CN111939311B - 一种基于微流控芯片的磁响应性载药栓塞微球的制备方法 - Google Patents
一种基于微流控芯片的磁响应性载药栓塞微球的制备方法 Download PDFInfo
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Abstract
一种基于微流控芯片的磁响应性载药栓塞微球的制备方法，该方法利用具有三个微通道入口的流动聚集型微芯片，分别利用O/O/W和W/O/W的乳化法实现对疏水性以及亲水性药物的包封，同时O/O/W中通过对中间油相溶液的调控实现了制备不同壳层厚度的微球。本发明利用注射泵分别将三种溶液注入微流控芯片相应的三个微通道，通过适当调整流速将分散相溶液剪切成单分散的液滴，然后采用旋转蒸发使得液滴固化，得到尺寸均一可控、单分散性良好的磁响应性载药微球。
Description
技术领域
本发明属于微流控技术领域和医学介入治疗领域，具体涉及一种基于微流控芯片的磁响应性载药栓塞微球的制备方法。
背景技术
肝细胞肝癌是肝脏最常见原发性恶性肿瘤，其病死率在恶性肿瘤中居第三位,也是我国恶性肿瘤的常见病、多发病。大多数肝癌患者发现时已处于晚期,受肿瘤转移、体积、数目等限制已不适合行外科手术治疗。因此，经导管动脉化疗栓塞术(TACE)成为目前首选的有效治疗方法。TACE是通过微导管将栓塞材料选择性地注入肿瘤血管及肿瘤供血动脉中，切断肿瘤供血，同时释放化疗药物，以达到治疗肿瘤的目的。传统的TACE是通过碘化油加阿霉素、顺铂或其他化疗药物混合给药，但存在增加全身性不良反应，降低局部治疗效果等不足之处。目前的载药微球TACE可以加载化疗药物，并在体内缓慢释放，兼具局部化疗和栓塞特性。微球的制备方法一般是离子交联法、乳化交联法、乳化-溶剂蒸发法等，但这些方法制备出的液滴具有结构不均一、粒径分布较宽且具有初始爆发突释等不足。
发明内容
为了解决现有的载药微球存在的技术问题，本发明的目的在于提供一种基于微流控芯片的磁响应性载药栓塞微球的制备方法，基于微流控技术，采用具有三个微通道溶液入口的流动聚焦型芯片制备O/O/W和W/O/W液滴，分别实现了对疏水性和亲水性药物的包封，且制备的液滴尺寸均一可控、微球壳层厚度可控。
为了实现上述技术目的，本发明采用如下技术方案：
一种基于微流控芯片的磁响应性载药栓塞微球的制备方法，所述微流控芯片由上层含微通道的芯片与下层空白芯片不可逆的贴合在一起，其中含微通道的芯片包括外环形微通道、中间环形微通道、内线形微通道和出口微通道，同侧的外环形微通道的一端、中间环形微通道的一端和内线形微通道的一端依次与外环形微通道溶液入口、中间环形微通道溶液入口和内线形微通道入口相连，相对的另一端交汇于出口微通道；所述载药栓塞微球为载有疏水性药物的微球或载有亲水性药物的微球，其具体制备过程包括：
方案一O/O/W乳化法制备载有疏水性药物的微球
(1)微流控芯片的表面处理：中间环形微通道和内线形微通道利用PVA溶液进行亲水处理，使得中间环形微通道和内线形微通道表面亲水；
(2)微球的制备：以PVA溶液作为外环形微通道溶液；PLGA溶液作为中间环形微通道溶液；PLGA溶液、Fe3O4磁性纳米粒和疏水性药物紫杉醇(PTX)的混合溶液作为内线形微通道溶液，通过控制中间环形微通道溶液和内线形微通道溶液的流速以及组分含量形成稳定的层流后，利用外环形微通道溶液的剪切力截断形成液滴，经出口微通道流出后收集，通过旋转蒸发固化成微球；
方案二W/O/W乳化法制备载有亲水性药物的微球
(1)微流控芯片的表面处理：中间环形微通道利用PVA溶液进行亲水处理，使得中间环形微通道表面亲水；内线形微通道利用乙醇稀释的(十三氟-1,1,2,2-四氢辛基)-1-三氯硅烷进行疏水处理，使得内线形微通道表面疏水；
(2)微球的制备：以PVA溶液作为外环形微通道溶液；PLGA溶液和Fe3O4磁性纳米粒的混合溶液作为中间环形微通道溶液；亲水性药物盐酸阿霉素溶液(DOX·HCl)作为内线形微通道溶液，通过控制中间环形微通道溶液和内线形微通道溶液的流速以及组分含量形成稳定的层流后，利用外环形微通道溶液和中间环形微通道溶液以及内线形微通道溶液的依次剪切包裹作用形成单分散的双乳液滴，经出口微通道流出后收集，通过旋转蒸发固化成微球。
作为优选，所述的微流控芯片的材料为可透光透气的PDMS聚合物，不可逆的贴合方式为等离子体处理30-60s。
作为优选，所述的外环形微通道、中间环形微通道、内线形微通道和出口微通道的高度均为100μm，外环形微通道、中间环形微通道和内线形微通道的宽度均为100μm，出口微通道的宽度为350μm。
作为优选，方案一的步骤(1)中，5mg/mL的PVA溶液分别注入中间环形微通道和内线形微通道后，置于60℃的烘箱中进行干燥，然后重复2～3次。
作为优选，方案一中的步骤(2)中，所述外环形微通道的PVA溶液的浓度为10mg/mL，中间环形微通道的PLGA溶液的浓度为10mg/mL，内线形微通道的PLGA浓度为10mg/mL，Fe3O4磁性纳米粒和疏水性药物紫杉醇(PTX)浓度随中间环形微通道溶液和内线形微通道溶液的流速进行调整，保证所制备的微球中物质含量相同。
作为优选，方案一的步骤(2)中，所述外环形微通道溶液的流速为200-600μL/min；中间环形微通道溶液的流速为10-50μL/min；内线形微通道溶液的流速为10-50μL/min。
作为优选，方案二的步骤(1)中，5mg/mL的PVA溶液注入中间环形微通道后，置于60℃的烘箱中进行干燥，然后重复2～3次；20％乙醇稀释的(十三氟-1,1,2,2-四氢辛基)-1-三氯硅烷溶液注入内线形微通道后，于120℃下烘烤3min，再采用无水乙醇洗涤、氮气冲洗。
作为优选，方案二中的步骤(2)中，所述外环形微通道的PVA溶液的浓度为20mg/mL，中间环形微通道的PLGA浓度为20mg/mL，Fe3O4浓度为0.5mg/mL；内线形微通道的DOX·HCl浓度为0.5mg/mL。
作为优选，方案二中的步骤(2)中，所述外环形微通道溶液的流速为200-500μL/min；中间环形微通道溶液的流速为10-50μL/min；内线形微通道溶液的流速为5-35μL/min。
本发明采用PLGA作为载体材料，用于包覆Fe3O4磁性纳米粒和亲水性或疏水性的抗肿瘤药物。其中，PLGA具有优良的生物可降解性和生物相容性；Fe3O4磁性纳米粒具有生物可降解性和优良的磁响应性，一方面其可在外加交变磁场条件下产热，从而对肿瘤细胞具有热杀死的作用；另一方面其具有超声造影功能，在磁场条件下具有自身MR成像功能，从而对载药微球进行实时追踪和观察肿瘤情况。疏水性抗肿瘤药物如PTX采用O/O/W的方法进行包封和制备；亲水性的抗肿瘤药物如DOX·HCl采用W/O/W的方法将其包载于内水相溶液中，最终得到具有粒径均一、尺寸可控、缓释可控且实现栓塞、化疗及热疗多重功效的联合运用并具有MR可视性的磁性载药栓塞微球。
本发明基于微流控的磁响应性栓塞微球的制备方法，利用O/O/W乳化法制备载有疏水性药物的液滴时，形成的磁响应性载药栓塞微球尺寸均一、可控；壳层厚度可调控；药物释放可控。利用W/O/W乳化法制备载有亲水性药物的液滴时，形成的液滴尺寸均一、可控；壳层厚度可调控；内核液滴数可控。
本发明利用两相油溶液的层流性质以及油水界面张力，在微流控芯片上一步形成核壳尺寸均一液滴，再经过旋转蒸发形成固化的微球。本发明采用微流控法制备的包载亲水性和疏水性的微球具有尺寸可控性好、壳层厚度可控等优点，该技术制备的微球可用于TACE术用于肝肿瘤治疗等医学方面的应用。
附图说明
图1是制备磁响应性栓塞微球的微流控芯片结构示意图；
其中，1代表外环形微通道；2代表中间环形微通道；3代表内线形微通道；4代表外环形微通道溶液入口；5代表中间环形通道溶液入口；6代表内线形微通道溶液入口；7代表出口微通道。
图2为实施例1中O/O/W法在流速为500/10/50μL/min条件下制备的微球的粒径分布图和光学显微镜成像图。
图3为实施例1中O/O/W法在三种流速下(500/10/50，500/30/30，500/50/10，从左到右依次对应)分别制得的微球的光学显微镜成像图。
图4为游离药物PTX和O/O/W法三种流速下(500/10/50，500/30/30，500/50/10)制备的载药微球的体外释放曲线。
图5为实施例2中W/O/W法在流速为300/40/10μL/min条件下制备的载亲水性药物DOX·HCl的单核双乳液的光学显微镜成像图和荧光显微镜成像图。
图6为实施例2中W/O/W法在流速为300/40/10μL/min条件下制备的载亲水性药物DOX·HCl的单核双乳液的内外直径的粒径分布图。
图7为实施例2中W/O/W法在六种流速下(300/30/10，300/30/15，300/30/20，300/30/22，300/30/30，300/30/35从A到F依次对应)分别制备的不同内核液滴数的单核双乳液的光学显微镜成像图。
图8为W/O/W法制备的单核双乳液滴，当外环形微通道(300μL/min)和中间环形微通道(30μL/min)溶液流速不变时，内线形微通道溶液的流速(6-35μL/min)与内核液滴数的关系。
图9为W/O/W法在流速为(A和A')300/20/10、(B和B')300/30/10、(C和C')300/40/10、(D和D')300/50/10四种流速下的液滴光学显微镜成像图和荧光成像图。
图10为W/O/W法单核液滴的情况下，外环形微通道(300μL/min)和内线形微通道(10μL/min)溶液流速不变时，中间环形微通道(20-50μL/min)溶液流速对液滴壳层厚度的影响。
具体实施方式
下面的实施例将对本发明予以进一步的说明，但并不因此而限制本发明。
如图1所示，为本发明的微流控芯片，其材料为可透光透气的PDMS聚合物，所述微流控芯片由上层含微通道的芯片与下层空白芯片通过等离子体处理30-60s后不可逆的贴合在一起，其中含微通道的芯片包括外环形微通道1、中间环形微通道2、内线形微通道3和出口微通道7，同侧的外环形微通道1的一端、中间环形微通道2的一端和内线形微通道3的一端依次与外环形微通道溶液入口4、中间环形微通道溶液入口5和内线形微通道入口6相连，相对的另一端交汇于出口微通道7。
外环形微通道1、中间环形微通道2、内线形微通道3和出口微通道7的高度均为100μm，外环形微通道1、中间环形微通道2和内线形微通道3的宽度均为100μm，出口微通道7的宽度为350μm。
具体制备过程中，分别利用注射泵将外环形微通道溶液、中间环形微通道溶液和内线形微通道溶液注入相应的微通道，通过控制中间环形微通道溶液和内线形微通道溶液的流速以及组分含量形成稳定的层流后，利用油溶液和水溶液之间的剪切力截断溶液后形成液滴，经出口微通道流出后收集，通过旋转蒸发固化成尺寸均一可控、单分散性良好的磁响应性载药微球。
实施例1
O/O/W乳化法制备载有疏水性药物的微球，具体包括下列步骤：
(1)微流控芯片的表面处理：5mg/mL的PVA溶液分别注入中间环形微通道和内线形微通道后，置于60℃的烘箱中进行干燥，然后重复2～3次，使得中间环形微通道和内线形微通道表面亲水；
(2)微球的制备：以PVA溶液作为外环形微通道溶液；PLGA溶液作为中间环形微通道溶液；PLGA溶液、Fe3O4磁性纳米粒和疏水性药物紫杉醇的混合溶液作为内线形微通道溶液，通过控制中间环形微通道溶液和内线形微通道溶液的流速以及组分含量形成稳定的层流后，利用外环形微通道溶液的剪切力截断形成液滴，经出口微通道流出后收集，通过旋转蒸发固化成微球。
外环形微通道的PVA溶液的浓度为10mg/mL，流速为500μL/min；中间环形微通道的PLGA溶液的浓度为10mg/mL，流速分别为10，30，50μL/min，内线形微通道溶液为PLGA溶液、Fe3O4磁性纳米粒和疏水性药物紫杉醇的混合溶液，流速分别为50，30，10μL/min，其流速下对应的PLGA溶液浓度为10mg/mL，Fe3O4纳米粒浓度分别为0.4，0.67，2mg/mL，PTX浓度分别为1.2，2，6mg/mL，制备的三种流速下的微球中各组分的含量相同。
如图2所示，O/O/W法在流速为500/10/50μL/min制备的微球的粒径分布图和光学显微镜成像图，说明制备的微球尺寸均一、粒径分布范围窄。
如图3所示，为三种流速方案(500/10/50μL/min；500/30/30μL/min；500/50/10μL/min)下制备的微球的光学显微镜成像图，其粒径大小分别为56.72±1.98μm、55.31±1.41μm、57.92±0.74μm，载药量分别为6.52±0.43％，6.98±0.33％和6.82±0.11％，说明了三种流速下对应的微球大小和载药量相差小，可用于体外药物释放研究和流速对药物释放快慢研究。
如图4所示；为游离药物PTX三种流速方案(500/10/50μL/min，500/30/30μL/min，500/50/10μL/min)下制备的载药微球的体外释放曲线，说明了游离药物PTX的释放速率明显高于微球的体外速率，此法制备的微球具有良好的缓释效果，且能够明显降低药物突释，中间环形微通道溶液流速越大时，微球的药物释放速率变慢，可通过调整流速和组份含量获得不同缓释效果的微球。
实施例2
W/O/W乳化法制备载有亲水性药物的微球，具体包括下列步骤：
(1)微流控芯片的表面处理：5mg/mL的PVA溶液注入中间环形微通道后，置于60℃的烘箱中进行干燥，然后重复2～3次，使得中间环形微通道表面亲水；20％乙醇稀释的(十三氟-1,1,2,2-四氢辛基)-1-三氯硅烷溶液注入内线形微通道后，于120℃下烘烤3min，再采用无水乙醇洗涤、氮气冲洗，使得内线形微通道表面疏水；
(2)微球的制备：以PVA溶液作为外环形微通道溶液；PLGA溶液和Fe3O4磁性纳米粒的混合溶液作为中间环形微通道溶液；亲水性药物盐酸阿霉素溶液(DOX·HCl)作为内线形微通道溶液，通过控制中间环形微通道溶液和内线形微通道溶液的流速以及组分含量形成稳定的层流后，利用油溶液和水溶液之间的剪切力截断溶液后形成液滴，经出口微通道流出后收集，通过旋转蒸发固化成微球。
所述外环形微通道的PVA溶液的浓度为20mg/mL，流速为300μL/min；中间环形微通道的PLGA溶液的浓度为20mg/mL，Fe3O4浓度为0.5mg/mL，流速分别为20-50μL/min；内线形微通道的DOX·HCl浓度为0.5mg/mL，流速分别为5-35μL/min。
如图5所示，为本实施例在外环形微通道的PVA溶液的浓度为20mg/mL，流速为300μL/min；中间环形微通道的PLGA溶液的浓度为20mg/mL，Fe3O4浓度为0.5mg/mL，流速为40μL/min；内线形微通道DOX·HCl浓度为0.5mg/mL，流速为10μL/min形成的载亲水性药物DOX·HCl的单核双乳液液滴，说明了液滴单分散性良好，且具有荧光成像，为DOX·HCl自身成像效果，其在绿光下可成红光，表明阿霉素的成功装载。
如图6所示，为本实施例在外环形微通道的PVA溶液的浓度为20mg/mL，流速为300μL/min；中间环形微通道的PLGA溶液的浓度为20mg/mL，Fe3O4浓度为0.5mg/mL，流速为40μL/min；内线形微通道DOX·HCl浓度为0.5mg/mL，流速为10μL/min形成的载亲水性药物DOX·HCl的单核双乳液液滴的内外直径的粒径分布图，微乳液的平均内直径为181.9±1.12μm，平均外直径为216.8±0.95μm，说明了液滴尺寸分布均匀。
如图7所示，为具有不同内核液滴数的双乳液的光学显微镜图，说明微流控W/O/W法可通过保持外环形微通道的PVA溶液的浓度为20mg/mL，流速为300μL/min不变；中间环形微通道的PLGA溶液的浓度为20mg/mL，Fe3O4浓度为0.5mg/mL，流速为30μL/min不变；内线形微通道DOX·HCl浓度为0.5mg/mL，流速分别为10，15，20，22，30，35μL/min从而获得具有单核、单核和双核、双核、双核和三核、三核、三核和四核双乳液滴。
图8为W/O/W法制备的双乳液滴，当保持外环形微通道的PVA溶液的浓度为20mg/mL，流速为300μL/min不变；中间环形微通道的PLGA溶液的浓度为20mg/mL，Fe3O4浓度为0.5mg/mL，流速为30μL/min不变；内线形微通道DOX·HCl浓度为0.5mg/mL，流速在6-35μL/min范围下，内线形微通道溶液的流速与内核液滴数的关系，说明在一定流速范围内可获得不同内核液滴数的双乳液。
图9为W/O/W法在流速为(A和A')300/20/10、(B和B')300/30/10、(C和C')300/40/10、(D和D')300/50/10四种流速下的液滴光学显微镜成像图和荧光成像图。
图10为W/O/W法单核液滴的情况下，保持外环形微通道的PVA溶液的浓度为20mg/mL，流速为300μL/min不变；保持内线形微通道DOX·HCl浓度为0.5mg/mL，流速为10μL/min不变，中间环形微通道的PLGA溶液的浓度为20mg/mL，Fe3O4浓度为0.5mg/mL，流速分别为20，30，40，50μL/min所得到的壳层厚度与液滴流速关系。外环形微通道和内线形微通道溶液流速不变时，液滴壳层厚度随着中间环形微通道溶液流速而增加，说明了微流控制备液滴的壳层厚度可控。
Claims (7)
1.一种基于微流控芯片的磁响应性载药栓塞微球的制备方法，其特征在于：所述微流控芯片由上层含微通道的芯片与下层空白芯片不可逆的贴合在一起，其中含微通道的芯片包括外环形微通道、中间环形微通道、内线形微通道和出口微通道，同侧的外环形微通道的一端、中间环形微通道的一端和内线形微通道的一端依次与外环形微通道溶液入口、中间环形微通道溶液入口和内线形微通道入口相连，相对的另一端交汇于出口微通道；所述载药栓塞微球为载有疏水性药物的微球或载有亲水性药物的微球，其具体制备过程包括：
方案一O/O/W乳化法制备载有疏水性药物的微球
(1)微流控芯片的表面处理：中间环形微通道和内线形微通道利用PVA溶液进行亲水处理，使得中间环形微通道和内线形微通道表面亲水；
(2)微球的制备：以PVA溶液作为外环形微通道溶液；PLGA溶液作为中间环形微通道溶液；PLGA溶液、Fe3O4磁性纳米粒和疏水性药物紫杉醇的混合溶液作为内线形微通道溶液，通过控制中间环形微通道溶液和内线形微通道溶液的流速以及组分含量形成稳定的层流后，利用外环形微通道溶液的剪切力截断形成液滴，经出口微通道流出后收集，通过旋转蒸发固化成微球；
方案一中的步骤(2)中，所述外环形微通道的PVA溶液的浓度为10mg/mL，中间环形微通道的PLGA溶液的浓度为10mg/mL，内线形微通道的PLGA浓度为10mg/mL，Fe3O4磁性纳米粒和疏水性药物紫杉醇浓度随中间环形微通道溶液和内线形微通道溶液的流速进行调整，保证所制备的微球中物质含量相同；
方案二W/O/W乳化法制备载有亲水性药物的微球
(1)微流控芯片的表面处理：中间环形微通道利用PVA溶液进行亲水处理，使得中间环形微通道表面亲水；内线形微通道利用乙醇稀释的(十三氟-1,1,2,2-四氢辛基)-1-三氯硅烷进行疏水处理，使得内线形微通道表面疏水；
(2)微球的制备：以PVA溶液作为外环形微通道溶液；PLGA溶液和Fe3O4磁性纳米粒的混合溶液作为中间环形微通道溶液；亲水性药物盐酸阿霉素溶液作为内线形微通道溶液，通过控制中间环形微通道溶液和内线形微通道溶液的流速以及组分含量形成稳定的层流后，利用外环形微通道溶液和中间环形微通道溶液以及内线形微通道溶液的依次剪切包裹作用形成单分散的双乳液滴，经出口微通道流出后收集，通过旋转蒸发固化成微球；
O/O/W乳化法制备载有疏水性药物的微球，增大中间环形微通道溶液的流速，减慢微球的药物释放速率；
W/O/W乳化法制备载有亲水性药物的微球，保持外环形微通道及中间环形微通道溶液的浓度及流速不变，改变内线形微通道溶液的流速，获得具有单核、单核和双核、双核、双核和三核、三核、三核和四核双乳液滴；
W/O/W乳化法制备载有亲水性药物的微球，保持外环形微通道及内线形微通道溶液的浓度及流速不变，液滴壳层厚度随中间环形微通道溶液流速而增加；
所述的微流控芯片的材料为可透光透气的PDMS聚合物，不可逆的贴合方式为等离子体处理30-60s。
2.根据权利要求1所述的一种基于微流控芯片的磁响应性载药栓塞微球的制备方法，其特征在于：所述的外环形微通道、中间环形微通道、内线形微通道和出口微通道的高度均为100μm，外环形微通道、中间环形微通道和内线形微通道的宽度均为100μm，出口微通道的宽度为350μm。
3.根据权利要求1所述的一种基于微流控芯片的磁响应性载药栓塞微球的制备方法，其特征在于：方案一的步骤(1)中，5mg/mLPVA溶液分别注入中间环形微通道和内线形微通道后，置于60℃的烘箱中进行干燥，然后重复2～3次。
4.根据权利要求1所述的一种基于微流控芯片的磁响应性载药栓塞微球的制备方法，其特征在于：方案一的步骤(2)中，所述外环形微通道溶液的流速为200-600μL/min；中间环形微通道溶液的流速为10-50μL/min；内线形微通道溶液的流速为10-50μL/min。
5.根据权利要求1所述的一种基于微流控芯片的磁响应性载药栓塞微球的制备方法，其特征在于：方案二的步骤(1)中，5mg/mL PVA溶液注入中间环形微通道后，置于60℃的烘箱中进行干燥，然后重复2～3次；20％乙醇稀释的(十三氟-1,1,2,2-四氢辛基)-1-三氯硅烷溶液注入内线形微通道后，于120℃下烘烤3min，再采用无水乙醇洗涤、氮气冲洗。
6.根据权利要求1所述的一种基于微流控芯片的磁响应性载药栓塞微球的制备方法，其特征在于：方案二中的步骤(2)中，所述外环形微通道的PVA溶液的浓度为20mg/mL，中间环形微通道的PLGA浓度为20mg/mL，Fe3O4浓度为0.5mg/mL；内线形微通道的盐酸阿霉素溶液的浓度为0.5mg/mL。
7.根据权利要求1所述的一种基于微流控芯片的磁响应性载药栓塞微球的制备方法，其特征在于：方案二中的步骤(2)中，所述外环形微通道溶液的流速为200-500μL/min；中间环形微通道溶液的流速为10-50μL/min；内线形微通道溶液的流速为5-35μL/min。
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