N-半乳糖-O-组胺酰化羧甲基壳聚糖纳米粒的制备与性能研究
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摘要
纳米给药系统因其具有提高药物的靶向性和药物的生物利用度,减少抗癌药物的毒副作用等优点,尤其是因其尺寸较小能避免被网状内皮系统(the reticuloendothelial system, RES)巨噬细胞吞噬,故被应用于癌症的治疗。其中,pH敏感型纳米粒受到外界pH值变化刺激时,纳米粒形态会发生溶胀或瓦解,并将药物释放出来。利用这一特性与癌组织的弱酸性环境及其血管具有较大的通透性相结合,将pH敏感型纳米粒应用于癌症治疗是极具潜力的。
为了制备能响应癌组织弱酸性环境特性的载体材料,本研究将半乳糖配基和组胺上的咪唑环接枝到O-羧甲基壳聚糖(O-carboxymethyl chitosan, O-CMCS),合成出的两亲性聚合物N-半乳糖-O-组胺酰化羧甲基壳聚糖(N-lactosam-O-histamine acylated carboxymethyl chitosan, LHCS)在磷酸盐缓冲液(pH 7.4)中能通过自聚集作用形成纳米粒。这种pH敏感型纳米粒在pH 7.4条件下能维持纳米粒结构,而在pH 6.5条件下解体从而将药物释放出来。主要研究内容和结论如下：
(1)以O-羧甲基壳聚糖为原料,在KBH4催化下与乳糖经胺化还原反应合成N-半乳糖-O-羧甲基壳聚糖；然后在1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)和N-羟基琥珀酰亚胺(NHS)催化下,N-半乳糖-O-羧甲基壳聚糖与组胺经酰化反应合成N-半乳糖-O-组胺酰化羧甲基壳聚糖。通过控制原料的物料比,合成了五种不同组胺取代度的产物。中间产物和目标化合物的结构通过红外光谱和核磁共振谱进行表征；采用电位滴定法测定半乳糖配基的取代度；采用元素分析仪测定组胺基的取代度。实验结果表明,经化合物结构表征确证成功合成了N-半乳糖-O-组胺酰化羧甲基壳聚糖；半乳糖配基的取代度为59.44%；最高的组胺取代度为8.36。
(2)采用探针式超声法制备了N-半乳糖-O-组胺酰化羧甲基壳聚糖纳米粒。采用稳态荧光探针法考察了N-半乳糖-O-组胺酰化羧甲基壳聚糖的临界胶束浓度(the critical micelle concentration, CMC);采用透射电镜考察了纳米粒的形态；采用动态光散射法测定了纳米粒的粒径；通过对不同pH值条件下纳米粒溶液的透光率考察了纳米粒的pH敏感性。实验结果表明,经TEM观察,在正常组织生理条件下(pH 7.4)纳米粒呈完整的球形,而在pH 6.5条件下未观察到粒子,表明纳米粒已完全崩解；纳米粒的平均粒径介于106.1-173.6 nm之间；随着组胺取代度的增加,纳米粒的平均粒径逐渐减小。
(3)考察载药纳米粒的包封率与体外释放性能。采用透析法研究了载药纳米粒在pH 6.5,7.4的释放介质中的体外释放行为,并比较不同组胺取代度的N-半乳糖-O-组胺酰化羧甲基壳聚糖制备的载药纳米粒的体外释放性能。实验结果表明,在正常组织生理条件下(pH 7.4)纳米粒能维持较低的释药速率和释放量,而在癌组织条件下(pH 6.5),释药速率显著加快,总累积释药率明显提高；组胺取代度越高,在pH 6.5条件下纳米粒的疏水内核越容易解聚,药物也越易于从纳米粒中释放出来。
因此,N-半乳糖-O-组胺酰化羧甲基壳聚糖纳米粒具有能响应癌组织的弱酸性环境的特点,有望作为pH敏感型纳米药物载体。
Nanocarrier systems have been applied in tumor therapy for improving targeting and bioavailability of drugs, reducing side effects of anti-tumor drugs, etc. Especially, nanocarrier systems can avoid the reticuloendothelial system (RES) because of the small nano-size. The pH-sensitive nanoparticles occur swelling or collapsing upon external pH stimuli, and releasing drug. It will be very promising in cancer treatment to combine the feature of pH-sensitive nanoparticles with the weak acid environment and vascular permeability of cancer.
In this paper, the pH-sensitive nanoparticles were prepared by introducing galatose ligand and imidazole group of histamine into O-carboxymethyl chitosan (O-CMCS) in order to respond to the physiological pH of tumor tissue. Thus, N-lactosam-O-histamine acylated carboxymethyl chitosan (LHCS) was synthesized as an amphiphilic polymer, which can form self-assembled nanoparticles in phosphate buffer solution (pH7.4). The nanoparticles can maintain the micelle structure at about pH 7.4, but disassemble and release drugs at about pH 6.5. The main contents and conclusions of study are as follows:
(1) N-lactosam-O-carboxymethyl chitosan was synthesized by 0-carboxymethyl chitosan (O-CMCS) and lactose under the catalystis of KBH4 through the reductive amination. Then N-lactosam-O-histamine acylated carboxymethyl chitosan (LHCS) was synthesized by N-lactosam-O-carboxymethyl chitosan and histamine under the catalystis of N-(3-dimethyl amino-propyl)-N'-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccimide (NHS) through the acylation. The five products of different degree of substitution (DS) of histamine were synthesized by controlling the ratio of raw materials. Intermediates and target compounds were characterized by Fourier Transform Infrared Spectroscopy (FTIR) and 1H-Nuclear Magnetic Resonance Spectroscopy (1H-NMR). The DS of galactose ligand was measured by the potentiometric titration method, and the DS of histamine groups was measured by the elemental analysis method. The results showed that it was confirmed by the structure characterization that N-lactosam-O-histamine acylated carboxymethyl chitosan was successfully synthesized. The DS of galactose ligand was 59.44%, and the highest DS of histamine was 8.36.
(2) The N-lactosam-O-histamine acylated carboxymethyl chitosan (LHCS) nanoparticles were prepared by the probe ultrasonication method. The critical micelle concentration (CMC) of LHCS was studied by the steady-state fluorescence probe method. The morphology of the nanoparticles was observed by transmission electron microscopy (TEM). The particle size of the nanoparticles was measured by dynamic light scattering (DLS). The results showed that the morphology of the nanoparticles was observed under TEM which showed an almost spherical shape at pH 7.4, but cannot be found at pH 6.5 due to disassembling of the nanoparticles. And the diameter of the nanoparticles was between 106.1-173.6 nm. It also indicated that the size of nanoparticles was decreasing with the increasing of the DS of histamine groups.
(3) The encapsulation efficiency (EE) and the drug releasing behaviors in vitro of the nanoparticles were studied. The release behaviors of the drug loaded nanoparticles in release medium (pH 6.5,7.4) were studied by the dialyzer method. And the release behaviors of the nanoparticles of different DS of histamine groups of LHCS were compared. The results showed that the nanoparticles can maintain a lower drug releasing rate at physiological conditions in normal tissues (pH 7.4), but showed a significantly accelerated releasing rate at cancer conditions (pH 6.5) and the total cumulative releasing rates were increasing. It also confirmed that the nanoparticles of the higher DS of histamine groups were much more easily releasing drugs at pH 6.5 due to the depolymerization of the hydrophobic core in nanoparticles.
Therefore, the N-lactosam-O-histamine acylated carboxymethyl chitosan (LHCS) nanoparticles with the pH-sensitive propery responded to the weak acid environment of cancer, which can be expected as a pH-sensitive nanocarrier for the anti-cancer drugs.
为了制备能响应癌组织弱酸性环境特性的载体材料,本研究将半乳糖配基和组胺上的咪唑环接枝到O-羧甲基壳聚糖(O-carboxymethyl chitosan, O-CMCS),合成出的两亲性聚合物N-半乳糖-O-组胺酰化羧甲基壳聚糖(N-lactosam-O-histamine acylated carboxymethyl chitosan, LHCS)在磷酸盐缓冲液(pH 7.4)中能通过自聚集作用形成纳米粒。这种pH敏感型纳米粒在pH 7.4条件下能维持纳米粒结构,而在pH 6.5条件下解体从而将药物释放出来。主要研究内容和结论如下：
(1)以O-羧甲基壳聚糖为原料,在KBH4催化下与乳糖经胺化还原反应合成N-半乳糖-O-羧甲基壳聚糖；然后在1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)和N-羟基琥珀酰亚胺(NHS)催化下,N-半乳糖-O-羧甲基壳聚糖与组胺经酰化反应合成N-半乳糖-O-组胺酰化羧甲基壳聚糖。通过控制原料的物料比,合成了五种不同组胺取代度的产物。中间产物和目标化合物的结构通过红外光谱和核磁共振谱进行表征；采用电位滴定法测定半乳糖配基的取代度；采用元素分析仪测定组胺基的取代度。实验结果表明,经化合物结构表征确证成功合成了N-半乳糖-O-组胺酰化羧甲基壳聚糖；半乳糖配基的取代度为59.44%；最高的组胺取代度为8.36。
(2)采用探针式超声法制备了N-半乳糖-O-组胺酰化羧甲基壳聚糖纳米粒。采用稳态荧光探针法考察了N-半乳糖-O-组胺酰化羧甲基壳聚糖的临界胶束浓度(the critical micelle concentration, CMC);采用透射电镜考察了纳米粒的形态；采用动态光散射法测定了纳米粒的粒径；通过对不同pH值条件下纳米粒溶液的透光率考察了纳米粒的pH敏感性。实验结果表明,经TEM观察,在正常组织生理条件下(pH 7.4)纳米粒呈完整的球形,而在pH 6.5条件下未观察到粒子,表明纳米粒已完全崩解；纳米粒的平均粒径介于106.1-173.6 nm之间；随着组胺取代度的增加,纳米粒的平均粒径逐渐减小。
(3)考察载药纳米粒的包封率与体外释放性能。采用透析法研究了载药纳米粒在pH 6.5,7.4的释放介质中的体外释放行为,并比较不同组胺取代度的N-半乳糖-O-组胺酰化羧甲基壳聚糖制备的载药纳米粒的体外释放性能。实验结果表明,在正常组织生理条件下(pH 7.4)纳米粒能维持较低的释药速率和释放量,而在癌组织条件下(pH 6.5),释药速率显著加快,总累积释药率明显提高；组胺取代度越高,在pH 6.5条件下纳米粒的疏水内核越容易解聚,药物也越易于从纳米粒中释放出来。
因此,N-半乳糖-O-组胺酰化羧甲基壳聚糖纳米粒具有能响应癌组织的弱酸性环境的特点,有望作为pH敏感型纳米药物载体。
Nanocarrier systems have been applied in tumor therapy for improving targeting and bioavailability of drugs, reducing side effects of anti-tumor drugs, etc. Especially, nanocarrier systems can avoid the reticuloendothelial system (RES) because of the small nano-size. The pH-sensitive nanoparticles occur swelling or collapsing upon external pH stimuli, and releasing drug. It will be very promising in cancer treatment to combine the feature of pH-sensitive nanoparticles with the weak acid environment and vascular permeability of cancer.
In this paper, the pH-sensitive nanoparticles were prepared by introducing galatose ligand and imidazole group of histamine into O-carboxymethyl chitosan (O-CMCS) in order to respond to the physiological pH of tumor tissue. Thus, N-lactosam-O-histamine acylated carboxymethyl chitosan (LHCS) was synthesized as an amphiphilic polymer, which can form self-assembled nanoparticles in phosphate buffer solution (pH7.4). The nanoparticles can maintain the micelle structure at about pH 7.4, but disassemble and release drugs at about pH 6.5. The main contents and conclusions of study are as follows:
(1) N-lactosam-O-carboxymethyl chitosan was synthesized by 0-carboxymethyl chitosan (O-CMCS) and lactose under the catalystis of KBH4 through the reductive amination. Then N-lactosam-O-histamine acylated carboxymethyl chitosan (LHCS) was synthesized by N-lactosam-O-carboxymethyl chitosan and histamine under the catalystis of N-(3-dimethyl amino-propyl)-N'-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccimide (NHS) through the acylation. The five products of different degree of substitution (DS) of histamine were synthesized by controlling the ratio of raw materials. Intermediates and target compounds were characterized by Fourier Transform Infrared Spectroscopy (FTIR) and 1H-Nuclear Magnetic Resonance Spectroscopy (1H-NMR). The DS of galactose ligand was measured by the potentiometric titration method, and the DS of histamine groups was measured by the elemental analysis method. The results showed that it was confirmed by the structure characterization that N-lactosam-O-histamine acylated carboxymethyl chitosan was successfully synthesized. The DS of galactose ligand was 59.44%, and the highest DS of histamine was 8.36.
(2) The N-lactosam-O-histamine acylated carboxymethyl chitosan (LHCS) nanoparticles were prepared by the probe ultrasonication method. The critical micelle concentration (CMC) of LHCS was studied by the steady-state fluorescence probe method. The morphology of the nanoparticles was observed by transmission electron microscopy (TEM). The particle size of the nanoparticles was measured by dynamic light scattering (DLS). The results showed that the morphology of the nanoparticles was observed under TEM which showed an almost spherical shape at pH 7.4, but cannot be found at pH 6.5 due to disassembling of the nanoparticles. And the diameter of the nanoparticles was between 106.1-173.6 nm. It also indicated that the size of nanoparticles was decreasing with the increasing of the DS of histamine groups.
(3) The encapsulation efficiency (EE) and the drug releasing behaviors in vitro of the nanoparticles were studied. The release behaviors of the drug loaded nanoparticles in release medium (pH 6.5,7.4) were studied by the dialyzer method. And the release behaviors of the nanoparticles of different DS of histamine groups of LHCS were compared. The results showed that the nanoparticles can maintain a lower drug releasing rate at physiological conditions in normal tissues (pH 7.4), but showed a significantly accelerated releasing rate at cancer conditions (pH 6.5) and the total cumulative releasing rates were increasing. It also confirmed that the nanoparticles of the higher DS of histamine groups were much more easily releasing drugs at pH 6.5 due to the depolymerization of the hydrophobic core in nanoparticles.
Therefore, the N-lactosam-O-histamine acylated carboxymethyl chitosan (LHCS) nanoparticles with the pH-sensitive propery responded to the weak acid environment of cancer, which can be expected as a pH-sensitive nanocarrier for the anti-cancer drugs.
引文
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