle and poresize, large specific surface area and high drug loading capacity, hollow mesoporous silicananoparticles (HMS) have received much attention in biomaterials. However, in thepractical application of drug delivery, there are still some defects in satisfying therequirements of “zero” release before carrier reaching target goals and controlled release.To solve the problem above, three part works were discussed below：
(1) We modified the Hollow mesoporous silica nanoparticles with the pH-sensitiveamphiphilic diblock copolymer to achieve the controlled drug release of carrier in cancercells. Firstly, hollow mesoporous silica nanoparticles were synthesized by model method,and an acid-sensitive amphiphilic polymer poly(PDM-b-PEGMEM) was grafted on thesurface of the nanoparticles by atom transfer radical polymerization (ATRP), the preparednanocomposites can achieve controlled drug releaas in acid enviroment of cancer cells. Weuse Nile Red and DOX with red fluorescence as model drugs and use fluorescencespectrophotometry to test the abilities of drug loading and release. The results showed thatthe nanocomposites possess high drug loading efficient about80%and good capacity ofcontrolled-release. Normal human liver cells L02and human lung cancer cells7402wereused as target cells, the results showed that the nanocomposites only release drug in cancercells.
(2) We modified the hollow mesoporous silica nanoparticles with fluorescencerare-earth and self-assemble with pH-sensitive amphiphilic diblock copolymer, thismaterials not only can achieve controlled drug release, but also can used foe cells imaging.Firstly, Fluorescence hollow mesoporous silica nanoparticles were synthesized bymodifying rare-earth via sol-gel process, then the fluorescence nanoparticles weremodified by long alkyl chains and coated with acid-sensitive amphiphilic polymer PMD through hydrophobic van der waals interactions. The results of characterization such asTEM and DLS reveal that the material shows excellent monodisperse sphericalmorphology and narrow size distribution (180nm) withhollow-core@mesoporous-silica-shell@thin-polymer-film structure. We use IBU as themodel drug and the drug loading content of the system is as high as834mg/g(drug/carrier). The time of releasing about80%drug was prolonged from50h to150h bythe effect of modified C18. The loaded drug is selectively released in mildly acidicenvironment by coating pH-sensitive polymer film. Besides, the nanocomposites wassuitable for cell imaging by modify the rare-earth.
(3) Hollow mesoporous silica nanoparticles were modified by β-cyclodextrin andself-assemble with amphiphilic polymers contained azobenzene groups, and this carrierscan release drugs in a control manner under UV-irradiation. β-Cyclodextrin (β-CD) wasmodified on the surface of hollow mesoporous silica nanoparticles by “click” reaction, andan amphiphilic polymer poly(PPHM-co-PEGMEM)(PPP) contain azobenzene groups wassynthesized. The azobenzene groups with lower energy state trans-structure can enter thecavity of β-CD under easily. After UV-irradiation, the structure of PPP would change intohigh energy state cis-structure and emerge from the β-CD cavity. This progress wasreversible and can be used in light-triggered drug release. The results of characterizationsuch as TEM and DLS reveal that the material shows excellent monodisperse sphericalmorphology and narrow size distribution. UV spectrophotometry comfirmed the carrieronly release drug under UV-irradiation. The nanocomposites have the performance withartificial control of drug release.
引文
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