基于壳聚糖的纳米载体系统的构建及其肿瘤靶向性研究
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摘要
癌症在当今社会已经成为人类健康的头号杀手之一,其治疗的关键在于靶向性。利用纳米技术结合受体－配体介导的肿瘤主动靶向技术，以天然无毒可降解的生物材料为载体材料用于包载抗癌药物，是一种治疗癌症的有效途径。
利用恶性肿瘤细胞较正常细胞过度表达葡萄糖转运蛋白1（GLUT1）的特点，将其配体葡萄糖以丁二酸为连接臂共价连接在水溶性壳聚糖（WSC）分子链上，得到新型壳聚糖衍生物，胺糖化壳聚糖（GSC）。红外、核磁检测证实了2-（3-羧基-1-丙酰氨基）-2-脱氧-D-葡萄糖（GS）侧链成功连接在壳聚糖上，元素分析结果表明GSC的侧链取代度为9.27%。热重分析结果表明侧链的引入，破坏了壳聚糖分子的刚性结构，削弱了分子内和分子间的作用力，使得GSC的热稳定性比WSC差。通过芘荧光探针法测定GSC的临界聚集浓度为0.021mg/ml，说明在高于此浓度下，GSC溶液中有稳定的疏水微区形成。以FITC为荧光标记，共价修饰在多糖主链上，不仅可以对该载体材料定位示踪，其疏水基团还有利于包载疏水性药物分子。根据FWSC和FGSC溶液的荧光强度计算得两种荧光材料的荧光标记效率分别为1.39%和1.23%。
利用离子交联法制备了WSC纳米粒（WSC NPs），zeta电位和平均粒径分别为11.5mV和185.5nm；利用超声自组装法分别制备了GSC纳米粒（GSCNPs）、FWSC纳米粒（FWSC NPs）和FGSC纳米粒（FGSC NPs），zeta电位依次为23.9mV，25.8mV和19.5mV，平均粒径依次为89.3nm、92.9nm和100.8nm。透射电镜观察WSC NPs和GSC NPs均为完整的球形，其中自组装法制得的GSC NPs大小均一，分散均匀；相比较而言，离子交联法制得的WSC NPs大小差异较大，粒径分布较宽，粒子间有团聚现象。红细胞溶血实验表明，WSCNPs和GSC NPs的溶血率均小于5%，符合生物医用材料对溶血率的要求。蛋白吸附实验结果表明WSC NPs和GSC NPs对牛血清蛋白（BSA）均有较低水平的非特异性蛋白吸附，结合溶血实验共同证明了两种纳米粒均具有较好的血液相容性。MTT法检测了新型载体材料GSC NPs和FGSC NPs的细胞毒性，结果表明两种纳米粒对胎鼠成纤维细胞（MEF）、小鼠乳腺癌细胞（4T1）和人乳腺癌细胞（MCF-7）在检测范围内的细胞成活率均大于70%，均未表现出细胞毒性。
选用脂溶性抗癌药物阿霉素（DOX）作为模型药物，通过超声结合透析法制备了DOX-FWSC纳米粒（DOX-FWSC NPs）和DOX-FGSC纳米粒（DOX-FGSCNPs），zeta电位分别为23mV和15.6mV；平均粒径分别为136.6nm和153.1nm；载药量分别为12.53%和20.1%；包封率分别为40.37%和64.8%。利用透析法研究了两种载药纳米粒的释药动力学：在pH7.4释药介质中，前7小时释放速率较快，有明显的突释现象；随后进入缓释阶段，47h内DOX-FWSC NPs和DOX-FGSC NPs的累积释药量分别为37%和32%；当改变释药介质的pH至4.9后，原本达到释药平衡的载药纳米粒又在7小时内出现明显的突释现象，在随后的64h继续缓释，118h内DOX-FWSC NPs和DOX-FGSC NPs的累积释药量分别为92%和85%，结果说明所制备的两种载药纳米粒均具有较好的缓控释性能。
利用MEF，MCF-7和4T1三种细胞对FWSC NPs和FGSC NPs的摄取率做了定量测定，结果表明相同实验条件下，FGSC NPs的细胞吞噬率均高于FWSCNPs，可以推断FGSC NPs的细胞吞噬不仅依赖于粒子表面与细胞膜之间的静电作用，同样受益于靶向基团的修饰，使得三种模型细胞均对其有较高的细胞摄取率。以4T1为细胞模型，考察了DOX-FWSC NPs，DOX-FGSC NPs和临床用药—盐酸阿霉素（ADR）对细胞的生长抑制效果，结果显示三种测试样品对细胞的生长抑制均随药物浓度的增大而提高，当药物浓度为2μg/ml时，三种材料对细胞的生长抑制作用由强到弱依次是：DOX-FGSC NPs＞ADR＞DOX-FWSCNPs，说明DOX-FGSC NPs在低药物浓度时比ADR具有更好的肿瘤细胞生长抑制作用，该结论与荧光显微镜观察到的结果相一致。体外细胞实验结果初步判断由GSC制备的纳米载体利于细胞吞噬，具有肿瘤细胞靶向性。
建立小鼠乳腺癌动物模型，分别检测ADR，DOX-FWSC NPs与DOX-FGSCNPs对荷瘤小鼠的体内抗肿瘤作用，通过测量小鼠的肿瘤体积、体重、各组织中的药物分布，结果发现DOX-FGSC NPs具有较好的抑瘤效果且对机体均无明显毒副作用，不仅得益于其亲水外壳和较小的粒径使之被动靶向蓄积于肿瘤组织，还得益于其靶向基团的修饰，使其能利用受体—配体介导的主动靶向作用，蓄积于肿瘤组织的同时减小药物在其他器官中的蓄积。双抗体一步夹心法测定了荷瘤小鼠各组织器官中的GLUT1表达水平，对照相应组织中的药物含量，进一步证实DOX-FGSC NPs对肿瘤组织的主动靶向性依赖于它对GLUT1的主动靶向性。
本论文以水溶性壳聚糖为基础材料，研究了一种新型受体—配体（GLUT1—葡萄糖）介导的肿瘤细胞靶向技术，通过体外、体内实验评价了该载体材料的生物安全性和靶向性。实验结果显示该靶向修饰的载体材料有望成为集药物缓控释、靶向定位蓄积于肿瘤组织于一体的功能性纳米载体系统。
At present，cancer has become one of the factors that endanger human health. The keyto cancer therapy is targeting treatment. Receptor-Ligand mediated tumor activetargeting technology in combination with nanotechnology, and the use of naturalbiodegradable materials as anti-cancer carriers, will be an effective approach forcancer therapy.
The overexpression of Glucose transporter protein1(GLUT1) in malignant cellsfacilitated the Receptor-Ligand (GLUT1-Glucose) mediated tumor targeting.Glucose-conjugated water soluble chitosan (GSC) nanoparticle was developed fortargeted breast cancer therapy. GSC polysaccharide was synthesized using succinicacid as linker between glucosamine and water soluble chitosan (WSC), confirmed byfourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonancespectroscopy (NMR), thermal gravimetric analysis (TG) and elemental analysis. Thecritical aggregation concentration (CAC) of GSC was0.021mg/ml, determined byfluorescence spectroscopy using pyrene as a fluorescence probe. FITC was covalentlylinked with GSC for futher fluorescence localization. The fluorescent labelingefficiency of FWSC and FGSC was1.39%and1.23%, respectively.
WSC NPs was prepared by ionic crosslinking method. GSC, FWSC and FGSCcould form self-assembled nanoparticles under ultrasonication. The nanoparticleswere characterized by dynamic light scattering, the zeta potential of WSC NPs, GSCNPs, FWSC NPs and FGSC NPs was11.5mV,23.9mV,25.8mV and19.5mV, withtheir average size of185.5nm,89.3nm,92.9nm and100.8nm, respectively. WSCNPs and GSC NPs observed by transmission electron microscope exhibited sphericalmorphology. WSC NPs and GSC NPs showed low hemolysis rate (﹤5%) and BSAadsorption rate. MTT assay showed that GSC NPs and FGSC NPs were nontoxic andbiocompatible to MEFs, MCF-7and4T1cells.
A model hydrophobic anticancer drug, doxorubicin (DOX) was efficiently entrapped in the nanoparticles, the loading capacity and encapsulation efficiency ofDOX-FWSC NPs was12.53%and40.37%, the loading capacity and encapsulationefficiency of DOX-FGSC NPs was20.1%and64.81%. Drug release of DOX-FWSCNPs and DOX-FGSC NPs was studied by the dynamic dialysis method, the result ofwhich indicated that the drug loaded nanoparticles exhibited pH controlled andsustained-release behavior in PBS buffer solution.
In vitro cellular uptake study showed that the phagocytosis of FGSC NPsdepended on not only the electrostatic interaction between the nanoparticles surfaceswith the cell membrane, but also the targeting groups modified on the surface ofnanoparticles. Both the fluorescence microscopy and quantitative determinationshowed that the FGSC NPs was easier to be endocytosed by cells than FWSC NPs.Besides, the antitumor activity of DOX-FGSC NPs was more effective in4T1cellkilling than that of DOX-FWSC NPs. Under the drug concentration of2μg/ml, thecell growth inhibitory effect order was: DOX-FGSC NPs＞ADR＞DOX-FWSC NPs,the result of which indicated that DOX-FGSC NPs had better tumor cell growthinhibitory effect than ADR at low drug concentrations. The in vitro experimentalresults demonstrated that GSC NPs was favorable for tumor cell phagocytosis,initially showed targeting effect to tumor cells.
The in vivo antitumor effect of ADR, DOX-FWSC NPs and DOX-FGSC NPswere studied in4T1bearing mice after i.v. injection. DOX-FGSC NPs couldobviously inhibit the growth of tumor and deduce the side effects of DOX to normaltissues. The hydrophilic shell and small particle size of DOX-FGSC NPs facilitatedthe passive targeting to tumor tissues. Meanwhile, the surface modifications oftargeting group enabled the nanocarriers to active targeting to tumor tissue, as well asreduce the accumulation in other organs. The concentration of GLUT1in varioustissues of tumor bearing mice was measured by ELISA. GLUT1was overexpressed intumor, which was consistent with the drug distribution, further confirmed thatDOX-FGSC NPs could active targeting to GLUT1.
Our results showed that nanoparticles decorated with glucose have specific reorganization and interaction with GLUT1over-expressed by tumor cells, whichrenders GSC NPs a promising anticancer drug delivery carrier for targeted cancertherapy.
利用恶性肿瘤细胞较正常细胞过度表达葡萄糖转运蛋白1（GLUT1）的特点，将其配体葡萄糖以丁二酸为连接臂共价连接在水溶性壳聚糖（WSC）分子链上，得到新型壳聚糖衍生物，胺糖化壳聚糖（GSC）。红外、核磁检测证实了2-（3-羧基-1-丙酰氨基）-2-脱氧-D-葡萄糖（GS）侧链成功连接在壳聚糖上，元素分析结果表明GSC的侧链取代度为9.27%。热重分析结果表明侧链的引入，破坏了壳聚糖分子的刚性结构，削弱了分子内和分子间的作用力，使得GSC的热稳定性比WSC差。通过芘荧光探针法测定GSC的临界聚集浓度为0.021mg/ml，说明在高于此浓度下，GSC溶液中有稳定的疏水微区形成。以FITC为荧光标记，共价修饰在多糖主链上，不仅可以对该载体材料定位示踪，其疏水基团还有利于包载疏水性药物分子。根据FWSC和FGSC溶液的荧光强度计算得两种荧光材料的荧光标记效率分别为1.39%和1.23%。
利用离子交联法制备了WSC纳米粒（WSC NPs），zeta电位和平均粒径分别为11.5mV和185.5nm；利用超声自组装法分别制备了GSC纳米粒（GSCNPs）、FWSC纳米粒（FWSC NPs）和FGSC纳米粒（FGSC NPs），zeta电位依次为23.9mV，25.8mV和19.5mV，平均粒径依次为89.3nm、92.9nm和100.8nm。透射电镜观察WSC NPs和GSC NPs均为完整的球形，其中自组装法制得的GSC NPs大小均一，分散均匀；相比较而言，离子交联法制得的WSC NPs大小差异较大，粒径分布较宽，粒子间有团聚现象。红细胞溶血实验表明，WSCNPs和GSC NPs的溶血率均小于5%，符合生物医用材料对溶血率的要求。蛋白吸附实验结果表明WSC NPs和GSC NPs对牛血清蛋白（BSA）均有较低水平的非特异性蛋白吸附，结合溶血实验共同证明了两种纳米粒均具有较好的血液相容性。MTT法检测了新型载体材料GSC NPs和FGSC NPs的细胞毒性，结果表明两种纳米粒对胎鼠成纤维细胞（MEF）、小鼠乳腺癌细胞（4T1）和人乳腺癌细胞（MCF-7）在检测范围内的细胞成活率均大于70%，均未表现出细胞毒性。
选用脂溶性抗癌药物阿霉素（DOX）作为模型药物，通过超声结合透析法制备了DOX-FWSC纳米粒（DOX-FWSC NPs）和DOX-FGSC纳米粒（DOX-FGSCNPs），zeta电位分别为23mV和15.6mV；平均粒径分别为136.6nm和153.1nm；载药量分别为12.53%和20.1%；包封率分别为40.37%和64.8%。利用透析法研究了两种载药纳米粒的释药动力学：在pH7.4释药介质中，前7小时释放速率较快，有明显的突释现象；随后进入缓释阶段，47h内DOX-FWSC NPs和DOX-FGSC NPs的累积释药量分别为37%和32%；当改变释药介质的pH至4.9后，原本达到释药平衡的载药纳米粒又在7小时内出现明显的突释现象，在随后的64h继续缓释，118h内DOX-FWSC NPs和DOX-FGSC NPs的累积释药量分别为92%和85%，结果说明所制备的两种载药纳米粒均具有较好的缓控释性能。
利用MEF，MCF-7和4T1三种细胞对FWSC NPs和FGSC NPs的摄取率做了定量测定，结果表明相同实验条件下，FGSC NPs的细胞吞噬率均高于FWSCNPs，可以推断FGSC NPs的细胞吞噬不仅依赖于粒子表面与细胞膜之间的静电作用，同样受益于靶向基团的修饰，使得三种模型细胞均对其有较高的细胞摄取率。以4T1为细胞模型，考察了DOX-FWSC NPs，DOX-FGSC NPs和临床用药—盐酸阿霉素（ADR）对细胞的生长抑制效果，结果显示三种测试样品对细胞的生长抑制均随药物浓度的增大而提高，当药物浓度为2μg/ml时，三种材料对细胞的生长抑制作用由强到弱依次是：DOX-FGSC NPs＞ADR＞DOX-FWSCNPs，说明DOX-FGSC NPs在低药物浓度时比ADR具有更好的肿瘤细胞生长抑制作用，该结论与荧光显微镜观察到的结果相一致。体外细胞实验结果初步判断由GSC制备的纳米载体利于细胞吞噬，具有肿瘤细胞靶向性。
建立小鼠乳腺癌动物模型，分别检测ADR，DOX-FWSC NPs与DOX-FGSCNPs对荷瘤小鼠的体内抗肿瘤作用，通过测量小鼠的肿瘤体积、体重、各组织中的药物分布，结果发现DOX-FGSC NPs具有较好的抑瘤效果且对机体均无明显毒副作用，不仅得益于其亲水外壳和较小的粒径使之被动靶向蓄积于肿瘤组织，还得益于其靶向基团的修饰，使其能利用受体—配体介导的主动靶向作用，蓄积于肿瘤组织的同时减小药物在其他器官中的蓄积。双抗体一步夹心法测定了荷瘤小鼠各组织器官中的GLUT1表达水平，对照相应组织中的药物含量，进一步证实DOX-FGSC NPs对肿瘤组织的主动靶向性依赖于它对GLUT1的主动靶向性。
本论文以水溶性壳聚糖为基础材料，研究了一种新型受体—配体（GLUT1—葡萄糖）介导的肿瘤细胞靶向技术，通过体外、体内实验评价了该载体材料的生物安全性和靶向性。实验结果显示该靶向修饰的载体材料有望成为集药物缓控释、靶向定位蓄积于肿瘤组织于一体的功能性纳米载体系统。
At present，cancer has become one of the factors that endanger human health. The keyto cancer therapy is targeting treatment. Receptor-Ligand mediated tumor activetargeting technology in combination with nanotechnology, and the use of naturalbiodegradable materials as anti-cancer carriers, will be an effective approach forcancer therapy.
The overexpression of Glucose transporter protein1(GLUT1) in malignant cellsfacilitated the Receptor-Ligand (GLUT1-Glucose) mediated tumor targeting.Glucose-conjugated water soluble chitosan (GSC) nanoparticle was developed fortargeted breast cancer therapy. GSC polysaccharide was synthesized using succinicacid as linker between glucosamine and water soluble chitosan (WSC), confirmed byfourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonancespectroscopy (NMR), thermal gravimetric analysis (TG) and elemental analysis. Thecritical aggregation concentration (CAC) of GSC was0.021mg/ml, determined byfluorescence spectroscopy using pyrene as a fluorescence probe. FITC was covalentlylinked with GSC for futher fluorescence localization. The fluorescent labelingefficiency of FWSC and FGSC was1.39%and1.23%, respectively.
WSC NPs was prepared by ionic crosslinking method. GSC, FWSC and FGSCcould form self-assembled nanoparticles under ultrasonication. The nanoparticleswere characterized by dynamic light scattering, the zeta potential of WSC NPs, GSCNPs, FWSC NPs and FGSC NPs was11.5mV,23.9mV,25.8mV and19.5mV, withtheir average size of185.5nm,89.3nm,92.9nm and100.8nm, respectively. WSCNPs and GSC NPs observed by transmission electron microscope exhibited sphericalmorphology. WSC NPs and GSC NPs showed low hemolysis rate (﹤5%) and BSAadsorption rate. MTT assay showed that GSC NPs and FGSC NPs were nontoxic andbiocompatible to MEFs, MCF-7and4T1cells.
A model hydrophobic anticancer drug, doxorubicin (DOX) was efficiently entrapped in the nanoparticles, the loading capacity and encapsulation efficiency ofDOX-FWSC NPs was12.53%and40.37%, the loading capacity and encapsulationefficiency of DOX-FGSC NPs was20.1%and64.81%. Drug release of DOX-FWSCNPs and DOX-FGSC NPs was studied by the dynamic dialysis method, the result ofwhich indicated that the drug loaded nanoparticles exhibited pH controlled andsustained-release behavior in PBS buffer solution.
In vitro cellular uptake study showed that the phagocytosis of FGSC NPsdepended on not only the electrostatic interaction between the nanoparticles surfaceswith the cell membrane, but also the targeting groups modified on the surface ofnanoparticles. Both the fluorescence microscopy and quantitative determinationshowed that the FGSC NPs was easier to be endocytosed by cells than FWSC NPs.Besides, the antitumor activity of DOX-FGSC NPs was more effective in4T1cellkilling than that of DOX-FWSC NPs. Under the drug concentration of2μg/ml, thecell growth inhibitory effect order was: DOX-FGSC NPs＞ADR＞DOX-FWSC NPs,the result of which indicated that DOX-FGSC NPs had better tumor cell growthinhibitory effect than ADR at low drug concentrations. The in vitro experimentalresults demonstrated that GSC NPs was favorable for tumor cell phagocytosis,initially showed targeting effect to tumor cells.
The in vivo antitumor effect of ADR, DOX-FWSC NPs and DOX-FGSC NPswere studied in4T1bearing mice after i.v. injection. DOX-FGSC NPs couldobviously inhibit the growth of tumor and deduce the side effects of DOX to normaltissues. The hydrophilic shell and small particle size of DOX-FGSC NPs facilitatedthe passive targeting to tumor tissues. Meanwhile, the surface modifications oftargeting group enabled the nanocarriers to active targeting to tumor tissue, as well asreduce the accumulation in other organs. The concentration of GLUT1in varioustissues of tumor bearing mice was measured by ELISA. GLUT1was overexpressed intumor, which was consistent with the drug distribution, further confirmed thatDOX-FGSC NPs could active targeting to GLUT1.
Our results showed that nanoparticles decorated with glucose have specific reorganization and interaction with GLUT1over-expressed by tumor cells, whichrenders GSC NPs a promising anticancer drug delivery carrier for targeted cancertherapy.
引文
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