壳聚糖季铵盐多功能靶向纳米微球的制备及在药物载体方面的应用
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摘要
如何使药物能够到达靶向(病灶)部位,并以预定的速率释放出来,提高治疗效果,减小副作用已成为当今药物学和药物制剂学的热点和难点。本论文的目的为开发一种高效多功能化的靶向纳米载药体系。通过O-羧甲基壳聚糖接枝二甲基十八烷基环氧丙基氯化铵,制备一种新型双亲性高分子材料O-羧甲基壳聚糖十八烷基季铵盐(OQCMC)。采用不同方法分别制备PEG和叶酸、PEG和跨膜肽TAT共修饰的OQCMC磁性高分子脂质体及叶酸修饰的OQCMC靶向缓释微球,并将其用于药物/基因载体。通过一系列体内外试验,探讨了该载体系统的细胞毒性和靶向缓释功能,及其在脊髓损伤动物模型中跨血脑屏障磁靶向定位功能和眼眶腺样囊性癌治疗方面的初步应用。
具体研究内容如下:
(1)制备了一系列不同取代度和分子量的OQCMC。结果表明:OQCMC可溶于水和有机溶剂,表面Zeta电位为正,具有较好的结晶性和热稳定性;其分子结构中羧酸盐和季铵盐两亲水基团对OQCMC吸湿保湿性的影响不具协同作用;其对小鼠成纤维细胞L929具有较低的细胞毒性,IC50>0.08±0.03 mg/ml。
(2)采用透析法制备OQCMC胶束,并研究其结构和性能。结果表明:OQCMC(DS=85.1%)的临界胶束浓度(CAC)值为2.4 mg.ml-1,水溶液中的表面张力可达20.21±0.03 mN.m-1;其胶束在水溶液中分布均匀;并与质粒pEGFP-N1有较强的结合能力;其对盐酸米诺环素(MH)的最大载药率可达22.7% (w/w);具有较好的缓控释功能。
(3)采用微乳液方法研究了OQCMC纳米微球的性质。结果表明:微乳液方法可制备包载水溶性药物长春新碱(VCR)、脂溶性药物消炎痛(IMC)或二者共载的OQCMC载药微球,微球粒径在20nm左右,分布均匀,Zeta电位可达+39.36mV;微乳液体系对VCR的最大载药率为22.7%,IMC的最大载药率为20.1%,并可实现对两种药物的共载和共释放;对药物的缓控释功能明显。
(4) OQCMC可代替合成磷脂同胆固醇复合制备阳离子高分子脂质体(CPL)。结果表明:可采用薄膜分散法和反向蒸发法制备CPL,其水溶液中平均粒径分别为172.5±2.1nm和108.5±0.5nm;CPL形状为不规则的球形,具有明显的脂质双层膜结构和较好的热稳定性;CPL颗粒的Zeta电位可达+42.17mV。CPL即可包载水溶性物质,如水溶性磁流体和药物VCR,又可包载油溶性物质,如油溶性磁颗粒和量子点(QDs);QDs标记的CPL保持了QDs的荧光特性;CPL对VCR的包封率可达90.1%以上;具有长效缓控释功能。
(5)制备并研究了OQCMC/Chol磁性高分子脂质体系统(MCPL)。MCPL在水溶液中可稳定存在,呈单分散分布,包载油溶性磁颗粒的MCPL水溶液中平均粒径为43.1nm;Zeta电位可达+45.4±3.4mV;具有超顺磁性,比饱和磁化强度可达39.96 emu/g。将MCPL分别或同时携载DNA和IMC,结果表明,其对抑癌基因p53质粒具有较强的结合能力和保护功能。采用层层包裹高分子脂质膜的方法,可以制备不同粒径的MCPL,水溶液中的粒径范围可为40-120nm。体系对IMC的包封率可达90%以上,平均粒径为69.2±0.5nm,多分散指数0.261,分散均匀;层层包裹方法可延长MCPL对IMC的缓释时间,降低突释现象。
(6)成功制备了PEG改性的OQCMC(PEG-OQCMC)和叶酸改性的OQCMC(FA-OQCMC)。用合成的PEG-OQCMC和OQCMC、FA-OQCMC、油溶性磁颗粒、IMC,分别或同时构建多功能MCPL系统。结果表明:PEG和叶酸修饰的载药MCPL在水相中可以稳定存在,平均粒径为118±8.4nm,多分散指数为0.005,Zeta电位为4.5±1.6mV,比饱和磁化强度为28.6 emu/g,具有超顺磁性。对IMC的最大载药率可达16%;并具有很好的缓控释功能。成功构建PEG和TAT共修饰的MCPL系统,其在水溶液中粒径分布均匀,大小在30nm左右;表面Zeta电位可达+39.7±1.6mV。在初步的动物试验中,MRI和普鲁士蓝染色结果表明多功能MCPL可在磁场作用下通过脊髓损伤大鼠的血脑屏障进入脊髓损伤部位,为今后靶向治疗脊髓损伤奠定了基础。
(7) OQCMC可作为乳化剂和表面修饰剂制备功能化PLGA/OQCMC缓释微球。结果表明:OQCMC可提高体系对药物VCR和MH的包封率,降低体系粒径。其对VCR和MH的包封率均大于90%,分散均匀。在此基础上成功构建了叶酸修饰的VCR靶向载药缓释微球。靶向微球细胞毒性较低,微球表面有叶酸存在,其对腺样囊性癌(ACC)细胞具有明显的靶向作用。靶向载药微球对ACC细胞有明显的抑制作用,抑制率可达96%,且具有长效抑制功能。裸鼠动物实验表明,靶向载药微球对眼眶腺样囊性癌有较好的治疗效果,抑瘤率高达90%;并有明显的药物缓释作用。
总之,通过上述研究,本研究已成功构建了以OQCMC为基础材料的多功能纳米载药微球,并可分别或同时赋予微球体系磁靶向定位功能、叶酸的细胞靶向功能、PEG修饰的长循环或TAT修饰的跨血脑屏障功能,其可作为一种有效的靶向药物载体用于药物的跨血脑屏障输送和肿瘤的靶向治疗。
The design and construction of more effective drug delivery system are very important. Octadecyl quaternized carboxymethyl chitosan (OQCMC) was synthesized through carboxymethyl chitosan (CMC) grafting with glycidyl octadecyl dimethylammonium chloride. Multifunctional targeted drug delivery systems, such as magnetic cationic polymeric liposomes (MCPL), PEG and trans-activating transcriptional activator protein (TAT) conjugated MCPL, PEG and folate conjugated MCPL and folate conjugated PLGA NPs, were designed by using OQCMC and its derivatives, cholesterol or PLGA.
OQCMC exhibited excellent solubility both in water and organic solvents. It also had a lower cytotoxic effect compared with PEI (25kDa). OQCMC had high degree of crystallinity with good thermal stabilization. Self-assembled OQCMC micelles were evaluated as carrier of lipophilic drug, minocycline hydrochloride (MH). MH was incorporated into cross-linked ionic cores of micelles with remarkably high efficiency (22.7% w/w). MH loaded OQCMC polymeric micelles exhibited slow steady release profile over one week period at 37°C. Three kinds of drug-loaded NPs formed from OQCMC were obtained by microemulsion method. These NPs had small size (20nm) and were suitable as drug-carrier for hydrophilic drug-vincristine (VCR), and hydrophobic drug-indomethacin (IMC). The maximal drug loading efficiency of VCR-loaded NPs was 22.7%, the IMC-loaded NPs was 20.1%, and the co-delivery NPs of VCR and IMC were 12.2% and 10.0%, respectively.
OQCMC in combination with cholesterol (Chol) could form stable vesicles with structure similar to that of conventional liposomes prepared from phosphatidylcholine/cholesterol (PC/Chol). Using different preparation methods, OQCMC/Chol could easily be made into nanoscale particles by encapsulating both hydrophilic and hydrophobic components. VCR was also encapsulated in the polymeric liposomes with high drug encapsulation efficiency (90.1%).
A simple and rapid method was introduced to prepare superparamagnetic, controlled size and monodispersed MCPL by OQCMC and cholesterol. These superparamagnetic CPL were stable in aqueous phase with small size 15.3nm, high Zeta potential +41.20mV and high saturation magnetization 39.96 emu/g at 300 K. IMC and VCR encapsulation efficiency of MCPL were both above 90% and drug-loaded MCPL exhibited slow steady release at 37℃in PBS solution (pH=7.4).
Hydrophilic Fe3O4 ferrofluid (LM) and BM can be encapsulated into CPL, simultaneously or respectively. The size of these stable hydrophilic magnetic nanospheres with functional groups (COOH, NH2) and controlled size (layer by layer method) ranges from 10nm to 120nm. A model hydrophobic drug IMC can be successfully filled in MCPL with high drug loading capacity 22%. The drug encapsulated MCPL have a long and controlled sustained release profile. PEG-modified OQCMC (PEG-OQCMC) and folate-modified OQCMC
(FA-OQCMC) were obtained by grafting reaction. Multifunctional MCPL were prepared with IMC encapsulating by using PEG-OQCMC, OQCMC, FA-OQCMC and BM. The results showed that the hydrodynamic diameter of this NPs was 118nm, with polydispersity index 0.005, high Zeta potential +41.20mV and high saturation magnetization 28.6 emu/g. PEG and TAT conjugated MCPL were prepared and approved to across the blood-brain-barrier(BBB) of spinal cord injury by magnetic force.
By the solvent evaporation method, the drug delivery system was prepared based on OQCMC, PLGA and hydroxyethyl cellulose. The targeted FA-OQCMC/PLGA NPs(FA NPs) were also prepared successfully with encapsulating VCR for Adenoid Cystic Carcinoma(ACC). The targeting effect of FA NPs is very clear compared with NPs without folate. VCR-loaded NPs had a longer sustained release profile for 2 weeks and FA NPs group has a better therapy effect due to its targeting effect of folate. The FA-OQCMC/PLGA/HEC NPs could be potentially applied for cancer cell targeted sustained delivery of various therapeutic agents.
具体研究内容如下:
(1)制备了一系列不同取代度和分子量的OQCMC。结果表明:OQCMC可溶于水和有机溶剂,表面Zeta电位为正,具有较好的结晶性和热稳定性;其分子结构中羧酸盐和季铵盐两亲水基团对OQCMC吸湿保湿性的影响不具协同作用;其对小鼠成纤维细胞L929具有较低的细胞毒性,IC50>0.08±0.03 mg/ml。
(2)采用透析法制备OQCMC胶束,并研究其结构和性能。结果表明:OQCMC(DS=85.1%)的临界胶束浓度(CAC)值为2.4 mg.ml-1,水溶液中的表面张力可达20.21±0.03 mN.m-1;其胶束在水溶液中分布均匀;并与质粒pEGFP-N1有较强的结合能力;其对盐酸米诺环素(MH)的最大载药率可达22.7% (w/w);具有较好的缓控释功能。
(3)采用微乳液方法研究了OQCMC纳米微球的性质。结果表明:微乳液方法可制备包载水溶性药物长春新碱(VCR)、脂溶性药物消炎痛(IMC)或二者共载的OQCMC载药微球,微球粒径在20nm左右,分布均匀,Zeta电位可达+39.36mV;微乳液体系对VCR的最大载药率为22.7%,IMC的最大载药率为20.1%,并可实现对两种药物的共载和共释放;对药物的缓控释功能明显。
(4) OQCMC可代替合成磷脂同胆固醇复合制备阳离子高分子脂质体(CPL)。结果表明:可采用薄膜分散法和反向蒸发法制备CPL,其水溶液中平均粒径分别为172.5±2.1nm和108.5±0.5nm;CPL形状为不规则的球形,具有明显的脂质双层膜结构和较好的热稳定性;CPL颗粒的Zeta电位可达+42.17mV。CPL即可包载水溶性物质,如水溶性磁流体和药物VCR,又可包载油溶性物质,如油溶性磁颗粒和量子点(QDs);QDs标记的CPL保持了QDs的荧光特性;CPL对VCR的包封率可达90.1%以上;具有长效缓控释功能。
(5)制备并研究了OQCMC/Chol磁性高分子脂质体系统(MCPL)。MCPL在水溶液中可稳定存在,呈单分散分布,包载油溶性磁颗粒的MCPL水溶液中平均粒径为43.1nm;Zeta电位可达+45.4±3.4mV;具有超顺磁性,比饱和磁化强度可达39.96 emu/g。将MCPL分别或同时携载DNA和IMC,结果表明,其对抑癌基因p53质粒具有较强的结合能力和保护功能。采用层层包裹高分子脂质膜的方法,可以制备不同粒径的MCPL,水溶液中的粒径范围可为40-120nm。体系对IMC的包封率可达90%以上,平均粒径为69.2±0.5nm,多分散指数0.261,分散均匀;层层包裹方法可延长MCPL对IMC的缓释时间,降低突释现象。
(6)成功制备了PEG改性的OQCMC(PEG-OQCMC)和叶酸改性的OQCMC(FA-OQCMC)。用合成的PEG-OQCMC和OQCMC、FA-OQCMC、油溶性磁颗粒、IMC,分别或同时构建多功能MCPL系统。结果表明:PEG和叶酸修饰的载药MCPL在水相中可以稳定存在,平均粒径为118±8.4nm,多分散指数为0.005,Zeta电位为4.5±1.6mV,比饱和磁化强度为28.6 emu/g,具有超顺磁性。对IMC的最大载药率可达16%;并具有很好的缓控释功能。成功构建PEG和TAT共修饰的MCPL系统,其在水溶液中粒径分布均匀,大小在30nm左右;表面Zeta电位可达+39.7±1.6mV。在初步的动物试验中,MRI和普鲁士蓝染色结果表明多功能MCPL可在磁场作用下通过脊髓损伤大鼠的血脑屏障进入脊髓损伤部位,为今后靶向治疗脊髓损伤奠定了基础。
(7) OQCMC可作为乳化剂和表面修饰剂制备功能化PLGA/OQCMC缓释微球。结果表明:OQCMC可提高体系对药物VCR和MH的包封率,降低体系粒径。其对VCR和MH的包封率均大于90%,分散均匀。在此基础上成功构建了叶酸修饰的VCR靶向载药缓释微球。靶向微球细胞毒性较低,微球表面有叶酸存在,其对腺样囊性癌(ACC)细胞具有明显的靶向作用。靶向载药微球对ACC细胞有明显的抑制作用,抑制率可达96%,且具有长效抑制功能。裸鼠动物实验表明,靶向载药微球对眼眶腺样囊性癌有较好的治疗效果,抑瘤率高达90%;并有明显的药物缓释作用。
总之,通过上述研究,本研究已成功构建了以OQCMC为基础材料的多功能纳米载药微球,并可分别或同时赋予微球体系磁靶向定位功能、叶酸的细胞靶向功能、PEG修饰的长循环或TAT修饰的跨血脑屏障功能,其可作为一种有效的靶向药物载体用于药物的跨血脑屏障输送和肿瘤的靶向治疗。
The design and construction of more effective drug delivery system are very important. Octadecyl quaternized carboxymethyl chitosan (OQCMC) was synthesized through carboxymethyl chitosan (CMC) grafting with glycidyl octadecyl dimethylammonium chloride. Multifunctional targeted drug delivery systems, such as magnetic cationic polymeric liposomes (MCPL), PEG and trans-activating transcriptional activator protein (TAT) conjugated MCPL, PEG and folate conjugated MCPL and folate conjugated PLGA NPs, were designed by using OQCMC and its derivatives, cholesterol or PLGA.
OQCMC exhibited excellent solubility both in water and organic solvents. It also had a lower cytotoxic effect compared with PEI (25kDa). OQCMC had high degree of crystallinity with good thermal stabilization. Self-assembled OQCMC micelles were evaluated as carrier of lipophilic drug, minocycline hydrochloride (MH). MH was incorporated into cross-linked ionic cores of micelles with remarkably high efficiency (22.7% w/w). MH loaded OQCMC polymeric micelles exhibited slow steady release profile over one week period at 37°C. Three kinds of drug-loaded NPs formed from OQCMC were obtained by microemulsion method. These NPs had small size (20nm) and were suitable as drug-carrier for hydrophilic drug-vincristine (VCR), and hydrophobic drug-indomethacin (IMC). The maximal drug loading efficiency of VCR-loaded NPs was 22.7%, the IMC-loaded NPs was 20.1%, and the co-delivery NPs of VCR and IMC were 12.2% and 10.0%, respectively.
OQCMC in combination with cholesterol (Chol) could form stable vesicles with structure similar to that of conventional liposomes prepared from phosphatidylcholine/cholesterol (PC/Chol). Using different preparation methods, OQCMC/Chol could easily be made into nanoscale particles by encapsulating both hydrophilic and hydrophobic components. VCR was also encapsulated in the polymeric liposomes with high drug encapsulation efficiency (90.1%).
A simple and rapid method was introduced to prepare superparamagnetic, controlled size and monodispersed MCPL by OQCMC and cholesterol. These superparamagnetic CPL were stable in aqueous phase with small size 15.3nm, high Zeta potential +41.20mV and high saturation magnetization 39.96 emu/g at 300 K. IMC and VCR encapsulation efficiency of MCPL were both above 90% and drug-loaded MCPL exhibited slow steady release at 37℃in PBS solution (pH=7.4).
Hydrophilic Fe3O4 ferrofluid (LM) and BM can be encapsulated into CPL, simultaneously or respectively. The size of these stable hydrophilic magnetic nanospheres with functional groups (COOH, NH2) and controlled size (layer by layer method) ranges from 10nm to 120nm. A model hydrophobic drug IMC can be successfully filled in MCPL with high drug loading capacity 22%. The drug encapsulated MCPL have a long and controlled sustained release profile. PEG-modified OQCMC (PEG-OQCMC) and folate-modified OQCMC
(FA-OQCMC) were obtained by grafting reaction. Multifunctional MCPL were prepared with IMC encapsulating by using PEG-OQCMC, OQCMC, FA-OQCMC and BM. The results showed that the hydrodynamic diameter of this NPs was 118nm, with polydispersity index 0.005, high Zeta potential +41.20mV and high saturation magnetization 28.6 emu/g. PEG and TAT conjugated MCPL were prepared and approved to across the blood-brain-barrier(BBB) of spinal cord injury by magnetic force.
By the solvent evaporation method, the drug delivery system was prepared based on OQCMC, PLGA and hydroxyethyl cellulose. The targeted FA-OQCMC/PLGA NPs(FA NPs) were also prepared successfully with encapsulating VCR for Adenoid Cystic Carcinoma(ACC). The targeting effect of FA NPs is very clear compared with NPs without folate. VCR-loaded NPs had a longer sustained release profile for 2 weeks and FA NPs group has a better therapy effect due to its targeting effect of folate. The FA-OQCMC/PLGA/HEC NPs could be potentially applied for cancer cell targeted sustained delivery of various therapeutic agents.
引文
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