多糖修饰的PLGA纳米粒作为抗肿瘤药物载体的研究
摘要
纳米控释系统作为新型的药物载体,具有缓释、靶向、提高生物利用度,减少副作用等特点。将载体材料制成不同粒径的纳米粒子与连接适当配体作为抗肿瘤药物载体的研究成为近年来国内外一个极为重要的研究热点。本研究制备了载表阿霉素(EPI)的纳米粒,并合成了生物素化的壳聚糖(Bio—CS),以此来修饰纳米粒,增强与肿瘤细胞的相互作用,达到靶向抗肿瘤作用,增强药物抗肿瘤效果。
本研究选用W_1/O/W_2复乳法制备了载EPI的PLGA纳米粒,采用两种方法用GS修饰PLGA纳米粒表面:吸附的方法和共价交联的方法。粒径分析未修饰的PLGA纳米粒平均粒径为(248.4±21.0)nm,Zeta电势为-(21.21±2.13)mV,扫描电镜(SEM)及透射电镜(TEM)下观察其形态圆整,测定药物包封率为(84.1±3.4)%。通过X射线光电子能谱(XPS)检测到CS修饰后的纳米粒表面含有氮元素信号;红外光谱(FT-IR)证实了具有氨基特征峰,证明修饰后的纳米粒表面为CS。两种方式修饰后纳米粒表面电势为正电荷,且粒径、包封率及释药性质发生了不同程度的改变,修饰后的纳米粒药物包封率下降,但药物的释放更加平缓且突释降低,特别是共价交联方法修饰的纳米粒具有释药平缓的特点。
其次本研究通过不同的投料比合成了三种不同取代度的Bio—CS,通过~1HNMR以及光电子能谱(ICP)确定了Bio—CS取代度,以此通过共价交联的方式修饰PLGA纳米粒表面,考察了纳米粒的表面电势、粒径、载药量、包封率以及体外释药性质等通过XPS以及生物素试剂盒确定修饰后的纳米粒表面生物素的量。选择最优取代度的Bio—CS来进行下阶段研究。体外抑瘤效应选用Hela细胞,研究了空白纳米粒载体的细胞毒效应,载药纳米粒在4、24、48、72h时的抑瘤效应,并考察了Hela细胞在不同时间点对各种纳米粒的吞噬能力。研究结果表明纳米粒的载体材料在24h、48h的细胞活力均在90%以上,材料无明显的细胞毒效应;载药纳米粒特别是修饰后的纳米粒在48h时表现出强的杀瘤效应,连接了靶向配体生物素的纳米粒杀瘤效应更强。荧光显微镜观察细胞吞噬纳米粒的能力,并且通过流式细胞术定量检测细胞的荧光强度,实验结果表明,随着时间的延长,细胞吞噬纳米粒的量增加,24h时未修饰的纳米粒荧光强度最强,48h时Bio—CS修饰的纳米粒组细胞内荧光强度最强,通过加入过量的生物素封闭细胞表面的生物素受体,可以观察到Bio-CS修饰的纳米粒进入细胞的能力减弱。
本研究通过小鼠体内急性及亚急性毒性实验初步评价了纳米粒的安全性,通过静脉注射给药,观察记录14d内小鼠的状态,实验组与对照组均未出现死亡,亦未出现明显的中毒体征;食量如常,体重增加亦没有明显差异,体内药动学实验选用6—8周龄180—200g雄性Wistar大鼠,静脉给药后测定不同时间点的血药浓度,药动学实验结果证实纳米粒改变了EPI在体内的药动学行为,具有良好的缓释性。
以上结果表明,Bio-CS修饰的纳米粒制剂在体内外可以达到平稳缓释EPI的效果,并具有一定的肿瘤靶向性,应用前景广阔,有望开发成一种新型抗肿瘤载体,提高生物利用度,改善疗效。
Nanospheres of biodegradable polymers can provide a way of sustained, controlled and targeted drug delivery to improve the therapeutic effects and reduce the side effects of the formulated drugs.Targeted drug delivery to cancer cells or tumor vasculature is an attractive approach to fight against cancer.In this study,biotin was introduced into a CS and the nanospheres were modified with bio-CS in an attempt to improve the design of nanospheres for an enhanced cancer targeting activity and intemalization into cancer cells.
Epirubicin(EPI) loaded PLGA nanospheres were prepared by a solvent evaporation technique(W_1/O/W_2).The PLGA nanospheres surface was modified with CS by two strategies(adsorption and covalent binding).PLGA nanospheres of (248.4±21.0) nm in diameter characterized by the laser light scattering technique, scanning electron microscopy(SEM) are spherical and its drug encapsulation efficiency is(84.1±3.4)%.Zeta potential of unmodified nanospheres was measured to be negative -(21.21±2.13)mV.The positive zeta potential of modified nanospheres reveals the presence of CS on the surface of the modified nanospheres.Modified nanospheres were characterized for surface chemistry by X-ray photoelectron spectroscopy(XPS) and Fourier transform infrared(FT-IR).FT-IR spectra exhibited peaks at 3420 cm~(-1) and 1570 cm~(-1),XPS spectra shows the N 1s(atomic orbital 1s of nitrogen) region of the surface of the nanospheres,corresponding to the primary amide of CS.In vitro drug release demonstrated that CS modified nanopheres have many advantages such as prolonged drug release property and decreased the burst release over the unmodified nanospheres, and the modified nanospheres by covalent binding method could achieve the release kinetics of a relatively constant release.
Bio-CS were synthesized and characterized.The degree of substitution(DS),as defined as the number of biotin per 100 anhydroglucose units of CS,was determined by ~1H-NMR and ICP.Nanospheres were successfully prepared and modified with Bio-CS. The resulting formulations were characterized in terms of size,charge,morphology,drug encapsulation and drug release.Number of biotin molecules on nanoparticle surface was determined using a commercially available Quant~*Tag Biotin Kit.Hela cells were used for in vitro cytotoxicity evaluation of the PLGA nanospheres versus that Bio-CS modified nanospheres with the EPI concentration 150μg/mL for 4,24,48 and 72 h incubation.Bio-CS midofied nanospheres increased markedly anti-tumoral activity of EPI at concentrations of 50 mg/ml when compared to the non-targeted nanospheres.Flow cytometry and fluorescence microscope revealed that bio-CS modified nanospheres exhibited greater extent of cellular uptake than unmodified nanospheres and free EPI at 48h.
To determine toxicity in vivo,mice were treated with nanospheres.No significant differences in clinical signs between the experimental group and the control group were found and no mortality occurred throughout the entire course of the study.Additionally, no significant differences in body weight between the two studied groups were observed. The aforementioned results indicated that no apparent toxicity to the studied animals was found after intravenous administration of the nanospheres prepared in the study.The in vivo pharmacokinetics was measured with male Wistar rats of 180-200g and 6-8 week old.The EPI loaded nanospheres can result much higher AUC and thus therapeutic effects of the drug than free EPI.
Bio-CS modified nanospheres shows excellent sustained release properties both in vitro and in vivo.Bio-CS modified nanospheres were helpful for EPI to reach a long circulation time and were hopeful to be its novel drug carrier.Due to the advantage of surface modified nanospheres with Bio-CS,it may be useful in the delivery of anticancer drugs.
本研究选用W_1/O/W_2复乳法制备了载EPI的PLGA纳米粒,采用两种方法用GS修饰PLGA纳米粒表面:吸附的方法和共价交联的方法。粒径分析未修饰的PLGA纳米粒平均粒径为(248.4±21.0)nm,Zeta电势为-(21.21±2.13)mV,扫描电镜(SEM)及透射电镜(TEM)下观察其形态圆整,测定药物包封率为(84.1±3.4)%。通过X射线光电子能谱(XPS)检测到CS修饰后的纳米粒表面含有氮元素信号;红外光谱(FT-IR)证实了具有氨基特征峰,证明修饰后的纳米粒表面为CS。两种方式修饰后纳米粒表面电势为正电荷,且粒径、包封率及释药性质发生了不同程度的改变,修饰后的纳米粒药物包封率下降,但药物的释放更加平缓且突释降低,特别是共价交联方法修饰的纳米粒具有释药平缓的特点。
其次本研究通过不同的投料比合成了三种不同取代度的Bio—CS,通过~1HNMR以及光电子能谱(ICP)确定了Bio—CS取代度,以此通过共价交联的方式修饰PLGA纳米粒表面,考察了纳米粒的表面电势、粒径、载药量、包封率以及体外释药性质等通过XPS以及生物素试剂盒确定修饰后的纳米粒表面生物素的量。选择最优取代度的Bio—CS来进行下阶段研究。体外抑瘤效应选用Hela细胞,研究了空白纳米粒载体的细胞毒效应,载药纳米粒在4、24、48、72h时的抑瘤效应,并考察了Hela细胞在不同时间点对各种纳米粒的吞噬能力。研究结果表明纳米粒的载体材料在24h、48h的细胞活力均在90%以上,材料无明显的细胞毒效应;载药纳米粒特别是修饰后的纳米粒在48h时表现出强的杀瘤效应,连接了靶向配体生物素的纳米粒杀瘤效应更强。荧光显微镜观察细胞吞噬纳米粒的能力,并且通过流式细胞术定量检测细胞的荧光强度,实验结果表明,随着时间的延长,细胞吞噬纳米粒的量增加,24h时未修饰的纳米粒荧光强度最强,48h时Bio—CS修饰的纳米粒组细胞内荧光强度最强,通过加入过量的生物素封闭细胞表面的生物素受体,可以观察到Bio-CS修饰的纳米粒进入细胞的能力减弱。
本研究通过小鼠体内急性及亚急性毒性实验初步评价了纳米粒的安全性,通过静脉注射给药,观察记录14d内小鼠的状态,实验组与对照组均未出现死亡,亦未出现明显的中毒体征;食量如常,体重增加亦没有明显差异,体内药动学实验选用6—8周龄180—200g雄性Wistar大鼠,静脉给药后测定不同时间点的血药浓度,药动学实验结果证实纳米粒改变了EPI在体内的药动学行为,具有良好的缓释性。
以上结果表明,Bio-CS修饰的纳米粒制剂在体内外可以达到平稳缓释EPI的效果,并具有一定的肿瘤靶向性,应用前景广阔,有望开发成一种新型抗肿瘤载体,提高生物利用度,改善疗效。
Nanospheres of biodegradable polymers can provide a way of sustained, controlled and targeted drug delivery to improve the therapeutic effects and reduce the side effects of the formulated drugs.Targeted drug delivery to cancer cells or tumor vasculature is an attractive approach to fight against cancer.In this study,biotin was introduced into a CS and the nanospheres were modified with bio-CS in an attempt to improve the design of nanospheres for an enhanced cancer targeting activity and intemalization into cancer cells.
Epirubicin(EPI) loaded PLGA nanospheres were prepared by a solvent evaporation technique(W_1/O/W_2).The PLGA nanospheres surface was modified with CS by two strategies(adsorption and covalent binding).PLGA nanospheres of (248.4±21.0) nm in diameter characterized by the laser light scattering technique, scanning electron microscopy(SEM) are spherical and its drug encapsulation efficiency is(84.1±3.4)%.Zeta potential of unmodified nanospheres was measured to be negative -(21.21±2.13)mV.The positive zeta potential of modified nanospheres reveals the presence of CS on the surface of the modified nanospheres.Modified nanospheres were characterized for surface chemistry by X-ray photoelectron spectroscopy(XPS) and Fourier transform infrared(FT-IR).FT-IR spectra exhibited peaks at 3420 cm~(-1) and 1570 cm~(-1),XPS spectra shows the N 1s(atomic orbital 1s of nitrogen) region of the surface of the nanospheres,corresponding to the primary amide of CS.In vitro drug release demonstrated that CS modified nanopheres have many advantages such as prolonged drug release property and decreased the burst release over the unmodified nanospheres, and the modified nanospheres by covalent binding method could achieve the release kinetics of a relatively constant release.
Bio-CS were synthesized and characterized.The degree of substitution(DS),as defined as the number of biotin per 100 anhydroglucose units of CS,was determined by ~1H-NMR and ICP.Nanospheres were successfully prepared and modified with Bio-CS. The resulting formulations were characterized in terms of size,charge,morphology,drug encapsulation and drug release.Number of biotin molecules on nanoparticle surface was determined using a commercially available Quant~*Tag Biotin Kit.Hela cells were used for in vitro cytotoxicity evaluation of the PLGA nanospheres versus that Bio-CS modified nanospheres with the EPI concentration 150μg/mL for 4,24,48 and 72 h incubation.Bio-CS midofied nanospheres increased markedly anti-tumoral activity of EPI at concentrations of 50 mg/ml when compared to the non-targeted nanospheres.Flow cytometry and fluorescence microscope revealed that bio-CS modified nanospheres exhibited greater extent of cellular uptake than unmodified nanospheres and free EPI at 48h.
To determine toxicity in vivo,mice were treated with nanospheres.No significant differences in clinical signs between the experimental group and the control group were found and no mortality occurred throughout the entire course of the study.Additionally, no significant differences in body weight between the two studied groups were observed. The aforementioned results indicated that no apparent toxicity to the studied animals was found after intravenous administration of the nanospheres prepared in the study.The in vivo pharmacokinetics was measured with male Wistar rats of 180-200g and 6-8 week old.The EPI loaded nanospheres can result much higher AUC and thus therapeutic effects of the drug than free EPI.
Bio-CS modified nanospheres shows excellent sustained release properties both in vitro and in vivo.Bio-CS modified nanospheres were helpful for EPI to reach a long circulation time and were hopeful to be its novel drug carrier.Due to the advantage of surface modified nanospheres with Bio-CS,it may be useful in the delivery of anticancer drugs.
引文
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