肿瘤靶向性普鲁兰基自组装纳米药物载体的研究
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摘要
随着纳米技术的高速发展,肿瘤靶向性纳米药物载体的研究成为热点之一,叶酸受体在某些癌细胞表面的高表达给靶向治疗提供了理论依据。本研究以乙酰普鲁兰叶酸偶合体(FPA)为材料,制备并研究肿瘤靶向性白组装纳米药物载体,同时制备一种新型的表阿霉素纳米药物制剂,评价普鲁兰基自组装体作为纳米药物载体的可行性。
本研究以普鲁兰多糖为主链,通过乙酰化反应合成疏水性的乙酰普鲁兰(PA),再以N,N’-二环己基碳二亚胺(DCC)为偶联剂,4-二甲氨基吡啶(DMAP)为催化剂,将叶酸与PA偶联合成FPA；采用氢核磁共振(1H-NMR)方法对PA和FPA的结构进行了表征,用透析法制备了FPA纳米粒子(FPANs)和包载表阿霉素的FPA纳米粒子(FPA／EPI),应用透射电子显微镜(TEM)和扫描电子显微镜(SEM)观察了纳米粒子的形貌,动态光散射法(DLS)测定了粒径及粒径分布；考察了FPANs和FPA／EPI在水溶液中的粒径和在不同介质中的电位；考察了FPANs和FPA／EPI在水溶液中的稳定性；应用流式细胞仪检测了宫颈癌Hela细胞对FPA／EPI的摄取,并研究了其摄取机制；通过将空白FPANs和乙酰普鲁兰纳米粒子(PANs)200mg／kg尾静脉注射到ICR小鼠体内,并观察动物的一般体征、体重和食量的变化,考察了其体内安全性；将FPA／EPI(EPI等效剂量10mg／kg)静脉注射到Wistar大鼠体内,测定了给药后血药浓度的变化趋势,计算其药代动力学参数,并与游离药物EPI进行比较,考察了其体内缓释效果；建立了宫颈癌Hela移植瘤动物模型,将FPA／EPI静脉注射到建立了肿瘤模型的动物体内,考察了其体内分布特征以及抗肿瘤作用效果,并用TUNEL法检测了肿瘤细胞的凋亡情况。
研究结果显示,成功合成的FPA其叶酸取代度为0.235；应用透析法制备的FPANs和FPA／EPI,纳米粒子呈均匀的球形,电中性,FPANs粒径为(204.2±10.9)nm,其分散度(PDI)为0.172±0.036,载药后粒径和分散度分别为(273.4±11.0)nm和0.165±0.026,在水溶液中,FPANs和FPA／EPI粒径及粒径分布三个月内没有明显改变；FPA／EPI通过叶酸受体介导进入细胞,具有明显的剂量效应关系；FPANs和PANs静脉注射到小鼠体内后对动物的一般体征、体重、食量及主要脏器均未见明显的毒副作用；FPA／EPI的半衰期(t1／2)、平均滞留时间(MRT0-24h)和血药浓度—时间曲线下面积(AUC 0-24h)分别是游离药物的1.57、1.33和3.95倍；静脉注射后2h药物主要蓄积于肿瘤动物的肝、脾和肺,与游离药物比较,在肿瘤组织和肝脏中,FPA／EPI较长时间保持较高的药物含量,在胃和肠的含量显著减少；FPA／EPI尾静脉注射Hela移植瘤到裸鼠体内,给药4次,给药剂量为5.0mg／kg和7.5mg／kg,相对肿瘤增殖率分别为81.38%和37.72%,瘤重抑制率分别为32.37%和61.19%,具有明显的剂量效应关系,EPI和FPA／EPI各组均可诱导Hela细胞凋亡。
本研究结果表明,肿瘤靶向性普鲁兰基自组装纳米药物载体体外稳定性和体内安全性较好,对药物具有缓释作用,可改变其体内分布特征,减小药物对部分脏器的毒性,具有一定的肿瘤靶向性和较好的抗肿瘤效果,并呈剂量效应关系。普鲁兰基自组装体可以作为一种有应用前景的肿瘤靶向性纳米药物载体。
Folate receptors (FRs), overexpressed on the surface of a variety of tumor cells, are potential targets for tumor targeting therapy. This study aimed to develop folate conjugated pullulan acetate as a FRs -mediated drug delivery system to target chemotherapeutic agents to FRs-overexpressed tumor cells and tumor in vitro and in vivo.
Folate was coupled to pullulan acetate (PA) by N, N'-Dicyclohexylcarbodiimide (DCC) and 4-Dimethylamino-pyridine (DMAP) mediated ester formation. The product was characterized by proton nuclear magnetic resonance (1H NMR) spectroscopy. The degree of folate substitution (DS) was caculated by ultraviolet spectrometry is 0.235 per sugar residues of PA. Folate conjugated pullulan acetate nanoparticles (FPANs) and Epirubicin-loaded FPANs (FPA/EPI) were prepared by dialysis method. Various physicochemical properties of FPA and FPA/EPI including size, surface charge and morphology were characterized by dynamic light scattering (DLS), scanning electron microscope (SEM) and transmission electron microscope (TEM). FPANs and FPA/EPI had the nearly spherical shape with a size range of (204.2±10.9) nm and (273.4±11.0) nm respectively, they had lowζpotentials both in distill water and in 10%FBS. The storage stability of FPA and FPA/EPI were observed in distilled water, the size andζpotential were determined once a month. The nanoparticles were stable for at least three months. Flow cytometry test revealed that FPA/EPI NPs exhibited a dose dependent cellular uptake against human epithelial cervical cancer (Hela) cells with over-expressing folate receptors on the surface. Ensemble-averaged measurements with flow cytometry indicate that FPA/EPI can be internalized by HeLa cells in a dose dependent manner through receptor-mediated endocytosis, as confirmed by competitive inhibition assays.
An in vivo toxicity study was performed to establish the safety of the prepared blank FPANs and PANs after i.v. administration in ICR mice. The study indicated that the NPs were well tolerated at 125mg/kg and 200mg/kg, respectively. The in vivo pharmacokinetics was investigated after an i.v. administration at 10mg EPI/kg in rats. Promisingly,1.57-fold increase in the half-life (t1/2),1.33-fold increase in the mean retention time (MRT0-24h) and 3.95-fold increase in the area under the curve (AUC0-24h) of EPI were achieved for the FPA/EPI compared with the free EPI. Moreover, the in vivo biodistribution and anticancer effects were investigated using a model of nude mice xenografted with Hela cells in the study. The drug level in stomach and gastric was significantly reduced, which is an indication of reduced side effects. The antitumor test demonstrated that when systemically administered at dose of 5.0mg/kg and 7.5mg/kg, the anti-cancer effects of FPA/EPI appear to be dose-dependent and the highest dose completely inhibits tumor growth through inducing the tumor cell apoptosis, the related rate of reproduction were 81.38% and 37.72%, and the rate of tumor inhibition were 32.37% and 61.19% respectively.
All results suggested that FPANs were prepared easily, stable, safe and showed a promising potential on reducing the toxicity and improving the anticancer efficiency of the encapsulated drug. The conjugate showed great potential to be a carrier of nanodrug.
本研究以普鲁兰多糖为主链,通过乙酰化反应合成疏水性的乙酰普鲁兰(PA),再以N,N’-二环己基碳二亚胺(DCC)为偶联剂,4-二甲氨基吡啶(DMAP)为催化剂,将叶酸与PA偶联合成FPA；采用氢核磁共振(1H-NMR)方法对PA和FPA的结构进行了表征,用透析法制备了FPA纳米粒子(FPANs)和包载表阿霉素的FPA纳米粒子(FPA／EPI),应用透射电子显微镜(TEM)和扫描电子显微镜(SEM)观察了纳米粒子的形貌,动态光散射法(DLS)测定了粒径及粒径分布；考察了FPANs和FPA／EPI在水溶液中的粒径和在不同介质中的电位；考察了FPANs和FPA／EPI在水溶液中的稳定性；应用流式细胞仪检测了宫颈癌Hela细胞对FPA／EPI的摄取,并研究了其摄取机制；通过将空白FPANs和乙酰普鲁兰纳米粒子(PANs)200mg／kg尾静脉注射到ICR小鼠体内,并观察动物的一般体征、体重和食量的变化,考察了其体内安全性；将FPA／EPI(EPI等效剂量10mg／kg)静脉注射到Wistar大鼠体内,测定了给药后血药浓度的变化趋势,计算其药代动力学参数,并与游离药物EPI进行比较,考察了其体内缓释效果；建立了宫颈癌Hela移植瘤动物模型,将FPA／EPI静脉注射到建立了肿瘤模型的动物体内,考察了其体内分布特征以及抗肿瘤作用效果,并用TUNEL法检测了肿瘤细胞的凋亡情况。
研究结果显示,成功合成的FPA其叶酸取代度为0.235；应用透析法制备的FPANs和FPA／EPI,纳米粒子呈均匀的球形,电中性,FPANs粒径为(204.2±10.9)nm,其分散度(PDI)为0.172±0.036,载药后粒径和分散度分别为(273.4±11.0)nm和0.165±0.026,在水溶液中,FPANs和FPA／EPI粒径及粒径分布三个月内没有明显改变；FPA／EPI通过叶酸受体介导进入细胞,具有明显的剂量效应关系；FPANs和PANs静脉注射到小鼠体内后对动物的一般体征、体重、食量及主要脏器均未见明显的毒副作用；FPA／EPI的半衰期(t1／2)、平均滞留时间(MRT0-24h)和血药浓度—时间曲线下面积(AUC 0-24h)分别是游离药物的1.57、1.33和3.95倍；静脉注射后2h药物主要蓄积于肿瘤动物的肝、脾和肺,与游离药物比较,在肿瘤组织和肝脏中,FPA／EPI较长时间保持较高的药物含量,在胃和肠的含量显著减少；FPA／EPI尾静脉注射Hela移植瘤到裸鼠体内,给药4次,给药剂量为5.0mg／kg和7.5mg／kg,相对肿瘤增殖率分别为81.38%和37.72%,瘤重抑制率分别为32.37%和61.19%,具有明显的剂量效应关系,EPI和FPA／EPI各组均可诱导Hela细胞凋亡。
本研究结果表明,肿瘤靶向性普鲁兰基自组装纳米药物载体体外稳定性和体内安全性较好,对药物具有缓释作用,可改变其体内分布特征,减小药物对部分脏器的毒性,具有一定的肿瘤靶向性和较好的抗肿瘤效果,并呈剂量效应关系。普鲁兰基自组装体可以作为一种有应用前景的肿瘤靶向性纳米药物载体。
Folate receptors (FRs), overexpressed on the surface of a variety of tumor cells, are potential targets for tumor targeting therapy. This study aimed to develop folate conjugated pullulan acetate as a FRs -mediated drug delivery system to target chemotherapeutic agents to FRs-overexpressed tumor cells and tumor in vitro and in vivo.
Folate was coupled to pullulan acetate (PA) by N, N'-Dicyclohexylcarbodiimide (DCC) and 4-Dimethylamino-pyridine (DMAP) mediated ester formation. The product was characterized by proton nuclear magnetic resonance (1H NMR) spectroscopy. The degree of folate substitution (DS) was caculated by ultraviolet spectrometry is 0.235 per sugar residues of PA. Folate conjugated pullulan acetate nanoparticles (FPANs) and Epirubicin-loaded FPANs (FPA/EPI) were prepared by dialysis method. Various physicochemical properties of FPA and FPA/EPI including size, surface charge and morphology were characterized by dynamic light scattering (DLS), scanning electron microscope (SEM) and transmission electron microscope (TEM). FPANs and FPA/EPI had the nearly spherical shape with a size range of (204.2±10.9) nm and (273.4±11.0) nm respectively, they had lowζpotentials both in distill water and in 10%FBS. The storage stability of FPA and FPA/EPI were observed in distilled water, the size andζpotential were determined once a month. The nanoparticles were stable for at least three months. Flow cytometry test revealed that FPA/EPI NPs exhibited a dose dependent cellular uptake against human epithelial cervical cancer (Hela) cells with over-expressing folate receptors on the surface. Ensemble-averaged measurements with flow cytometry indicate that FPA/EPI can be internalized by HeLa cells in a dose dependent manner through receptor-mediated endocytosis, as confirmed by competitive inhibition assays.
An in vivo toxicity study was performed to establish the safety of the prepared blank FPANs and PANs after i.v. administration in ICR mice. The study indicated that the NPs were well tolerated at 125mg/kg and 200mg/kg, respectively. The in vivo pharmacokinetics was investigated after an i.v. administration at 10mg EPI/kg in rats. Promisingly,1.57-fold increase in the half-life (t1/2),1.33-fold increase in the mean retention time (MRT0-24h) and 3.95-fold increase in the area under the curve (AUC0-24h) of EPI were achieved for the FPA/EPI compared with the free EPI. Moreover, the in vivo biodistribution and anticancer effects were investigated using a model of nude mice xenografted with Hela cells in the study. The drug level in stomach and gastric was significantly reduced, which is an indication of reduced side effects. The antitumor test demonstrated that when systemically administered at dose of 5.0mg/kg and 7.5mg/kg, the anti-cancer effects of FPA/EPI appear to be dose-dependent and the highest dose completely inhibits tumor growth through inducing the tumor cell apoptosis, the related rate of reproduction were 81.38% and 37.72%, and the rate of tumor inhibition were 32.37% and 61.19% respectively.
All results suggested that FPANs were prepared easily, stable, safe and showed a promising potential on reducing the toxicity and improving the anticancer efficiency of the encapsulated drug. The conjugate showed great potential to be a carrier of nanodrug.
引文
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