基于聚乳酸的靶向药物释放载体材料的研究
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摘要
近年来，随着肿瘤发病率的不断提高，靶向药物治疗也得到了越来越多的关注，其中叶酸受体介导的靶向肿瘤药物释放系统也成为全球研究的热点。由叶酸介导的靶向药物释放系统和传统的药物释放系统相比较，前者对肿瘤细胞的生长增殖具有明显的抑制作用，并且对正常细胞来说具有较小的毒性，这为靶向药物治疗方案的发展提供了保证。然而，就目前的研究资料分析，对作为载体材料的纳米球与不同细胞之间的相互作用研究缺乏。由于普遍存在的一般细胞吞噬行为，所以正常细胞对靶向药物释放系统运输过程中的吞噬作用不容忽视，因为恰是这些正常细胞对载药粒子的吞噬引发了肿瘤化疗的毒副作用。因此，设计一种对肿瘤细胞具有很好的生长抑制作用而对正常细胞反之的纳米粒子将是一件有意义的事情。本研究拟以叶酸（FA），聚乳酸（PLA），聚乙二醇（PEG）为原料，在N，N-二环己基碳二亚胺（DCC）与N-羟基琥珀酰亚胺（NHS）或4-二甲氨基吡啶（DMAP）存在的条件下，利用活性酯溶液聚合法制备叶酸偶合的聚乙二醇-聚乳酸（FA-PEG-PLA）类材料，并通过傅里叶红外光谱仪（FTIR）、核磁共振波谱仪（1HNMR）、差式量热扫描仪（DSC）、接触角测定仪等对材料结构与有关性能进行定性及定量表征，初步考察了反应时间对偶合速率的影响；并以此制备材料为模型，采用溶剂挥发-纳米自组装法制备不同粒径的纳米球，初步考察了纳米球的溶血性能、降解性能、在一定体积水中聚合物胶束稳定存在的最大溶解度、降解液的体外细胞毒性、体外细胞的靶向选择性，并详细考察了不同粒径纳米球对正常细胞与肿瘤细胞生长增殖的不同影响，以此方法来筛选用于靶向肿瘤药物释放系统的合适纳米粒径等。主要研究内容与结论如下：
（1）以FA，PEG，PLA为原料，在DCC与NHS或DMAP存在的条件下，采用活性酯溶液聚合法制备FA-PEG-PLA，其中重点考察了反应时间对聚合产物中FA偶联效率的影响。
①FTIR与1HNMR的定性定量检测分析结果表明，采用本研究所述实验条件可制备出基于FA，PEG，PLA的FA-PEG-PLA多组分聚合物。研究表明，随着反应时间的进行，聚合物中FA的偶联量也随之增加；在经过24h前的快速增长后，FA偶联速率开始逐渐下降，说明随着生成物的增加，反应物的减少，反应速率逐渐下降，这种现象符合反应平衡规律；
②1HNMR检测结果分析表明，在本研究所设定的实验条件下，聚合产物中FA的偶联率在约11.6%～15.7%（mol%）或0.39%～0.53%（wt%）之间；
③DSC结果分析表明，在PEG分子量一定的情况下，随着PLA分子量的增加，FA的引入，产物玻璃化转变温度（Tg）由一个转变为两个，聚合产物出现微相分离，且温差范围呈现向两原料各自Tg中间靠拢趋势，这也表明所制得的聚合产物由微结构相容良好转向为部分相容；而在以dol-PLA为原料制备靶向性材料过程中，FA的引入，使得偶合前后的材料微结构发生了质的变化，Tg由未引入前的一个变为引入后的两个，这是一个有意思的发现；
结合②③的检测结果，分析表明所制备聚合物为多组分聚合物，微结构的相容程度主要由PEG与PLA链段长短决定；
④静态水接触角测试结果分析显示，材料的亲疏水性与FA的引入影响不大，其主要由PEG与PLA链段长度决定；
结合③④的检测结果，分析表明：虽然FA的引入对材料偶联前后亲疏水性影响不大，但对多组分聚合物的相容程度有时却起着关键作用；
⑤纳米空球的降解实验显示，在前三周降解速度非常快，主要为链段中酯键的无序断裂以及后来的酰胺键的断裂，到第三周时残留物分子量为最初聚合物分子量的25%，在降解进行到第七周时，残余物的分子量为最初分子量的8.8%，而根据降解拟合曲线方程，该纳米球在第八周将降解完全。
（2）以制备的FA-PEG-PLA为材料模型，采用溶剂挥发-纳米自组装法制备纳米粒子，并对其形态、粒径、表面电荷、临界胶束浓度（CMC）、稀释稳定性以及溶血性能等进行表征。
①通过FESEM观察得知所制备粒子呈现球状，不同条件制备纳米球粒径分别在65～160nm之间，球体表面携带负电荷；
②纳米球稀释稳定性实验表明，作为局部注射用药物释放系统载体，纳米球较小的CMC可以满足临床应用的要求，在生物体内保持聚合物胶束的稳定存在，以期避免药物“暴释”或“滞后”现象的发生；
③通过对纳米球制备工艺研究获知：聚合物纳米球在水溶液中稳定存在的最大浓度为18mg/20mL，在该条件下所制备纳米球的粒径在200nm以下；
④溶血性试验结果表明，采用该材料制备的纳米球具有很好的生物相容性，并且粒径大于120nm的粒子随浓度的升高，溶血率呈现降低趋势；
（3）在体外细胞实验中，将纳米球浸提液与人血管内皮细胞（EC）和人乳腺癌细胞（MCF-7）共同培养，采用CCK-8方法初步考察浸提液对细胞增殖的影响，同时详细考察了不同粒径、不同浓度的纳米球对正常细胞与肿瘤细胞增殖的影响，以确定用于靶向肿瘤药物释放系统载体的合适粒径。
①FA-PEG-PLA纳米球浸提液对细胞增殖-毒性影响实验表明，MCF-7比EC对浸提液的反应更为敏感，在实验过程中，浸提液对MCF-7的细胞毒性一直处于1级水平，而随着时间的延续，对EC的细胞毒性分级变化为：0级→1级→0级，这也说明了浸提液的生物安全性和EC细胞对浸提液所产生的影响从感应到适应的变化过程；
②通过研究不同粒径粒子对MCF-7与EC增殖的影响来确定用于靶向药物释放系统合适的载体粒径。结果表明，粒子随作用对象不同呈现不同作用效果，并且通过不同粒径粒子对MCF-7与EC生长情况的影响，筛选出纳米粒径在120nm左右为靶向肿瘤药物释放系统载体的最佳粒子，在这个尺寸范围，在不考虑包埋药物的作用下，单纯的药物释放系统载体——纳米粒子的纳米特性对MCF-7细胞生长具有明显抑制性，而对EC的生长则没有影响，同时保证纳米球具有最大载药能力；
③根据不同浓度纳米球对细胞增殖的影响结果表明，在本研究实验范围内，浓度变化对EC生长影响不大，呈现差异无统计学意义；而MCF-7则对纳米球呈现浓度依赖性趋势，随浓度的增加影响更加明显，细胞增殖呈现差异显著性统计学意义。
The targeted therapies have been obtained more and more attention as the tumor incidence increases recently. Among of which, folate-mediated targeting-drug released system (FMTDRS) based on biodegradable and biocompatible polymers have been a hot point research throughout the world. Comparing with the conventional tumor therapies, FMTDRS have obviously targeting effect on tumor cells and have slightly inhibited effect to normal tissue cells, which provide a guarantee for targeting therapies. But to our knowledge, there is little research only pure without drug-loaded nanoparticles materials. Hereon, folate conjugated poly(ethylene glycol) block poly(D,L-lactic acid)(FA-PEG-PLA) was synthesized from poly(D,L-lactic acid)(PLA) with different molecular weight, amino-terminated poly(ethylene glycol)(NH2-PEG-NH2) and folic acid (FA), using dicyclo-hexylcarbodiimide (DCC) and N-hydroxy-succinimide (NHS) or4-dimethylaminopyrid (DMAP) as dehydrating agent and activating agent respectively. Fourier transform infrared spectrometry (FTIR), nuclear magnetic resonance spectrometry (NMR), differential scanning calorimeter (DSC) and contact angle meter were employed to characterize the structures and properties of the obtained polymers. Nanoparticles (NPs) were further fabricated from FA-PEG-PLA by using solvent evaporation-induced interfacial self-assembly method, and thereafter, the hemolysis, biodegradation, cell proliferation and cytotoxicity, and selecting capability to different cells in vitro were investigated to nanoparticles. The main works and conclusions are summarized as follows:
(1) FA-PEG-PLA was prepared of FA, NH2-PEG-NH2and PLA via active ester method using DCC and NHS or DMAP as dehydrating agent and activating agent respectively. Then, an extensive investigation effort was expended in understanding the effects of reaction time on grafting folate onto FA-PEG-PLA.
①FTIR,1H NMR analysis showed that FA-PEG-PLA was successfully synthesized by using above mentioned method. And as the reacting time, more and more FA grafted on copolymer. During the first24h of reacting time, the ratio of graftion increased more quickly but after that it became slowdown, which agreeing with the reaction balance law that reaction rate slowed down gradually along with the formation of product and the reduction of reactant;
②1H NMR analysis indicated that the percent grafting of FA onto FA-PEG-PLA was in the range of11.6%-15.7%(mol%) or0.39%-0.53%(wt%);
③DSC analysis showed that multicomponent polymer appeared the microphase-separation along with the increase of molecular weight of PLA in certain case, glass transition temperature (Tg) changing from one to two, and the difference temperature range appeared to two raw materials temperature intermediate closing tendency, all which also showed that the obtained materials was component polymer;
The combination of the test results of②and③analysis showed that the obtained polymer was multicomponent polymer;
④The static water contact angle test results showed that the introduction of FA had little effect on material hydrophobicity, and which is mainly decided by composting of PEG and PLA chain length;
The combination of the test results of③and④analysis indicated that:The introduction effect of FA on coupling material hydrophilic and hydrophobic property would-be ignored in most time but on the material microphase-separation sometimes maybe play a key role;
⑤The result of the degradation of nanoparticles showed that the nanoparticles degradation speed was very fast, mainly for the bond fracture in disorder in the first three weeks, and the residues molecular weight was25%of its initial value after three weeks. As the degradation, the ratio of bond fracture became slowdown and the residues molecular weight gradually decreased, reaching8.8%of its initial value after seven weeks. According to the fitting equation of a degradation curve, the nanoparticles will be degraded completely in eighth weeks.
(2) The obtained FA-PEG-PLA was further used to fabricate nanoparticles by solvent evaporation-induced interfacial self-assembly method and the nanoparticles surface morphology, size, distribution, zeta potential, critical micelle concentration (CMC) and the dilution stability were characterized respectively.
①The particles prepared was spherical and size was in a range from65to160nm characterized by FESEM and DLS, and at the same time, nanoparticles surface carrying the negative charge;
②The dilution stability test result indicated that the CMC of nanoparticles could meet the requirements for clinical application and the nanoparticles could keep stable micelle structure in vivo as local injection of drug release system carrier, hoping to prevent drug "bursting" or "lagging" release;
③By the study on preparing technology of nanoparticles, we found the maximal stable concentration of the obtained FA-PEG-PLA nanoparticles was0.9mg/mL, and on this condition, the obtained nanoparticles size was below200nm;
④The hemolysis results showed that these nanoparticles have good biocompatibility, and which has not dose-dependent when the particle size was bigger than121nm.
(3) The effect of polymer extraction solution on different cells was studied by cell counting kit-8(CCK-8), and then, an extensive investigation effort was made to determine the right particles size using for targeting tumor drug release system carrier, which was about the effect of different size/dose nanoparticles on EC and MCF-7cell proliferation and cytotoxicity in vitro.
①The cell proliferation and cytotoxicity of FA-PEG-PLA NPs extraction solution were evaluated by means of CCK-8assay using MCF-7and EC as model cells. The result showed that MCF-7whose cytotoxicity grade kept1was more sensitive than EC to extract, and that of EC changed from0to1to0according to the relationship between cell proliferation rate and cytotoxicity grade of USP, suggesting that extract is almost non-toxic to normal tissue cells;
②The effect of different size nanoparticles on MCF-7and EC cell proliferation were investigated according on①of (3) method to determine the right particles size for targeting drug release system. The result told that the difference was happened between two kinds of cells. And by this way, it was found that the particles size about121nm was the right size for targeting tumor drug release system, which affected MCF-7proliferation and not for EC, furthermore, it's a guarantee for nanoparticles promising higher drug encapsulation;
③In this study, MCF-7cell proliferation showed dose-dependence of nanoparticles but EC not.
（1）以FA，PEG，PLA为原料，在DCC与NHS或DMAP存在的条件下，采用活性酯溶液聚合法制备FA-PEG-PLA，其中重点考察了反应时间对聚合产物中FA偶联效率的影响。
①FTIR与1HNMR的定性定量检测分析结果表明，采用本研究所述实验条件可制备出基于FA，PEG，PLA的FA-PEG-PLA多组分聚合物。研究表明，随着反应时间的进行，聚合物中FA的偶联量也随之增加；在经过24h前的快速增长后，FA偶联速率开始逐渐下降，说明随着生成物的增加，反应物的减少，反应速率逐渐下降，这种现象符合反应平衡规律；
②1HNMR检测结果分析表明，在本研究所设定的实验条件下，聚合产物中FA的偶联率在约11.6%～15.7%（mol%）或0.39%～0.53%（wt%）之间；
③DSC结果分析表明，在PEG分子量一定的情况下，随着PLA分子量的增加，FA的引入，产物玻璃化转变温度（Tg）由一个转变为两个，聚合产物出现微相分离，且温差范围呈现向两原料各自Tg中间靠拢趋势，这也表明所制得的聚合产物由微结构相容良好转向为部分相容；而在以dol-PLA为原料制备靶向性材料过程中，FA的引入，使得偶合前后的材料微结构发生了质的变化，Tg由未引入前的一个变为引入后的两个，这是一个有意思的发现；
结合②③的检测结果，分析表明所制备聚合物为多组分聚合物，微结构的相容程度主要由PEG与PLA链段长短决定；
④静态水接触角测试结果分析显示，材料的亲疏水性与FA的引入影响不大，其主要由PEG与PLA链段长度决定；
结合③④的检测结果，分析表明：虽然FA的引入对材料偶联前后亲疏水性影响不大，但对多组分聚合物的相容程度有时却起着关键作用；
⑤纳米空球的降解实验显示，在前三周降解速度非常快，主要为链段中酯键的无序断裂以及后来的酰胺键的断裂，到第三周时残留物分子量为最初聚合物分子量的25%，在降解进行到第七周时，残余物的分子量为最初分子量的8.8%，而根据降解拟合曲线方程，该纳米球在第八周将降解完全。
（2）以制备的FA-PEG-PLA为材料模型，采用溶剂挥发-纳米自组装法制备纳米粒子，并对其形态、粒径、表面电荷、临界胶束浓度（CMC）、稀释稳定性以及溶血性能等进行表征。
①通过FESEM观察得知所制备粒子呈现球状，不同条件制备纳米球粒径分别在65～160nm之间，球体表面携带负电荷；
②纳米球稀释稳定性实验表明，作为局部注射用药物释放系统载体，纳米球较小的CMC可以满足临床应用的要求，在生物体内保持聚合物胶束的稳定存在，以期避免药物“暴释”或“滞后”现象的发生；
③通过对纳米球制备工艺研究获知：聚合物纳米球在水溶液中稳定存在的最大浓度为18mg/20mL，在该条件下所制备纳米球的粒径在200nm以下；
④溶血性试验结果表明，采用该材料制备的纳米球具有很好的生物相容性，并且粒径大于120nm的粒子随浓度的升高，溶血率呈现降低趋势；
（3）在体外细胞实验中，将纳米球浸提液与人血管内皮细胞（EC）和人乳腺癌细胞（MCF-7）共同培养，采用CCK-8方法初步考察浸提液对细胞增殖的影响，同时详细考察了不同粒径、不同浓度的纳米球对正常细胞与肿瘤细胞增殖的影响，以确定用于靶向肿瘤药物释放系统载体的合适粒径。
①FA-PEG-PLA纳米球浸提液对细胞增殖-毒性影响实验表明，MCF-7比EC对浸提液的反应更为敏感，在实验过程中，浸提液对MCF-7的细胞毒性一直处于1级水平，而随着时间的延续，对EC的细胞毒性分级变化为：0级→1级→0级，这也说明了浸提液的生物安全性和EC细胞对浸提液所产生的影响从感应到适应的变化过程；
②通过研究不同粒径粒子对MCF-7与EC增殖的影响来确定用于靶向药物释放系统合适的载体粒径。结果表明，粒子随作用对象不同呈现不同作用效果，并且通过不同粒径粒子对MCF-7与EC生长情况的影响，筛选出纳米粒径在120nm左右为靶向肿瘤药物释放系统载体的最佳粒子，在这个尺寸范围，在不考虑包埋药物的作用下，单纯的药物释放系统载体——纳米粒子的纳米特性对MCF-7细胞生长具有明显抑制性，而对EC的生长则没有影响，同时保证纳米球具有最大载药能力；
③根据不同浓度纳米球对细胞增殖的影响结果表明，在本研究实验范围内，浓度变化对EC生长影响不大，呈现差异无统计学意义；而MCF-7则对纳米球呈现浓度依赖性趋势，随浓度的增加影响更加明显，细胞增殖呈现差异显著性统计学意义。
The targeted therapies have been obtained more and more attention as the tumor incidence increases recently. Among of which, folate-mediated targeting-drug released system (FMTDRS) based on biodegradable and biocompatible polymers have been a hot point research throughout the world. Comparing with the conventional tumor therapies, FMTDRS have obviously targeting effect on tumor cells and have slightly inhibited effect to normal tissue cells, which provide a guarantee for targeting therapies. But to our knowledge, there is little research only pure without drug-loaded nanoparticles materials. Hereon, folate conjugated poly(ethylene glycol) block poly(D,L-lactic acid)(FA-PEG-PLA) was synthesized from poly(D,L-lactic acid)(PLA) with different molecular weight, amino-terminated poly(ethylene glycol)(NH2-PEG-NH2) and folic acid (FA), using dicyclo-hexylcarbodiimide (DCC) and N-hydroxy-succinimide (NHS) or4-dimethylaminopyrid (DMAP) as dehydrating agent and activating agent respectively. Fourier transform infrared spectrometry (FTIR), nuclear magnetic resonance spectrometry (NMR), differential scanning calorimeter (DSC) and contact angle meter were employed to characterize the structures and properties of the obtained polymers. Nanoparticles (NPs) were further fabricated from FA-PEG-PLA by using solvent evaporation-induced interfacial self-assembly method, and thereafter, the hemolysis, biodegradation, cell proliferation and cytotoxicity, and selecting capability to different cells in vitro were investigated to nanoparticles. The main works and conclusions are summarized as follows:
(1) FA-PEG-PLA was prepared of FA, NH2-PEG-NH2and PLA via active ester method using DCC and NHS or DMAP as dehydrating agent and activating agent respectively. Then, an extensive investigation effort was expended in understanding the effects of reaction time on grafting folate onto FA-PEG-PLA.
①FTIR,1H NMR analysis showed that FA-PEG-PLA was successfully synthesized by using above mentioned method. And as the reacting time, more and more FA grafted on copolymer. During the first24h of reacting time, the ratio of graftion increased more quickly but after that it became slowdown, which agreeing with the reaction balance law that reaction rate slowed down gradually along with the formation of product and the reduction of reactant;
②1H NMR analysis indicated that the percent grafting of FA onto FA-PEG-PLA was in the range of11.6%-15.7%(mol%) or0.39%-0.53%(wt%);
③DSC analysis showed that multicomponent polymer appeared the microphase-separation along with the increase of molecular weight of PLA in certain case, glass transition temperature (Tg) changing from one to two, and the difference temperature range appeared to two raw materials temperature intermediate closing tendency, all which also showed that the obtained materials was component polymer;
The combination of the test results of②and③analysis showed that the obtained polymer was multicomponent polymer;
④The static water contact angle test results showed that the introduction of FA had little effect on material hydrophobicity, and which is mainly decided by composting of PEG and PLA chain length;
The combination of the test results of③and④analysis indicated that:The introduction effect of FA on coupling material hydrophilic and hydrophobic property would-be ignored in most time but on the material microphase-separation sometimes maybe play a key role;
⑤The result of the degradation of nanoparticles showed that the nanoparticles degradation speed was very fast, mainly for the bond fracture in disorder in the first three weeks, and the residues molecular weight was25%of its initial value after three weeks. As the degradation, the ratio of bond fracture became slowdown and the residues molecular weight gradually decreased, reaching8.8%of its initial value after seven weeks. According to the fitting equation of a degradation curve, the nanoparticles will be degraded completely in eighth weeks.
(2) The obtained FA-PEG-PLA was further used to fabricate nanoparticles by solvent evaporation-induced interfacial self-assembly method and the nanoparticles surface morphology, size, distribution, zeta potential, critical micelle concentration (CMC) and the dilution stability were characterized respectively.
①The particles prepared was spherical and size was in a range from65to160nm characterized by FESEM and DLS, and at the same time, nanoparticles surface carrying the negative charge;
②The dilution stability test result indicated that the CMC of nanoparticles could meet the requirements for clinical application and the nanoparticles could keep stable micelle structure in vivo as local injection of drug release system carrier, hoping to prevent drug "bursting" or "lagging" release;
③By the study on preparing technology of nanoparticles, we found the maximal stable concentration of the obtained FA-PEG-PLA nanoparticles was0.9mg/mL, and on this condition, the obtained nanoparticles size was below200nm;
④The hemolysis results showed that these nanoparticles have good biocompatibility, and which has not dose-dependent when the particle size was bigger than121nm.
(3) The effect of polymer extraction solution on different cells was studied by cell counting kit-8(CCK-8), and then, an extensive investigation effort was made to determine the right particles size using for targeting tumor drug release system carrier, which was about the effect of different size/dose nanoparticles on EC and MCF-7cell proliferation and cytotoxicity in vitro.
①The cell proliferation and cytotoxicity of FA-PEG-PLA NPs extraction solution were evaluated by means of CCK-8assay using MCF-7and EC as model cells. The result showed that MCF-7whose cytotoxicity grade kept1was more sensitive than EC to extract, and that of EC changed from0to1to0according to the relationship between cell proliferation rate and cytotoxicity grade of USP, suggesting that extract is almost non-toxic to normal tissue cells;
②The effect of different size nanoparticles on MCF-7and EC cell proliferation were investigated according on①of (3) method to determine the right particles size for targeting drug release system. The result told that the difference was happened between two kinds of cells. And by this way, it was found that the particles size about121nm was the right size for targeting tumor drug release system, which affected MCF-7proliferation and not for EC, furthermore, it's a guarantee for nanoparticles promising higher drug encapsulation;
③In this study, MCF-7cell proliferation showed dose-dependence of nanoparticles but EC not.
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