CN114848846A - 一种药物递送系统及其制备方法与应用 - Google Patents
一种药物递送系统及其制备方法与应用 Download PDFInfo
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Abstract
本发明提供一种药物递送系统及其制备方法与应用,所述药物递送系统以磁性纳米颗粒为核层,以石墨烯量子点修饰的二氧化硅为壳层,所述石墨烯量子点负载阿霉素。本发明提供的药物递送系统可用于通过检测FRET信号来监测药物输送;GQDs在FRET模型中同时作为药物载体和供体,而DOX在FRET模型中作为抗癌药物和受体;通过FRET模型来进行有效的药物加载和控释。本发明提供的药物递送系统不仅可以作为生物标志物追踪靶向肿瘤,还可以实现对药物的监测交付,从而提高诊断准确性。本发明提供的药物递送系统不仅可以用于监测药物输送和荧光/MRI双峰细胞成像,用于同时进行癌症诊断和治疗。
Description
技术领域
本发明属于生物医学领域,具体涉及一种药物递送系统及其制备方法与应用。
背景技术
近些年来,纳米技术的进步推动了其在生物医学领域不断增长的需求,这归功于多功能纳米平台对纳米级癌症诊断和治疗的贡献。多功能纳米平台是一种集医学靶向、生物成像、诊断和治疗为一体的系统,对未来癌症诊断和治疗具有广阔的前景。目前,多功能纳米平台仍然需要减少伪影并显着提高诊断准确性,减少有害的非特异性副作用,旨在克服与常规抗癌药物相关的限制,例如快速清除、在水溶液中不溶和缺乏选择性等。
目前,荧光成像技术作为监测策略中最灵敏的技术之一,可以提供灵敏、快速的全身成像,甚至可以检测微观肿瘤。磁共振成像技术(Magnetic Resonance Imaging,MRI)由于针对不同软组织之间的对比度好、无电离辐射、空气分辨率高的优点,被广泛应用于癌症的诊断和治疗,但其需要的扫描时间长,阻止了体内和体外检测。由于每种成像方式都有其优点和缺点,因此通过协同多模式成像来提高治疗效果的成像方式组合引起了极大的兴趣,这是单一方式无法实现的。
CN103571493A公开了一种磁性荧光纳米微球,通过在磁性纳米粒子表面包裹上聚苯胺大分子,通过聚苯胺分子末端的功能氨基成功的连接了荧光纳米材料量子点,得到了具有磁性荧光双功能的纳米微球。所述磁性荧光纳米微球既保留了量子点优异的荧光特性,又具有磁性粒子的超顺磁性,通过简单的外加磁场即可进行采集和分离,可应用于免疫检测、靶向治疗和细胞分离等领域。
CN103571494A公开了一种磁性荧光纳米复合微球,具有以下组成:磁性纳米粒子和荧光量子点;所述磁性纳米粒子与荧光量子点通过甘露寡糖分子末端的功能性羟基与荧光量子点的羧基基团通过化学偶联连接。磁性荧光纳米微球既具有磁性粒子的超顺磁性,又保留了量子点优异的荧光特性,通过简单的外加磁场即可进行采集和分离,可应用于化学分析检测、免疫检测、荧光追踪和磁性分离等领域。
基于以上研究,可以看出采用磁性和荧光双功能的纳米复合微球,能够使得微球既具有荧光特性又具有磁性,能够实现荧光和MRI协同成像。但目前,针对磁性颗粒和荧光粒子的选择还有待进一步优化。
发明内容
针对现有技术的不足,本发明的目的在于提供一种药物递送系统及其制备方法与应用,所述药物递送系统可以实现药物输送和荧光/MRI双模态细胞成像的监测。
为达到此发明目的,本发明采用以下技术方案:
第一方面,本发明提供一种药物递送系统,所述药物递送系统以磁性纳米颗粒为核层,以石墨烯量子点修饰的二氧化硅为壳层,所述石墨烯量子点负载阿霉素。
石墨烯量子点(Graphene Quantum Dots,GQDs)是一类新型的零维荧光碳基纳米材料,可作为标记生物标志物和抗癌药物载体,具有离域电子的大表面积、理想的光致发光、稳定的荧光、在多种溶剂中的溶解性、优异的生物相容性和低毒性的特点。另外,它们较小的横向尺寸和丰富的外围羧基,能够与靶向分子结合,为癌症诊断的肿瘤靶向成像的潜在应用提供支持。
磁性纳米颗粒在酸性条件下容易聚集和溶解,而二氧化硅涂层可以有效保护磁性纳米颗粒的内部磁铁矿核,保持磁性纳米颗粒的稳定性。
在本发明中,所述磁性纳米颗粒包括钴铁氧体、四氧化三铁或三氧化二铁中的任意一种或至少两种的组合,优选为钴铁氧体。
钴铁氧体(CoFe2O4)是一种尖晶石型铁氧体,具有高饱和磁化强度和矫顽力,且比表面积大,化学稳定性好,易于合成,是作为癌症治疗过程中的药物载体的极好候选物。
优选地,所述磁性纳米颗粒与二氧化硅之间通过Si-O键进行连接。
优选地,所述石墨烯量子点与二氧化硅之间通过酰胺键进行连接。
所述石墨量子点与阿霉素之间通过π-π键进行相互作用。
优选地,所述药物递送系统的载药量为60-70%(例如可以是60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%等)。
在本发明中,所述石墨烯量子点还负载有肿瘤靶向分子。
优选地,所述肿瘤靶向分子包括叶酸。
所述靶向分子均能够实现药物递送过程中的靶向作用,其中叶酸(Folic acid,FA)作为一个活跃的肿瘤定位信号对过表达叶酸受体的肿瘤细胞具有高亲和力。
优选地,所述肿瘤靶向分子与石墨烯量子点之间通过酰胺键连接。
优选地,所述肿瘤靶向分子的负载量占所述药物递送系统总质量的60-70%(例如可以是60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%等)。
在本发明中,所述药物递送系统以钴铁氧体为核层,以石墨烯量子点修饰的二氧化硅为壳层,所述石墨烯量子点负载有阿霉素和叶酸;
所述钴铁氧体与二氧化硅之间通过Si-O键进行连接,所述石墨烯量子点与二氧化硅之间通过酰胺键进行连接;通过π-π堆积将所述阿霉素负载到石墨烯量子点表面;所述石墨烯量子点与叶酸之间通过酰胺键进行连接。
第二方面,本发明提供一种FRET模型,所述FRET模型包括第一方面所述的药物递送系统。
优选地,所述石墨烯量子点作为所述FRET模型中的药物载体和/或供体。
优选地,所述阿霉素作为所述FRET模型的中的抗癌药物和/或受体。
DOX/GQD-CFO@SiO2/FA纳米平台用于受控药物输送系统,允许通过FRET信号实时监测药物释放过程。GQDs在FRET模型中同时作为药物载体和供体,而DOX在FRET模型中作为抗癌药物和受体。FRET“开”/FRET“关”的变化可以通过将DOX加载到GQD上/从GQD释放来调整,从而允许通过FRET信号监测药物输送。
在本发明中,通过FRET的相应变化来监测药物输送。通过对GQD-CFO@SiO2/FA进行MRI测试;T2加权MRI图像的亮度降低表明GQD-CFO@SiO2/FA作为负MRI造影剂的潜力。荧光/MRI双峰细胞成像可以促进药物递送的运输。此外,细胞毒性试验证实了GQD-CFO@SiO2/FA纳米平台的理想生物相容性,DOX/GQD-CFO@SiO2/FA对HeLa细胞表现出显著的细胞毒性,这有助于增强FA修饰的DOX/GQD-CFO@SiO2/FA的靶向作用。这些结果表明本发明提供的药物递送系统的治疗效率显着提高。因此,本发明提供的药物递送系统可监测药物输送和荧光/MRI双峰细胞成像,用于同时诊断和治疗癌症。
第三方面,本发明提供一种根据第一方面所述的药物递送系统的制备方法,所述制备方法包括以下步骤:
(1)将磁性纳米颗粒通过乳液聚合法修饰二氧化硅,得到磁性纳米颗粒@二氧化硅;
(2)将磁性纳米颗粒@二氧化硅进行氨基化反应,然后与石墨烯量子点进行反应,得到石墨烯量子点-磁性纳米颗粒@二氧化硅;
(3)将石墨烯量子点-磁性纳米颗粒@二氧化硅与阿霉素混合,得到阿霉素/石墨烯量子点-磁性纳米颗粒@二氧化硅。
在本发明中,步骤(1)中,所述磁性纳米颗粒为钴铁氧体,所述钴铁氧体的制备方法包括以下步骤:将钴源、铁源、油酸、1,2-十四烷二醇、油胺和溶剂混合,得到所述钴铁氧体。
优选地,所述钴源包括Co(acac)2,所述铁源包括Fe(acac)3。
优选地,所述钴源和铁源的摩尔比为1:(1.5-2.5);
其中,“1.5-2.5”可以是1.5、1.7、1.9、2.1、2.3、2.5等。
优选地,所述溶剂包括苯醚。
优选地,所述油酸、1,2-十四烷二醇和油胺的摩尔比为(4-8):(8-12):(4-8);
其中,“4-8”可以是4、5、6、7、8等;
“8-12”可以是8、9、10、11、12等。
优选地,所述混合的温度为180-300℃(例如可以是180℃、200℃、220℃、240℃、260℃、280℃、300℃等),时间为1-5h(例如可以是1h、2h、3h、4h、5h等)。
优选地,步骤(1)中,所述乳液聚合法的制备方法包括以下步骤:将磁性纳米颗粒分散到含有去离子水和无水乙醇的混合溶液中,超声,然后加入氨水;再与四乙氧基硅烷混合反应,得到所述磁性纳米颗粒@二氧化硅。
优选地,所述去离子水、无水乙醇和氨水的体积比为(8-12):(30-50):(0.5-1.5);
其中,“8-12”可以是8、9、10、11、12等;
“30-50”可以是30、35、40、45、50等;
“0.5-1.5”可以是0.5、0.7、0.9、1.1、1.3、1.5等。
优选地,所述超声的时间为0.5-1.5h(例如可以是0.5h、0.7h、0.9h、1.1h、1.3h、1.5h等)。
优选地,所述混合反应的时间为0.5-1.5h(例如可以是0.5h、0.7h、0.9h、1.1h、1.3h、1.5h等)。
在本发明中,步骤(2)中,所述氨基化反应所采用的氨基化试剂为3-氨丙基三乙氧基硅烷。
优选地,步骤(2)中,所述石墨烯量子点的制备方法包括以下步骤:将柠檬酸进行加热,然后与碱混合,得到所述石墨烯量子点。
优选地,所述加热的温度为180-200℃(例如可以是180℃、185℃、190℃、195℃、200℃等),时间为10-40min(例如可以是10min、20min、30min、40min等)。
优选地,所述碱包括氢氧化钠水溶液,所述氢氧化钠水溶液的摩尔浓度为0.05-0.2M(例如可以是0.05M、0.07M、0.09M、0.11M、0.13M、0.15M、0.18M、0.2M等)。
优选地,步骤(2)中,所述石墨烯量子点进行反应前需要进行活化,所述活化采用的活化试剂包括1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和N-羟基琥珀酰亚胺。
优选地,步骤(3)中,所述将石墨烯量子点-磁性纳米颗粒@二氧化硅与阿霉素混合之前,还包括以下步骤:将石墨烯量子点-磁性纳米颗粒@二氧化硅与叶酸进行缩合反应。
优选地,所述缩合反应所采用的缩合试剂包括1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和N-羟基琥珀酰亚胺。
作为本发明优选地技术方案,所述药物递送系统的制备方法包括以下步骤:
(a)将磁性纳米颗粒通过反乳液相修饰二氧化硅,得到磁性纳米颗粒@二氧化硅;
(b)将磁性纳米颗粒@二氧化硅进行氨基化反应,然后与石墨烯量子点进行酰胺缩合反应,得到石墨烯量子点-磁性纳米颗粒@二氧化硅;
其中,所述石墨烯量子点进行反应前需要进行活化,所述活化采用的活化试剂包括1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和N-羟基琥珀酰亚胺;
(c)将石墨烯量子点-磁性纳米颗粒@二氧化硅与叶酸进行酰胺缩合反应,得到石墨烯量子点-磁性纳米颗粒@二氧化硅/叶酸;
(d)将石墨烯量子点-磁性纳米颗粒@二氧化硅/叶酸与阿霉素进行π-π堆积,得到阿霉素/石墨烯量子点-磁性纳米颗粒@二氧化硅/叶酸。
第四方面,本发明提供一种根据第一方面所述的药物递送系统或第二方面所述的FRET模型在监测药物输送和/或荧光/MRI双峰细胞成像中的应用。
术语解释
CoFe2O4/CFO------------钴铁氧体
NPs------------纳米粒子
SiO2------------二氧化硅
GQDs------------石墨烯量子点
FA------------叶酸(FA)
DOX------------阿霉素
FR------------叶酸受体
MRI------------核磁共振成像
Iron(III)acetylacetonate------------乙酰丙酮铁(III)、Fe(acac)3
Cobalt(II)acetylacetonate------------乙酰丙酮钴(II)、Co(acac)2
Aqueous ammonia-----------氨水(25%)、
3-aminopropyl triethoxysilane(APTES,99%)------------3-氨基丙基三乙氧基硅烷(APTES,99%)、
Polyoxyethylene(10)octylphenyl ether(Triton X-100)-----------聚氧乙烯(10)辛基苯基醚
tetraethyl orthosilicate(TEOS,98%)------------原硅酸四乙酯(TEOS,98%),
Citric acid(99.5%)------------柠檬酸(99.5%)购自Sigma。
Oleic acid------------油酸(90%)、
Oleylamine------------油胺(>70%)、
Phenyl ether(99%)------------苯醚(99%)、
1,2-tetradecanediol(97%)------------1,2-十四烷二醇(97%)。
1-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride(EDC,99%),------------1-(3-二甲氨基丙基)-N-乙基碳二亚胺盐酸盐(EDC,99%)、
N-hydroxysuccinimide(NHS,98%)------------N-羟基琥珀酰亚胺(NHS,98%)、
Methyl thiazolyl tetrazolium(MTT)------------甲基噻唑基四唑(MTT)、
Dimethyl sulfoxide(DMSO)------------二甲亚砜(DMSO)和
Phosphate buffered saline(PBS,7.4)------------磷酸盐缓冲盐水(PBS,7.4)
Dulbecco's modified Eagle's medium-----------Eagle培养基(DMEM)、
Penicillin-streptomycin------------青霉素-链霉素、
Fetal bovine serum(FBS)------------胎牛血清(FBS)和
Trypsin-EDTA------------胰蛋白酶-EDTA。
相对于现有技术,本发明具有以下有益效果:
(1)本发明提供的药物递送系统可用于通过检测FRET信号来监测药物输送。GQDs在FRET模型中同时作为药物载体和供体,而DOX在FRET模型中作为抗癌药物和受体;通过FRET模型来进行有效的药物加载和控释。
(2)本发明提供的药物递送系统不仅可以作为生物标志物追踪靶向肿瘤,还可以实现对药物的监测交付,从而提高诊断准确性。
(3)本发明提供的药物递送系统对HeLa细胞表现出显着的细胞毒性,可以显着增强治疗效果。
(4)本发明提供的药物递送系统不仅可以用于监测药物输送和荧光/MRI双峰细胞成像,用于同时进行癌症诊断和治疗。
附图说明
图1为CFO@SiO2 NPs和GQD的形貌图;
其中,图a为CFO@SiO2 NPs的电镜图,图b为GQD的电镜图。
图2为DOX/GQD-CFO@SiO2/FA的合成示意图。
图3为DOX的标准曲线图。
图4为GQD-CFO@SiO2/FA负载能力图。
图5为DOX/GQD-CFO@SiO2/FA体外DOX的释放图。
图6为CFO、CFO@SiO2和GQD-CFO@SiO2/FA在300K下的滞后回线;
其中,1为CFO,2为GQD-CFO@SiO2,3为GQD-CFO@SiO2/FA。
图7为GQD-CFO@SiO2/FA在不同CFO浓度下的T2加权MRI。
图8为GQD-CFO@SiO2/FA在不同CFO浓度下的弛豫率。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
实施例1
本实施例提供一种CFO,所述CFO的制备方法包括以下步骤:
将Co(acac)2(1mmol)和Fe(acac)3(2mmol)添加到含有6mmol油酸、10mmol1,2-十四烷二醇、6mmol油胺和20mL苯醚的溶液中,在N2下进行磁力搅拌。随后将得到的混合物加热至200℃保持1.5h,并在280℃回流1h。除去热源并冷却后,将黑色混合物用丙酮和氯仿溶剂洗涤,得到CFO。
实施例2
本实施例提供一种CFO@SiO2 NPs,所述CFO@SiO2 NPs的制备方法包括以下步骤:
将4mL实施例1制备得到的CFO重新分散到含有10mL去离子水和40mL无水乙醇的混合溶液中。超声搅拌1h后,加入1mL NH3·H2O。然后加入2mL TEOS(原硅酸四乙酯),继续反应10h,得到CFO@SiO2 NPs。
实施例3
本实施例提供一种NH2-CFO@SiO2 NPs,所述NH2-CFO@SiO2 NPs的制备方法包括以下步骤:
将实施例2制备得到的CFO@SiO2 NPs(棕色混合物)重新分散在6mL无水乙醇中,取4mL悬浮液分散在含有10mL去离子水和40mL无水乙醇的混合溶液中。然后,将混合物滴加含有溶解在乙醇(10mL)中的3-氨丙基三乙氧基硅烷(APTES)(0.75mL)的溶液,然后轻轻搅拌8h。经过多次洗涤,得到NH2-CFO@SiO2 NPs,备用。
实施例4
本实施例提供一种GQD-CFO@SiO2纳米粒子,所述GQD-CFO@SiO2纳米粒子的制备方法如下包括以下步骤:
(1)GQD的制备:将0.5g柠檬酸加热至190℃,保持25min,将所得的黄色溶液加入至50mL 0.1M NaOH溶液中,NaOH与柠檬酸中和后得到GQDs的水溶液。
(2)GQD-CFO@SiO2/FA纳米粒子的制备:将EDC(50mg)和NHS(10mg)添加到10mL的GQDs溶液中(步骤(1)制备得到),搅拌30min,得到悬浮液。随后将实施例3制备的NH2-CFO@SiO2 NPs添加到上述悬浮液中,与GQD共轭以获得GQD-CFO@SiO2。其中GQDs的羧基和CFO@SiO2的胺基团之间形成经典的酰胺键,用胺改性的CFO@SiO2 NPs对GQDs进行改性
实施例5
本实施例提供一种GQD-CFO@SiO2/FA纳米粒子,所述GQD-CFO@SiO2/FA纳米粒子的制备方法包括以下步骤:
将FA通过EDC/NHS反应共价结合到GQD-CFO@SiO2纳米粒子上:将含有50mg用EDC和NHS预处理的FA的10mL MES缓冲液添加到实施例4制备得到的GQD-CFO@SiO2纳米粒子溶液中,轻轻摇动24h,得到GQD-CFO@SiO2/FA纳米粒子。最后,将得到的GQD-CFO@SiO2/FA纳米粒子纯化并重新分散在PBS溶液中。
如图1所示,采用飞利浦CM-100透射电子显微镜对CFO@SiO2 NPs和GQD进行表面形貌的表征;
其中,图(a)为CFO@SiO2 NPs的电镜图,从图中可以看出平均尺寸约为25nm,具有近5nm的壳;图(b)为GQD粒子的电镜图,从图中可以看出GQD粒子是球形的,平均尺寸为3.5nm,标准偏差为0.6nm。
实施例6
本实施例提供一种DOX/GQD-CFO@SiO2/FA,所述DOX/GQD-CFO@SiO2/FA的制备方法包括以下步骤:
将DOX(4.5mg/mL,PBS)与实施例5制备得到的GQD-CFO@SiO2/FA NPs的PBS缓冲液(2mg/mL)混合,进行药物加载。将混合物超声处理30分钟,然后在黑暗中室温搅拌24小时,得到DOX/GQD-CFO@SiO2/FA。
如图2所示,DOX/GQD-CFO@SiO2/FA的合成示意图,从图中可以看出,Co(acac)2和Fe(acac)3首先合成CFO,然后和TEOS反应,生成CFO@SiO2 NPs;经APTES氨基化生成NH2-CFO@SiO2 NPs;再与GQD经过酰胺缩合反应生成GQD-CFO@SiO2;再与叶酸通过酰胺缩合反应生成GQD-CFO@SiO2/FA;然后经过π-π堆积得到DOX/GQD-CFO@SiO2/FA。GQDs作为FRET模型中的药物载体和供体,而DOX作为抗癌剂药物和受体。DOX/GQD-CFO@SiO2/FA进入癌细胞后,可与癌细胞上的叶酸受体结合,释放药物。
测试例1
GQD-CFO@SiO2/FA纳米平台的载药和释药实验
测试方法:将DOX(0-0.9mg/mL,PBS)添加到GQD-CFO@SiO2/FA NPs的PBS缓冲液中的(2mg/mL)中来进行药物加载。将混合物超声处理30分钟,然后在黑暗中室温搅拌24小时。
GQD-CFO@SiO2/FA NPs上的DOX负载通过紫外/可见光谱法通过480nm处的吸光度确定。负载在GQD-CFO@SiO2/FA NPs上的DOX量通过已报道文献(Dr.Liu在2008年发表在Adv.Mater.的改进方法进行量化。文献:Liu,Z.;Liu,Q.;Huang,Y.;Ma,Y.;Yin,S.;Zhang,X.;Sun,W.;Chen,Y.J.A.M.,Organic photovoltaic devices based on a novelacceptor material:graphene.Adv.Mater.,,2008,20(20),3924-3930.)的改进方法进行量化。
为了进一步探索基于FRET模型的药物递送,通过将DOX与GQD-CFO@SiO2/FA在PBS缓冲液中混合来进行载药量测量。DOX的UV-VIS标准曲线通过UV/Vis光谱法通过480nm处的吸光度确定。
如图3所示DOX的标准曲线图,Y=18.2077X-0.0079,R2=0.9997,线性关系良好。
如图4所示GQD-CFO@SiO2/FA负载能力图,GQD-CFO@SiO2/FA的负载能力随着初始DOX浓度的增加而增加,GQD-CFO@SiO2/FA的最大负载量为65.4wt%。
为了获得DOX的释放曲线,将DOX/GQD-CFO@SiO2/FA在37℃下连续搅拌分散在不同pH值的PBS溶液中。在预定的时间间隔内,将DOX/GQD-CFO@SiO2/FA样品与缓冲液分离,并根据DOX的标准曲线来确定上清液中释放的DOX浓度。DOX/GQD-CFO@SiO2/FA在48小时内释放的DOX累积量按下式计算:
累积DOX释放[%]=(Mt/M0)×100%;其中Mt是在时间t从DOX/GQD-CFO@SiO2/FA释放的DOX总量,M0是加载到GQD-CFO@SiO2/FA中的DOX的初始量。
如图5所示,DOX/GQD-CFO@SiO2/FA体外DOX的释放图。在pH值7.4时,6小时内释放的DOX少于18%,并表现出极大的稳定性。相比之下,高达42.6%的DOX在pH值为5.5的情况下在6小时内迅速释放。48小时后,近71%的DOX在pH=5.5的酸性缓冲液中释放,而在pH=7.4时释放的DOX不到30%。pH控制释放依赖于DOX,在低pH介质中的质子化作用,这可以使DOX更具亲水性和水溶性,从而导致DOX从纳米平台在水溶液中的释放增加。实验结果与其他描述类似pH响应性药物释放行为的文献非常吻合。
测试例2
GQD-CFO@SiO2/FA纳米平台的MRI实验
测试方法:为了研究获得的纳米粒子的磁性并评估GQD-CFO@SiO2/FA作为诊断MR造影剂的性能,对GQD-CFO@SiO2/FANPs进行了MRI测试。将制备的具有不同CFO浓度的GQD-CFO@SiO2/FA NPs分散并悬浮在200μL 1.0%琼脂糖凝胶中。然后将所有样品快速转移到6孔板中进行T2加权MRI成像。此外,HeLa细胞与GQD-CFO@SiO2/FA NPs一起孵育过夜,然后通过胰蛋白酶消化分离。HeLa细胞用PBS洗涤后,用200μL 1.0%琼脂糖凝胶分散悬浮,快速转移至试管中进行MRI实验。
如图6所示,CFO、CFO@SiO2和GQD-CFO@SiO2/FA在300K下的滞后回线;结果表明CFO的饱核磁化强度(Ms)为69.4emu/g,而CFO@SiO2和CFO@SiO2-NH2的饱核磁化强度(Ms)分别降至22.1和15.3emu/g。由于纳米复合材料中CFO分数的减少和壳的非磁性贡献,二氧化硅涂层导致饱核磁化强度明显降低。尽管二氧化硅涂层和GQDs改性降低了CFO的饱核磁化强度,GQD-CFO@SiO2/FA表现出近乎超顺磁性的行为,这与CFO NPs相似。
如图7所示,GQD-CFO@SiO2/FA在不同CFO浓度下的T2加权MRI。T2加权图像的亮度直接对应于T2的值。由于CFO的磁矩与周围介质中的质子之间的偶极相互作用,信号强度随着CFO浓度的增加而降低。由于GQD-CFO@SiO2/FA可以缩短T2、横向弛豫时间,因此导致MR图像更暗。
弛豫率通过单指数曲线提取,拟合信号强度与不同浓度下的回波时间,使用以下等式:
Mxy(t)=Mxy(0)e-t/T2
其中Mxy(0)和Mxy(t)分别为初始和时间等于t横向磁化。
如图8所示,GQD-CFO@SiO2/FA在不同CFO浓度下的弛豫率,T2弛豫时间与粒子浓度成线性比例。GQD-CFO@SiO2/FA的R2弛豫系数值为75.6mM-1S-1。MRI结果表明GQD-CFO@SiO2/FA表现出理想的对比效果,表明GQD-CFO@SiO2/FA适合用作负MRI造影剂。
测试例3
GQD-CFO@SiO2/FA纳米平台的细胞毒性试验
MTT法测定了CFO@SiO2、GQD、GQD-CFO@SiO2和GQD-CFO@SiO2/FA对HeLa细胞的细胞毒性。简而言之,将HeLa细胞接种到96孔板中并过夜生长。然后将每个孔中的培养基更换为含有游离DOX、DOX/GQD-CFO@SiO2或DOX/GQD-CFO@SiO2/FA处理的培养基(150μL)。孵育24h后,将每孔培养基更换为含MTT试剂的新鲜培养基,浓度为0.5mg/mL,孵育4h。小心洗涤并除去培养基后,将100μL DMSO加入孔中以溶解甲臜晶体。记录酶标仪每个孔在490nm处的吸光度,以确定细胞活力。进行MTT测试以评估制造的纳米平台的杀肿瘤潜力。
HeLa细胞分别与CFO@SiO2、GQD-CFO@SiO2、GQD-CFO@SiO2/FA、GQD、游离DOX、DOX/GQD-CFO@SiO2和DOX/GQD-CFO@SiO2/FA一起孵育。
结果表明CFO@SiO2、GQD-CFO@SiO2、GQD-CFO@SiO2/FA、GQDs对HeLa细胞的活力没有显着影响,这表明GQD-CFO@SiO2/FA具有理想的生物相容性。
与分别与DOX/GQD-CFO@SiO2和游离DOX孵育的HeLa细胞相比,负载DOX的DOX/GQD-CFO@SiO2/FA对Hela细胞表现出更高的毒性。显然,DOX/GQD-CFO@SiO2/FA表明显著增强对HeLa细胞的细胞毒性(84.7%),远高于非FA纳米平台DOX/GQD-CFO@SiO2(67.2%);在10μg/mL DOX浓度下,由于靶向效果的提高DOX/GQD-CFO@SiO2/FA纳米平台通过靶向分子修饰带来的HeLa细胞。这些结果表明基于FRET的-DOX/GQD-CFO@SiO2/FA显着提高了治疗效果。
申请人声明,本发明通过上述实施例来说明本发明的工艺方法,但本发明并不局限于上述工艺步骤,即不意味着本发明必须依赖上述工艺步骤才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明所选用原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
Claims (10)
1.一种药物递送系统,其特征在于,所述药物递送系统以磁性纳米颗粒为核层,以石墨烯量子点修饰的二氧化硅为壳层,所述石墨烯量子点负载阿霉素。
2.根据权利要求1所述的药物递送系统,其特征在于,所述磁性纳米颗粒包括钴铁氧体、四氧化三铁或三氧化二铁中的任意一种或至少两种的组合,优选为钴铁氧体;
优选地,所述磁性纳米颗粒与二氧化硅之间通过Si-O键进行连接;
优选地,所述石墨烯量子点与二氧化硅之间通过酰胺键进行连接;
所述石墨量子点与阿霉素之间通过π-π键进行相互作用;
优选地,所述药物递送系统的载药量为60-70%。
3.根据权利要求1或2所述的药物递送系统,其特征在于,所述石墨烯量子点还负载有肿瘤靶向分子;
优选地,所述肿瘤靶向分子包括叶酸;
优选地,所述肿瘤靶向分子与石墨烯量子点之间通过酰胺键连接;
优选地,所述肿瘤靶向分子的负载量占所述药物递送系统总质量的60-70%。
4.根据权利要求1-3中任一项所述的药物递送系统,其特征在于,所述药物递送系统以钴铁氧体为核层,以石墨烯量子点修饰的二氧化硅为壳层,所述石墨烯量子点负载有阿霉素和叶酸;
所述钴铁氧体与二氧化硅之间通过Si-O键进行连接,所述石墨烯量子点与二氧化硅之间通过酰胺键进行连接;通过π-π堆积将所述阿霉素负载到石墨烯量子点表面;所述石墨烯量子点与叶酸之间通过酰胺键进行连接。
5.一种FRET模型,其特征在于,所述FRET模型包括权利要求1-4中任一项所述的药物递送系统;
优选地,所述石墨烯量子点作为所述FRET模型中的药物载体和/或供体;
优选地,所述阿霉素作为所述FRET模型的中的抗癌药物和/或受体。
6.一种根据权利要求1-4中任一项所述的药物递送系统的制备方法,其特征在于,所述制备方法包括以下步骤:
(1)将磁性纳米颗粒通过乳液聚合法修饰二氧化硅,得到磁性纳米颗粒@二氧化硅;
(2)将磁性纳米颗粒@二氧化硅进行氨基化反应,然后与石墨烯量子点进行反应,得到石墨烯量子点-磁性纳米颗粒@二氧化硅;
(3)将石墨烯量子点-磁性纳米颗粒@二氧化硅与阿霉素混合,得到阿霉素/石墨烯量子点-磁性纳米颗粒@二氧化硅。
7.根据权利要求6所述的制备方法,其特征在于,步骤(1)中,所述磁性纳米颗粒为钴铁氧体,所述钴铁氧体的制备方法包括以下步骤:将钴源、铁源、油酸、1,2-十四烷二醇、油胺和溶剂混合,得到所述钴铁氧体;
优选地,所述钴源包括Co(acac)2,所述铁源包括Fe(acac)3;
优选地,所述钴源和铁源的摩尔比为1:(1.5-2.5);
优选地,所述溶剂包括苯醚;
优选地,所述油酸、1,2-十四烷二醇和油胺的摩尔比为(4-8):(8-12):(4-8);
优选地,所述混合的温度为180-300℃,时间为1-5h;
优选地,步骤(1)中,所述乳液聚合法的制备方法包括以下步骤:将磁性纳米颗粒分散到含有去离子水和无水乙醇的混合溶液中,超声,然后加入氨水;再与四乙氧基硅烷混合反应,得到所述磁性纳米颗粒@二氧化硅;
优选地,所述去离子水、无水乙醇和氨水的体积比为(8-12):(30-50):(0.5-1.5);
优选地,所述超声的时间为0.5-1.5h;
优选地,所述混合反应的时间为0.5-1.5h。
8.根据权利要求6或7所述的制备方法,其特征在于,步骤(2)中,所述氨基化反应所采用的氨基化试剂为3-氨丙基三乙氧基硅烷;
优选地,步骤(2)中,所述石墨烯量子点的制备方法包括以下步骤:将柠檬酸进行加热,然后与碱混合,得到所述石墨烯量子点;
优选地,所述加热的温度为180-200℃,时间为10-40min;
优选地,所述碱包括氢氧化钠水溶液,所述氢氧化钠水溶液的摩尔浓度为0.05-0.2M;
优选地,步骤(2)中,所述石墨烯量子点进行反应前需要进行活化,所述活化采用的活化试剂包括1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和N-羟基琥珀酰亚胺;
优选地,步骤(3)中,所述将石墨烯量子点-磁性纳米颗粒@二氧化硅与阿霉素混合之前,还包括以下步骤:将石墨烯量子点-磁性纳米颗粒@二氧化硅与叶酸进行缩合反应;
优选地,所述缩合反应所采用的缩合试剂包括1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和N-羟基琥珀酰亚胺。
9.根据权利要求6-8中任一项所述的制备方法,其特征在于,所述制备方法包括以下步骤:
(a)将磁性纳米颗粒通过反乳液相修饰二氧化硅,得到磁性纳米颗粒@二氧化硅;
(b)将磁性纳米颗粒@二氧化硅进行氨基化反应,然后与石墨烯量子点进行酰胺缩合反应,得到石墨烯量子点-磁性纳米颗粒@二氧化硅;
其中,所述石墨烯量子点进行反应前需要进行活化,所述活化采用的活化试剂包括1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和N-羟基琥珀酰亚胺;
(c)将石墨烯量子点-磁性纳米颗粒@二氧化硅与叶酸进行酰胺缩合反应,得到石墨烯量子点-磁性纳米颗粒@二氧化硅/叶酸;
(d)将石墨烯量子点-磁性纳米颗粒@二氧化硅/叶酸与阿霉素进行π-π堆积,得到阿霉素/石墨烯量子点-磁性纳米颗粒@二氧化硅/叶酸。
10.一种根据权利要求1-4中任一项所述的药物递送系统或权利要求5所述的FRET模型在监测药物输送和/或荧光/MRI双峰细胞成像中的应用。
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