CN114569741A - 一种基于稀土纳米颗粒的x射线激发型化疗药物递送系统及应用 - Google Patents
一种基于稀土纳米颗粒的x射线激发型化疗药物递送系统及应用 Download PDFInfo
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Abstract
本发明提供了一种基于稀土纳米颗粒的X射线激发型化疗药物递送系统及其应用,该系统为核壳结构,包括X射线响应性纳米颗粒内核,以及包覆于该所述内核表面的光敏双亲性脂质体外壳;所述的光敏脂质体亲水端负载有化疗药物,所述的纳米颗粒在X射线的照射下能发出被所述光敏脂质体吸收的紫外光或可见光,从而使脂质体分子结构发生改变,释放所述化疗药物,实现了深部肿瘤的智能精准药物递送,从而降低药物非特异性释放造成的剧烈副作用,为临床精准化疗提供了新思路与新方法。
Description
技术领域
本发明属于生物医学材料技术领域,具体而言,涉及一种基于稀土纳米颗粒的X射线激发型化疗药物递送系统及应用。
背景技术
化疗(Chemotherapy)作为临床治疗癌症的常规手段,始终受限于非特异性分布或不受控的药物释放所造成的强烈副作用,以及相对较短的体循环时间引起的药效不持久、瘤体药物浓度较低、疗效不足等问题(Zhou,X.,et al.,Dual-Responsive MesoporousSilica Nanoparticles Mediated Codelivery of Doxorubicin and Bcl-2 SiRNA forTargeted Treatment of Breast Cancer.The Journal of Physical Chemistry C,2016.120(39):p.22375-22387.;Zhu,H.,et al.,Effects of interlayer polarizationfield on the band structures of the WS2/MoS2 and WSe2/MoSe2heterostructures.Surface Science,2017.661:p.1-9.)。而借助刺激-响应型药物递送系统进行更精准的化疗药物递送,可有效降低副作用,提升抗肿瘤疗效。因此,研发一种以化疗药物和免疫疗法药物精准可控递送并可承载其他疗法的新型药物递送系统意义重大。
智能药物递送系统按释药机理可区分为内部刺激触发和外部刺激触发。内部刺激触发释药机理主要是利用患处(含肿瘤)与身体正常组织之间存在的环境差异,如pH差异、特定的酶的浓度差异、氧化还原稳态的差异等。外部刺激触发释药,主要是利用外部刺激源对药物递送部位进行刺激造成药物精准释放,如光、超声、磁场等。由于人体本身的复杂性,内部刺激触发释药仍存在着释药部位不精准的问题,如基于酸性pH内部刺激释药的药物递送系统,是基于肿瘤部位的酸性细胞环境进行刺激响应释药,但胃中的pH要明显低于肿瘤部位,亦会造成药物的非特异性释放,造成一定的副作用。
外部刺激触发机理的智能药物递送系统在这方面存在着明显的优势,其利用外部磁场、光、热、微波、超声等,对患处累积的药物递送系统进行刺激释药,具备着作用精准、无非特异性释药的特性。外部光刺激触发智能药物递送系统,由于其利用紫外-可见-近红外光作为激发光源,具备良好的时间与空间操控性,目前已在Hela、PC3等细胞系验证了其有效性(Zhang,A.,et al.(2019)."Recent advances in stimuli-responsive polymersystems for remotely controlled drug release."Progress in Polymer Science 99:101164.)。但受到紫外-可见-近红外光的物理性质所限,其在人体组织穿透深度严重受限,最大仅为2cm,且具备光毒性(紫外)或热效应(近红外),无法被应用于过大或过深的肿瘤部位刺激释药。因此,需寻找组织穿透性更强的替代光源。
X射线,由于其在人体组织中具备良好穿透性、准直性以及时间空间控制分辨率,目前已在临床广泛应用于成像与放疗治疗。2017年起,本发明人一直致力于高效X射线激发发光纳米颗粒的研究,并已成功将其应用于X射线激发光学断层成像以及X射线激发光动力学治疗肿瘤的研究(Wenli Zhang,etc.Sub-10 nm Water-Dispersible β-NaGdF4:X%Eu3+Nanoparticles with Enhanced Biocompatibility for in Vivo X-ray LuminescenceComputed Tomography.ACS Applied materials&Interface.2017,9(46),pp 39985-39993;Zhang,W.,et al.(2018)."Ultra-high FRET efficiency NaGdF4:Tb3+-RoseBengal biocompatible nanocomposite for X-ray excited photodynamic therapyapplication."Biomaterials 184:31-40.;Zhang,X.,et al.(2019)."Low-Dose X-rayExcited Photodynamic Therapy Based on NaLuF4:Tb3+–Rose Bengal Nanocomposite."Bioconjugate Chemistry 30(8):2191-2200.)。然而,传统的光刺激触发药物递送系统无法直接有效的吸收X射线的高能光子,从而限制了X射线在光激发药物递送系统中的应用。
发明内容
鉴于现有技术的不足,本发明的首要目的在于利用X射线作为激发光源,开发一种基于X射线外部刺激触发的智能化疗药物递送系统,从而应用于深部肿瘤的精准化疗,并期望降低化疗药物非特异性释放给病患带来的副作用。
为了实现上述技术目的,本发明人创新性地引入一个“X射线能量转化单元”,从而实现将X射线高能光子的能量转化为紫外-可见光,并借助可负载药物的光敏感脂质体,制备新型的X射线激发化疗药物递送系统。
在上述技术构思的基础上,本发明人对前期研究的以NaLuF4为基质的X射线激发发光纳米颗粒进行双亲性脂质体包覆,并进一步搭载化疗药物,使其具备优异的放疗药物装载特性,与此同时,有效防止药物的非特异性释放造成的副作用。整个药物递送系统在X射线的照射下,以NaLuF4为基质的纳米发光颗粒可高效发出被双亲性脂质体有效吸收的紫外或可见光,使其分子结构发生改变,造成药物的释放,通过X射线对肿瘤部位的照射,可实现化疗药物在肿瘤部位的精准递送,从而实现本发明的目的。
具体地,本发明的技术方案概况如下:一种基于稀土纳米颗粒的X射线激发型化疗药物递送系统,该系统为核壳结构,包括X射线响应性纳米颗粒内核,以及包覆于该所述内核表面的光敏脂质体外壳;所述的光敏脂质体亲水端负载有化疗药物,所述的纳米颗粒在X射线的照射下能发出被所述光敏脂质体吸收的紫外光或可见光,从而使脂质体分子结构发生改变,释放所述化疗药物。
进一步优选地,如上所述基于稀土纳米颗粒的X射线激发型化疗药物递送系统,其中发光中心离子以Er3+为佳,整个X射线响应性纳米颗粒选用β-NaLuF4:X%Er3+,进并一步筛选掺杂离子浓度,优选出发光效率最高的离子摩尔浓度,即X=2~5。
进一步优选地,如上所述基于稀土纳米颗粒的X射线激发型化疗药物递送系统,其中的光敏脂质体中选择具备良好水溶性与生物安全性的聚氧化乙烯PEO作为亲水基团,亲油端将选用具备良好生物安全性与光敏感性的PSCSSMA(基于氧杂萘邻酮的二硫化物),其结构式如下所示:
再进一步优选地,如上所述基于稀土纳米颗粒的X射线激发型化疗药物递送系统,其中的光敏脂质体中亲水基团PEO的聚合度为25-35,亲油基团PSCSSMA的聚合度为25-35。
在本发的实施例中,为了研究不同PEO或PSCSSMA链长对530nm波长的激光的响应灵敏度,发明人分别选取PEO的链长为10/20/30/35个PEO分子,以及PSCSSMA的链长为15/20/25/30/35个分子,分别进行实验,发现当PEO的链长为30个分子时,脂质体的水溶性较好;随着PSCSSMA的链长的增加,双亲性脂质体对光的敏感性增加,为适应实验环境,将选取PSCSSMA链长为30的分子脂质体。
再进一步优选地,如上所述基于稀土纳米颗粒的X射线激发型化疗药物递送系统,其中的X射线响应性纳米颗粒通过物理吸附作用,将光敏感的双亲性脂质体(如含双硫键或双硒键或双碲键的化合物等)吸附于纳米颗粒亲油性表面,其亲水端与化疗药物以及更多的脂质体形成另外一层保护外壳,在实现高密度载药的同时,杜绝药物的非特异性释放。
需要说明的是,本发明所述基于稀土纳米颗粒的X射线激发型化疗药物递送系统,其中的化疗药物选自如下的一种或两种以上:阿霉素、紫杉醇、长春新碱、喜树碱、环磷酰胺、长春新碱、长春地辛、柔红霉素、伊立替康、米托蒽醌、吉西他滨、甲氨蝶呤、多西他赛、丝裂霉素C、氟尿嘧啶、顺铂、卡铂、奥沙利铂。
另外,本发明还提供了一种上述基于稀土纳米颗粒的X射线激发型化疗药物递送系统的制备方法,该方法包括如下步骤:
(1)X射线响应性纳米颗粒的制备:采用高温共沉淀法制备β-NaLuF4:X%Er3+纳米颗粒,其中作为摩尔掺杂量的X=2~5;
(2)双亲性光敏脂质体的制备:采用冰浴法合成双亲性光敏脂质体PEOm-b-PSCSSMAn,其中m=25-35,n=25-35(Ziqiang Sun,Guhuan Liu,Jinming Hu,Shiyong Liu;Photo-and Reduction-Responsive Polymersomes for Programmed Release of Smalland Macromolecular Payloads.Biomacromolecules 2018,19,2071-2081);PEOm-b-PSCSSMAn的结构式如下所示:
(3)取步骤(1)制备的β-NaLuF4:X%Er3+纳米粒、步骤(2)制备的PEOm-b-PSCSSMAn以及化疗药物,混合,利用物理吸附作用进行自组装反应,得到X射线激发型化疗药物递送系统。
进一步优选地,如上所述基于稀土纳米颗粒的X射线激发型化疗药物递送系统的制备方法,其中步骤(2)的具体操作步骤为:取三乙胺和双硫键氨基甲酸叔丁酯醇(BOC-NH2-SS-OH)溶解于0℃的四氢呋喃中,在冰浴条件下逐滴加入甲基丙烯酰氯的四氢呋喃溶液,并剧烈搅拌,常温反应过夜,制得BOC-NH2-SS-MA前驱体;将制得的BOC-NH2-SS-MA前驱体与三氟乙酸溶于二氯甲烷中,室温下反应0.5-2小时后,加入氧杂萘邻酮咪唑(Coumarin-Imidazole),室温反应8-16小时,然后加入PEO,65-75℃反应0.5-2小时,生成PEOm-b-PSCSSMAn。需要说明的是,氧杂萘邻酮咪唑的结构式如下所示:
进一步优选地,如上所述基于稀土纳米颗粒的X射线激发型化疗药物递送系统的制备方法,其中步骤(3)的具体操作步骤为:取双亲性光敏脂质体PEOm-b-PSCSSMAn和β-NaLuF4:X%Er3+纳米颗粒分散于1,4-二氧六环,然而逐滴加入含有化疗药物的水溶液,剧烈搅拌0.5-2小时,过滤除去多余的化疗药物。
本发明所述的X射线激发型化疗药物递送系统与鼠源结肠癌细胞CT26共培养,结果显示该药物递送系统可通过经典的EPR效应进入细胞,并稳定停留在细胞质中。通过CT26荷瘤Balb/C小鼠肿瘤模型进行实验,通过尾静脉注射该药物递送系统12小时后,该药物递送系统在X射线的激发下,由于其化疗药物及免疫疗法药物的释放,同时实现了化疗-免疫疗法-光动力学治疗-放疗联合治疗。因此,本发明还提供了上述的X射线激发型化疗药物递送系统在制备化疗-免疫疗法-光动力学治疗-放疗协同抗肿瘤治疗药物中的应用。进一步优选地,所述的肿瘤包含结肠癌、肝癌等深部及浅表肿瘤。
与现有技术相比,本发明涉及的X射线激发型化疗药物递送系统以X射线激发发光纳米颗粒NaLuF4作为能量转换单元,光敏感的油水双亲性脂质体包壳作为化疗药物载药单元及刺激-响应单元,同时搭载化疗药物,实现深部肿瘤的智能精准药物递送,从而降低药物非特异性释放造成的剧烈副作用,为临床精准化疗提供了新思路与新方法,其具有如下优点和显著进步性还表现如下:
(1)本发明首次实现了利用X射线激发的药物精准递送系统,突破了传统光激发药物递送系统的激发光穿透深度不足所造成的无法在深部肿瘤进行应用的现状。
(2)本发明的药物递送系统,由于其特殊新颖的设计,具备与其他疗法(基因疗法、免疫疗法、光动力学疗法)联合治疗的特性。
(3)本发明的药物递送系统具备良好的稳定性与生物安全性,体外细胞实验与小鼠体内实验均证明该药物递送系统无明显毒性,从侧面也证明了药物较低的非特异性释放。
(4)本发明的药物递送系统,由于其良好的光敏感性,所需的X射线剂量极低,仅为0.3Gy的剂量可达到良好的治疗效果,不会因为X射线照射产生组织损伤。
附图说明
图1:基于β-NaLuF4:15%Er3+的X射线激发药物递送系统示意图。
图2:β-NaLuF4:3%Er3+的透射电镜图。
图3:不同Er掺杂浓度的β-NaLuF4:Er3+的光谱图。
图4:PEO30-b-PSCSSMA30的H1 NMR谱图。
图5:PEO30-b-PSCSSMA30的光敏感性测定结果。
图6:不同X射线剂量照射后阿霉素释放情况。
图7:CCK-8测得不同药物递送系统浓度下CT26细胞的存活率。
图8:X射线照射后,不同分组肿瘤体积增长倍数曲线。
具体实施方式
本发明研制了一种采用紫外-可见光产额高的(β-NaLuF4:3%Er3+)纳米颗粒进行光敏感双亲性脂质体包覆用于载药(化疗药物)与响应释药,从而制备出具备化疗药物精准递送的X射线激发药物递送系统。通过X射线精准照射肿瘤部位,β-NaLuF4:3%Er3+纳米颗粒发出紫外-可见光,发出的紫外-可见光被光敏感双亲脂质体吸收造成其结构改变,释放化疗药物,同时X射线亦具备放疗的作用,实现在肿瘤部位精准释放化疗药物的抗肿瘤作用。其整体设计如图1所示,整个制备和实验思路如下:
1.X射线激发发光纳米颗粒β-NaLuF4:3%Er3+的制备。
主要采用“高温共沉淀法”制备β-NaLuF4:3%Er3+纳米颗粒,取不同摩尔比例的ErCl3、LuCl3与油酸和1-十八烯进行混合搅拌,并通过加热生成Er和Lu的油酸盐,进一步加入NaOH和NH4F进行搅拌,加热300℃反应生成β-NaLuF4:Er3+纳米粒。并对制备的纳米粒进行TEM、XRD表征,分析其颗粒形态、颗粒尺寸、晶格结构等;使用X射线照射发光纳米粒,利用荧光分光光度计分析其光产额性能。
2.PEOm-b-PSCSSMAn双亲性光敏感脂质体合成。
主要采用冰浴法进行合成,2.84mmol的三乙胺和1.89mmol的BOC-NH2-SS-OH(氨基甲酸叔丁酯-S-S-OH,Pires,M.M.;Chmielewski,J.Fluorescence imaging of cellularglutathione using a latent rhodamine.Org.Lett.2008,10,837-840.)溶解于0℃的四氢呋喃中,并将反应体系置于冰浴后,逐滴加入溶于10mL四氢呋喃的2.08mmol的甲基丙烯酰氯,并剧烈搅拌,常温反应过夜,制得BOC-NH2-SS-MA前驱体。将制得的BOC-NH2-SS-MA前驱体3.2mmol与5mL三氟乙酸溶于5mL二氯甲烷中,室温下反应1小时后,加入Coumarin-Imidazole 3.55mmol,室温反应12小时,后加入聚氧化乙烯,70℃反应1小时,生成PEOm-b-PSCSSMAn。每一步的产物均可采用H1 NMR和高效液相色谱进行分析。
3.β-NaLuF4:3%Er3+纳米颗粒与PEOm-b-PSCSSMAn的药物递送系统的制备。
整个制备过程主要采用“自组装”的方式进行合成,1mg的PEOm-b-PSCSSMAn和1mg的β-NaLuF4:3%Er3+纳米颗粒溶解于1mL的1,4-二氧六环,并逐滴加入含有阿霉素的水溶液,剧烈搅拌1小时,后通过过滤的方式,移除多余的阿霉素。药物递送系统可以通过TEM进行微观形貌特征鉴定。
4.药物递送系统在X射线激发下的药物释放测试。
将1mg药物递送系统分散于1mL的水中,置于透明一次性比色皿中,照射X射线后,离心收集上清液,通过光吸收法,分析上清液中药物释放的量。
5.药物递送系统的生物安全性及胞吞测试。
基于制备的新型药物递送系统,将其与小鼠结肠癌细胞CT26共培养,通过共聚焦显微镜,研究新型药物递送系统的入胞能力以及入胞过程。采用MTT或CCK8法验证不同浓度的药物递送系统的细胞浓度。
6.药物递送系统的在体抗肿瘤评价。
将药物递送系统通过尾静脉注射入CT26荷瘤小鼠体内,24小时后,使药物递送系统通过EPR效应有效的进入肿瘤部位,并通过照射不同剂量X射线进行抗肿瘤治疗,每三天监测一次肿瘤体积及老鼠体重,以此来评判药物递送系统的在体抗肿瘤疗效。
上述说明仅是本发明技术方案的概述,为了能够更清楚了解本发明的技术手段,并可依照说明书的内容和本领域的常规技术手段予以实施,下面结合具体的实施例对本发明做进一步详细说明,所述是对本发明的解释而不是限定。
实施例1:X射线激发发光纳米颗粒β-NaLuF4:3%Er3+的制备
称量出377mg的LuCl3·6H2O和1mg的ErCl3·6H2O,并将10mL的油酸(Oleic acid,OA)和15mL的1-十八烯(1-Octadecene,ODE)加入到100mL圆底烧瓶中。在氩气保护的条件下,将混合物加热至160℃反应60分钟,形成淡黄色透明溶液。关闭加热设备,使其冷却至室温,加入溶解在10mL甲醇中的NH4F(4mmol,0.1481g)、NaOH(2.5mmol,0.1g),室温搅拌反应1小时,然后以20℃/min的速率升温至300℃,反应1小时。反应结束后,使体系自然冷却至室温,用无水乙醇和环己烷混合物离心洗涤3次,并分散于环己烷中。图2是β-NaLuF4:3%Er3+的透射电镜图,可以看到该种纳米颗粒形貌为均一的球形,在环己烷中分散性良好,尺寸在25-35nm左右。图3是不同Er3+掺杂比例的X射线激发光谱图。
实施例2:PEO-b-PCSSMA双亲性光敏感脂质体合成
在100mL圆底烧瓶中,2.84mmol的三乙胺和1.89mmol的BOC-NH2-SS-OH(氨基甲酸叔丁酯-S-S-OH)溶解于0℃的四氢呋喃中,并将反应体系置于冰浴后,逐滴加入溶于10mL四氢呋喃的2.08mmol的甲基丙烯酰氯,并剧烈搅拌,常温反应过夜,制得BOC-NH2-SS-MA前驱体。将制得的BOC-NH2-SS-MA前驱体3.2mmol与5mL三氟乙酸溶于5mL二氯甲烷中,室温下反应1小时后,加入Coumarin-Imidazole 3.55mmol,室温反应12小时,后加入聚氧化乙烯,70℃反应1小时,生成PEO30-b-PSCSSMA30。每一步的产物均可采用H1 NMR和高效液相色谱进行分析。图4为PEO30-b-PSCSSMA30的H1 NMR图谱。并通过光吸收法,测定不同X射线照射剂量下,PEO30-b-PSCSSMA30的光吸收改变情况,从而测定其光敏感性,如图5所示。
实施例3:β-NaLuF4:3%Er3+纳米颗粒与PEO30-b-PSCSSMA30的药物递送系统的制备
整个制备过程主要采用“自组装”的方式进行合成,1mg的PEO30-b-PSCSSMA30和1mg的β-NaLuF4:3%Er3+纳米颗粒溶解于1mL的1,4-二氧六环,将1mg阿霉素溶于1mL的水中,将阿霉素水溶液逐滴加入到含有PEO30-b-PSCSSMA30和β-NaLuF4:3%Er3+纳米颗粒的1,4-二氧六环中,剧烈搅拌1小时,后通过负压过滤的方式(滤纸孔径2.5微米),移除多余的阿霉素与PEO30-b-PSCSSMA30。
实施例4:药物递送系统在X射线激发下的药物释放测试
将1mg药物递送系统(实施例3制备)分散于1mL的水中,照射X射线后,离心收集上清液,通过光吸收法检测484nm处的吸收峰,分析上清液中药物释放的量。如图6所示,该药物递送系统在X射线照射下,能够有效的释放药物,并且在0.8Gy的照射条件下,经过48小时后,药物全部释放。
实施例5:药物递送系统的生物安全性及胞吞测试
小鼠结肠癌细胞CT26购于中国科学院典型培养物保藏委员会细胞库(NationalCollection of Authenticated Cell Cultures)。将处于对数生长期的CT26细胞分别与0.001–1mg/mL的药物递送系统(实施例3制备)进行共培养12小时,然后利用MTT或CCK-8测试其生物毒性。将处于对数生长期的CT26细胞(置于共聚焦显微镜专用培养皿)与0.1mg/mL的药物递送系统进行共培养12小时后,用PBS冲洗细胞3次,去除未被胞吞的药物递送系统后,置于共聚焦显微镜下进行观察。如图7所示,通过CCK-8对不同浓度下培养的CT26细胞进行测试,发现即使在1mg/mL的高浓度药物递送系统的条件下,仍未发现细胞有明显死亡的情况,这意味着该药物递送系统具备良好的生物安全性。药物递送系统经过与CT26细胞12小时的共培养,能够成功通过胞吞的途径进入细胞,为抗肿瘤药物在细胞内的释放提供了基础条件。
实施例6:药物递送系统的在体抗肿瘤评价
将CT26小鼠分为对照组(注射生理盐水,无X射线照射)、无药物对照组(注射生理盐水,0.3Gy的X射线照射)、DDS对照组(按照阿霉素剂量10mg/kg的给药剂量注射实施例3制备的药物递送系统,无X射线照射)以及实验组(按照阿霉素剂量10mg/kg的给药剂量注射实施例3制备的药物递送系统,0.3Gy的X射线照射)。将药物递送系统或生理盐水通过尾静脉注射的方式,注射入CT26荷瘤小鼠体内,24小时后,对小鼠肿瘤部位进行X射线照射进行治疗。每三天监测一次小鼠肿瘤体积以及体重。如图8所示,实验组小鼠的肿瘤增长倍数明显低于三组对照组,并存在统计学差异,所有组中的小鼠体重及饮食饮水均未发现异常,证明该药物递送系统在X射线的激发下,由于其化疗药物及免疫疗法药物的释放,同时实现了化疗-免疫疗法-光动力学治疗-放疗联合治疗,获得了良好的肿瘤抑制效果。
Claims (10)
1.一种基于稀土纳米颗粒的X射线激发型化疗药物递送系统,其特征在于,该系统为核壳结构,包括X射线响应性纳米颗粒内核,以及包覆于该所述内核表面的光敏脂质体外壳;所述的光敏脂质体亲水端负载有化疗药物,所述的纳米颗粒在X射线的照射下能发出被所述光敏脂质体吸收的紫外光或可见光,从而使脂质体分子结构发生改变,释放所述化疗药物。
2.根据权利要求1所述基于稀土纳米颗粒的X射线激发型化疗药物递送系统,其特征在于,所述的X射线响应性纳米颗粒为β-NaLuF4:X%Er3+,其中X=2~5。
3.根据权利要求1所述基于稀土纳米颗粒的X射线激发型化疗药物递送系统,其特征在于,所述的光敏脂质体中亲水基团为PEO,亲油基团为PSCSSMA。
4.根据权利要求3所述基于稀土纳米颗粒的X射线激发型化疗药物递送系统,其特征在于,所述的光敏脂质体中亲水基团PEO的聚合度为25-35,亲油基团PSCSSMA的聚合度为25-35。
5.根据权利要求3所述基于稀土纳米颗粒的X射线激发型化疗药物递送系统,其特征在于,所述的X射线响应性纳米颗粒通过物理吸附作用被光敏脂质体包覆。
6.根据权利要求1-5任一项所述基于稀土纳米颗粒的X射线激发型化疗药物递送系统,其特征在于,所述的化疗药物选自如下的一种或两种以上:阿霉素、紫杉醇、长春新碱、喜树碱、环磷酰胺、长春新碱、长春地辛、柔红霉素、伊立替康、米托蒽醌、吉西他滨、甲氨蝶呤、多西他赛、丝裂霉素C、氟尿嘧啶、顺铂、卡铂、奥沙利铂。
7.一种根据权利要求1所述基于稀土纳米颗粒的X射线激发型化疗药物递送系统的制备方法,其特征在于,该方法包括如下步骤:
(1)X射线响应性纳米颗粒的制备:采用高温共沉淀法制备β-NaLuF4:X%Er3+纳米颗粒,其中X=2~5;
(2)双亲性光敏脂质体的制备:采用冰浴法合成双亲性光敏脂质体PEOm-b-PSCSSMAn,其中m=25-35,n=25-35;
(3)取步骤(1)制备的β-NaLuF4:X%Er3+纳米粒、步骤(2)制备的PEOm-b-PSCSSMAn以及化疗药物,混合,利用物理吸附作用进行自组装反应,得到X射线激发型化疗药物递送系统。
8.根据权利要求7所述基于稀土纳米颗粒的X射线激发型化疗药物递送系统的制备方法,其特征在于,步骤(2)的具体操作步骤为:取三乙胺和BOC-NH2-SS-OH溶解于0℃的四氢呋喃中,在冰浴条件下逐滴加入甲基丙烯酰氯的四氢呋喃溶液,并剧烈搅拌,常温反应过夜,制得BOC-NH2-SS-MA前驱体;将制得的BOC-NH2-SS-MA前驱体与三氟乙酸溶于二氯甲烷中,室温下反应0.5-2小时后,加入氧杂萘邻酮咪唑,室温反应8-16小时,然后加入PEO,65-75℃反应0.5-2小时,生成PEOm-b-PSCSSMAn。
9.根据权利要求7所述基于稀土纳米颗粒的X射线激发型化疗药物递送系统的制备方法,其特征在于,步骤(3)的具体操作步骤为:取双亲性光敏脂质体PEOm-b-PSCSSMAn和β-NaLuF4:X%Er3+纳米颗粒分散于1,4-二氧六环,然而逐滴加入含有化疗药物的水溶液,剧烈搅拌0.5-2小时,过滤除去多余的化疗药物。
10.权利要求1所述的X射线激发型化疗药物递送系统在制备化疗-免疫疗法-光动力学治疗-放疗协同抗肿瘤治疗药物中的应用。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005316174A (ja) * | 2004-04-28 | 2005-11-10 | Fuji Photo Film Co Ltd | 感光性樹脂組成物およびクマリン化合物 |
WO2015140160A1 (en) * | 2014-03-17 | 2015-09-24 | Fundación Centro Nacional De Investigaciones Cardiovasculares Carlos Iii | Micellar nanoparticles containing antitumoral glycosides |
CN109200286A (zh) * | 2018-09-30 | 2019-01-15 | 南京理工大学 | 近红外光响应香豆素改性的纳米复合材料及其制备方法 |
CN110947006A (zh) * | 2019-08-26 | 2020-04-03 | 上海大学 | 一种稀土上转换-铋诊疗一体化纳米杂化体系、制备方法及应用 |
CN111187624A (zh) * | 2020-02-10 | 2020-05-22 | 天津大学 | 上转换微米颗粒及其制备方法、荧光寿命调控方法 |
CN112451485A (zh) * | 2020-12-07 | 2021-03-09 | 南京大学 | 一种短时间近红外光照激活的纳米胶束用于药物快速释放 |
-
2022
- 2022-03-14 CN CN202210249954.0A patent/CN114569741A/zh active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005316174A (ja) * | 2004-04-28 | 2005-11-10 | Fuji Photo Film Co Ltd | 感光性樹脂組成物およびクマリン化合物 |
WO2015140160A1 (en) * | 2014-03-17 | 2015-09-24 | Fundación Centro Nacional De Investigaciones Cardiovasculares Carlos Iii | Micellar nanoparticles containing antitumoral glycosides |
CN109200286A (zh) * | 2018-09-30 | 2019-01-15 | 南京理工大学 | 近红外光响应香豆素改性的纳米复合材料及其制备方法 |
CN110947006A (zh) * | 2019-08-26 | 2020-04-03 | 上海大学 | 一种稀土上转换-铋诊疗一体化纳米杂化体系、制备方法及应用 |
CN111187624A (zh) * | 2020-02-10 | 2020-05-22 | 天津大学 | 上转换微米颗粒及其制备方法、荧光寿命调控方法 |
CN112451485A (zh) * | 2020-12-07 | 2021-03-09 | 南京大学 | 一种短时间近红外光照激活的纳米胶束用于药物快速释放 |
Non-Patent Citations (3)
Title |
---|
LI ET AL.: "Water dispersive upconversion nanoparticles for intelligent drug delivery system", 《COLLOIDS AND SURFACES A》, vol. 555, pages 2 - 2 * |
孙自强: "光和还原性响应的两亲性嵌段共聚物的合成及应用", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》, no. 05, pages 2 * |
郑尧 等: "NaLuF4掺杂Tm3+和Er3+的X射线激发发光特性研究", 《中国稀土学报》, vol. 38, no. 5, pages 1 * |
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