CN115252877A - 一种碘代聚乙二醇-聚乳酸羟基乙酸-聚赖氨酸显影多孔微球、制备方法和应用 - Google Patents
一种碘代聚乙二醇-聚乳酸羟基乙酸-聚赖氨酸显影多孔微球、制备方法和应用 Download PDFInfo
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Abstract
本发明提供一种碘代聚乙二醇‑聚乳酸羟基乙酸‑聚赖氨酸显影多孔微球的制备方法及应用;所述显影微球由碘代聚乙二醇‑聚乳酸羟基乙酸‑聚赖氨酸组成,采用微流控技术可制备出大小为1μm~1000μm的微球,具有的多孔结构是药物、基因、蛋白、金属离子、放射性核素的优良载体。本发明操作简单、易于重复、批次稳定。该微球是兼具作为支架、栓塞、显影、负载等多重功能的微球,有望用于细胞3D培养、临床栓塞、药物负载、疾病的诊断与原位治疗等领域。
Description
技术领域
本发明涉及生物医学领域,特别是涉及一种碘代聚乙二醇-聚乳酸羟基乙酸-聚赖氨酸显影多孔微球及其制备方法和应用。
背景技术
微球是直径在微米范围内(通常为1μm至1000μm)的球形颗粒,或称为微颗粒。根据微球是特征自由流动的粉末状颗粒,根据组分的不同微球可分为蛋白质、合成聚合物、玻璃、陶瓷微球等。其中最常用的材料是聚合物,如聚乳酸、聚(乳酸-乙醇酸)(PLGA)、壳聚糖、聚己内酯(PCL)、二乙烯基苯和其他聚合物或共聚物,这些聚合物在形成微球时配合成孔剂可形成多孔聚合物微球,极大地增加了微球的比表面积,拓展了其在化学、医学、生物医学工程等领域的应用。如药物递送及控制释放、3D细胞培养支架、组织修复辅料、介入显影微球及综合以上功能的多功能微球。
在微球的应用中,介入栓塞是微球应用较多的场景之一,介入治疗通常是在电子数字减影血管造影机(DSA)、电子计算机断层扫描(CT)、以及核磁共振等影像设备的辅助和监测下,通过使用穿刺针、导丝导管和其他一些介入治疗器材,通过股动脉穿刺等方法以微创型的伤口将栓塞微球等植入材料导入体内的肿瘤部位,以切断肿瘤的营养供给,饿死肿瘤细胞,从而达到治疗肿瘤的目的。由于其自身具有显影功能,故无需借助其他造影剂的辅助,避免了异位栓塞。
随着介入治疗的发展,介入治疗材料研发与制造发展迅速,这也对介入治疗相关材料提出了更高的要求,例如材料的示踪性以及药物包覆能力等。X射线下具有显影的无机材料为金属盐类造影剂。但这些金属盐类造影剂影响栓塞材料的机械性能,在使用后期,容易扩散至机体其它部位,并对机体产生毒性。
因此研究人员开始尝试将X射线显影剂以共价键的方式结合到聚合物链上,以确保稳定的材料性能,与较低的生物毒性。碘原子因其具有相对较大的原子质量、较高的电子云密度,其系列化合物也具有很好的X光不透过性,目前己广泛应用于临床诊疗当中与重金属盐的离子键相比较,碘原子具有更低的生物毒性,且其与聚合物的键合方式通常是更为稳固的共价键,因此引入含碘化合物的方式能够获得显影性能更为稳定的X光自显影高分子材料。
发明内容
本发明的目的是提供一种碘代聚乙二醇单甲醚-聚乳酸羟基乙酸-聚赖氨酸显影多孔微球。
本发明所要解决的技术问题是提供制备碘代PEAL显影微球的制备方法及应用,以克服现有技术中栓塞微球不具备显影功能。本发明采用的微球材料是一种以聚乙二醇单甲醚-聚乳酸羟基乙酸-聚赖氨酸(mPEG-PLGA-PLL,简写为PEAL,专利号:CN101732723B)阳离子聚合物为骨架的多孔显影微球。PEAL分子量为1.0×103-9.0×106,聚乙二醇单甲醚/乳酸的摩尔比为1-50∶50-100,乳酸/羟基乙酸的摩尔比为1-100∶1-100,羟基乙酸/赖氨酸的摩尔比为50-100∶1-50。该材料具有良好的生物相容性、药物包载能力,可被修饰而具有多功能特性,如肿瘤靶向、逆转耐药和医学诊断功能等,已被证明可用于负载有机药物、水溶性药物、水不溶性药物或用于诊断用的显影剂。此外,PEAL易溶于二氯甲烷、四氢呋喃等易挥发有机溶剂,这使得以PEAL为基础的纳米颗粒、微球等在制备时更容易去除残留的有机溶剂。
放射学利用碘吸收X射线特性来增强影像观察效果。碘造影剂在X下有更高的密度,增加正常与异常组织间的差异,造影剂充盈的地方就可以充分显影,使医生发现并鉴定一些早期的、小的病变,并区分病变的良恶程度。PEAL材料本身不具备显影功能,所以需要对其进行碘代改性以赋予其显影功能。碘代PEAL微球的显影能力与链接的碘原子比例相关,碘含量越高,微球的显影能力越强。但无孔将使微球的密度变大,从而使其可操作性变差,本发明的碘代PEAL显影微球中PEAL与碘代分子的摩尔比为1:1-1:50,通过改变碘代分子的比例可得到同时含有碘代分子与氨基的碘代PEAL。
PEAL可通过共价键接枝含碘化合物使其具有显影功能,之后可以通过改变分子量或者分子链的臂长调节相关性能。PEAL为一种性能良好的生物可降解材料,具有良好的生物相容性。本发明采用了简便高效的功能化法制备具有X射线自显影功能的碘代PEAL材料。PEAL在如N,N’-二环己基碳二亚胺(DCC)和4-二甲氨基吡啶(DMAP)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(EDC)和N-羟基丁二酰亚胺(NHS)催化下将显影小分子如2,3,5-三碘苯甲酸(TIBA)、3-氨基-2,4,6-三碘苯甲酸(ATBA)、一定量的2,3,5-三碘苯甲醛(TBA)、2,3,5-三碘苯甲酰氯(TBC)接到聚赖氨酸上,合成了具有X射线自显影能力的碘代PEAL,极大降低了碘造影剂引起的诸多不良反应,并进一步使用微流控法制备了碘代PEAL微球。小鼠和兔的动物实验表明碘代PEAL具有在X射线下的显影能力和较好的栓塞及载药能力,在生物医学领域能够有更为广泛的应用价值。
通过化学键合的碘代PEAL微球所含碘元素相较于包载或混合方法制备的含碘微球更为稳定,碘原子不易游离出来,相较于碘化油露置空气或日光中会分解析出游离碘的特点,增加了微球的安全性。所选碘代分子每个分子上均含有三个碘原子,在较少的试剂用量下即可获得显著的显影效果,在含量相同的情况下,四种碘代PEAL微球表现出相同的显影效果。此外,通过生产工艺的调节可以在粒径为1μm~1000μm的微球上产生100nm-1μm的孔,所制备的微球在具有显影功能的同时还能负载0-30wt%的多种药物组分。
碘代PEAL易溶于多数有机试剂,与壳聚糖相比不使用酸性溶液,其中多数为挥发性试剂,这使得有机试剂的清除变得简单快捷,不影响材料和药物的理化特性,也避免了因有机试剂清除不彻底带来的生物毒性,且该材料成球不需要交联试剂的加入,成球性好于常见的海藻酸钠。
本发明的目的是提供一种碘代聚乙二醇单甲醚-聚乳酸羟基乙酸-聚赖氨酸的显影多孔微球,所述微球包含基于PEAL与碘代分子的摩尔比计,PEAL:碘代分子=1:1-1:50制成。
本发明的目的是提供一种聚乙二醇单甲醚-聚乳酸羟基乙酸-聚赖氨酸/硫酸钡的显影多孔微球,所述微球主要由基于PEAL与碘代分子的摩尔比计,PEAL:碘代分子=1:1-1:50制成。
所述碘代分子选自2,3,5-三碘苯甲酸(TIBA)、3-氨基-2,4,6-三碘苯甲酸(ATBA)、一定量的2,3,5-三碘苯甲醛(TBA)、2,3,5-三碘苯甲酰氯(TBC)等。
本发明提供一种微流控法制备碘代PEAL显影多孔微球的制备方法,包括:
本发明提供的碘代PEAL显影多孔微球的制备方法及应用包括:
(1)碘代PEAL的合成:
a.方法一:称取PEAL、二环己基碳二亚胺(DCC)、4-二甲氨基吡啶(DMAP)与一定量的2,3,5-三碘苯甲酸(TIBA)或3-氨基-2,4,6-三碘苯甲酸(ATBA)并溶解。反应结束后旋蒸、溶解、透析、冻干以备用。
b.方法二:称取PEAL、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(EDC)、N-羟基丁二酰亚胺(NHS)与一定量的TIBA或ATBA并溶解,反应结束后旋蒸、溶解、透析、冻干后备用。
c.方法三:称取PEAL、三氟乙酸、2,3,5-三碘苯甲基醛(TBA)溶解于三氯甲烷中,反应结束之后对产品进行旋蒸、溶解、透析、冻干后备用。
d.方法四:称取PEAL、溶于二氯甲烷,搅拌至充分溶解,并加入三乙胺(1-10%)。将一定量的2,3,5-三碘苯甲酰氯(TBC)充分溶解后在冰浴的条件下逐滴滴入,反应后对产品进行过滤、水洗、重结晶,备用。
本步骤所用PEAL分子量为1.0×103-9.0×106,PEAL与TIBA、ATBA、TBA、TBC的摩尔比为1:1-1:50。方法一至方法二中的PEAL与两种催化剂的摩尔比为1:(1-50):(1-50)。
(2)微流控法制备微球:
搭建微流控装置,该装置微通道由内通道和外通道交叉组成,配制收集液,收集液与连续相相同,为1-6wt%(优选浓度3wt%)表面活性剂的水溶液。
根据所制备的微球大小,分散相微通道内径可选择范围为20μm~1000μm,连续相微通道内径可选择范围为40μm~3mm,分散相与连续相的流速比为1:6-1:10。制备完成的微球使用去离子水清洗数次,冷冻干燥后备用。所制备的微球孔径大小为10-1000nm。
表面活性剂可为甲基纤维素、卡巴浦尔、藻酸钠、聚乙烯醇、铵盐型、季铵盐型、两性表面活性剂、高级脂肪酸盐、磺酸盐、硫酸酯盐、泊洛沙姆、聚乙二醇、聚乙二醇-聚乳酸、聚乙二醇-聚乳酸-羟基乙酸共聚物、聚乙二醇-聚己内酯、聚乙烯吡咯烷酮等。
有机相可为二氯甲烷、三氯甲烷、丙酮、四氢呋喃、石油醚、乙酸乙酯等可用于溶解碘代PEAL的有机溶剂。
本发明的目的是提供一种制备碘代PEAL显影多孔微球的方法,包括配制微流控合成微球所需的分散相、连续相、收集液。分散相为1-40wt%(优选浓度15wt%)碘代PEAL的有机相溶液,连续相和接收浴为1-10wt%(优选浓度3wt%)的表面活性剂水溶液。搭建微流控装置,该装置微通道由分散相微通道和连续相微通道交叉组成,将单组芯片并联可得微流控芯片组,实现高分子微球的大批量生产。制备好的微球使用去离子水清洗,最后冷冻干燥备用。
此外,向所得的微球中还可加入药用成分后使用,添加量相对于微球的质量分数为0.1-30wt%。所述药用成分可为临床常见药、抗肿瘤基因、抗肿瘤药物或分子靶向药物、放射性核素等。
抗肿瘤基因选自siRNA、microRNA、piRNA、IncRNA、circRNA;例如:下调NF-κBp65基因表达的siRNA、干扰Gab1的siRNA、沉默蛋白激酶Cε基因的siRNA、miRNA-21、miRNA-605、miRNA-376c、miRNA-200b/c、miRNA-101等。
抗肿瘤药物选自奥沙利铂、顺铂、卡铂、米铂、洛铂、奈达铂、环铂、紫杉醇、米托蒽醌、阿霉素、表阿霉素、吡喃阿霉素、丝裂霉素、5-氟尿嘧啶、雷替曲塞、多西他赛、吉西他滨、博来霉素、三氧化二砷、亚叶酸钙、脱氧氟尿苷、伊立替康、拓扑替康、羟基喜树碱、依托泊苷、长春瑞宾、长春新碱、或甲氨蝶呤等。
分子靶向药物选自表皮生长因子受体(EGFR)酪氨酸激酶抑制剂、表皮生长因子受体2(HER-2)抑制剂、血管内皮生长因子抑制剂等。
免疫检查点抑制剂选自抗PD-1抗体、抗PD-L1抗体、抗CTLA-4抗体等。
放射性核素选择90Y,131I,125I,123I,32P,153Sm,186Re,211At,212Bi,18F,61Cu,64Cu,89Zr,66Ga,68Ga,44Sc,72As,69Ge,51Mn,52Mn,45Ti,86Y,55Co,111In,225Ac等。
本发明所述的微球用于栓塞、载药皮下或者肌肉或者原位疾病治疗、口服和腹腔给药、显影、细胞3D培养等应用。
有益效果
本发明基于微流控技术制备了粒径均一可控的碘代PEAL自显影高分子多孔微球。多孔、圆形的结构使其比表面积进一步增大,这赋予了微球显影、负载药物、栓塞等多重功能,在很大程度上拓展了微球的应用。本发明操作简单、载药量高、易于重复、批次稳定。该微球有望成为药物、基因、蛋白、金属离子、放射性核素的优良载体。有望用于临床栓塞、药物负载、疾病的诊断与治疗等领域。
本发明与现有技术相比,微流控设备与芯片组的搭建实现了使用微流控技术大批量生产栓塞微球的工艺。
附图说明
以下,结合附图来详细说明本发明的实施方案,其中:
图1为实施例1中微流控法制备的碘代PEAL微球的SEM及其显影图像
图2为实施例2中微流控法制备的碘代PEAL微球的SEM及其显影图像
图3为实施例3中微流控法制备的碘代PEAL微球的SEM及其显影图像
图4为实施例4中微流控法制备的碘代PEAL微球的SEM及其显影图像
图5为实施例5中碘代PEAL微球的光学显微镜图片。
图6为实施例6中碘代PEAL微球的SEM图片。
图7将碘代PEAL微球注入到老鼠左右后腿中的显影效果图。
图8兔子肾部栓塞实验过程数码照片。
图9栓塞4周后兔肾部CT图像。
图10兔栓塞4周后,肾部H&E染色组织切片图。
具体实施方式
以下实施例是对本发明的进一步说明,但绝不是对本发明范围的限制。下面参照实施例进一步详细阐述本发明,但是本领域技术人员应当理解,本发明并不限于这些实施例以及使用的制备方法。而且,本领域技术人员根据本发明的描述可以对本发明进行等同替换、组合、改良或修饰,但这些都将包括在本发明的范围内。
实施例1碘代PEAL微球的制备
(1)制备PEAL:TIBA=1:10(摩尔比)的碘代PEAL材料,其中PEAL分子量为1×104g/mol:称取0.3g的PEAL,0.02gEDC及0.012gNHS,加入到100mL烧瓶中,在氮气保护下抽排3次后,加入烧瓶中,将0.05g的2,3,5-三碘苯甲酸(TIBA)溶解二氯甲烷中,在氮气抽排3次后反应12h。旋蒸除去二氯甲烷,之后加3mL DMF溶解,转移到透析袋透析48h,冷冻干燥后备用。
(2)微流控法制备碘代PEAL微球(图1):配制碘代PEAL的二氯甲烷溶液,碘代PEAL质量分数为10wt%,分散相选择3wt%聚乙烯醇(PVA)水溶液,收集液为3wt%的PVA水溶液。制备过程中,不停搅拌收集液,搅拌速率为60rpm/min。搭建微流控装置,使用微流控技术制备碘代PEAL显影微球。微流控管道选择聚四氟乙烯管搭建,两相交汇处及收集处通道内径为500μm,使用单个微流控芯片时分散相与连续相流速分别为40μL/min与240μL/min(分散相:连续相=1:6),得到粒径为180μm,孔径为100-300nm的碘代PEAL微球。制备过程结束后,静置48小时,收集微球。使用去离子水清洗3次,冷冻干燥后备用。
实施例2载90Y的碘代PEAL微球的制备
(1)制备PEAL:TIBA=1:1(摩尔比)的碘代PEAL材料,其中PEAL分子量为2×105g/mol:称取0.3g的PEAL,0.002g EDC及0.0012gNHS,加入到100mL烧瓶中,在氮气保护下抽排3次后,加入烧瓶中,将0.005g的2,3,5-三碘苯甲酸(TIBA)溶解二氯甲烷中,在氮气抽排3次后反应12h。旋蒸除去二氯甲烷,之后加3mLDMF溶解,转移到透析袋透析48h,冻干后备用。
(2)微流控制备碘代PEAL显影载药微球(图2):配制制备微球所需的分散相、连续相、接收浴。分散相为10wt%的碘代PEAL的有机相溶液,连续相和接收浴为2wt%的PVA水溶液。搭建微流控装置,使用微流控技术制备碘代PEAL显影微球。微流控管道选择聚四氟乙烯管搭建,两相交汇处及收集处通道内径为500μm,使用单个微流控芯片时分散相与连续相流速分别为40μL/min与240μL/min(分散相:连续相=1:6),得到粒径为210μm,孔径为50-500nm的碘代PEAL微球。制备过程结束后,静置48小时,收集微球。使用去离子水清洗3次,冷冻干燥后备用。
使用时向3mL含有1g的显影微球的水中加入0.3g的90Y后使用(药物所占比重为30%)。
实施例3载阿霉素的碘代PEAL微球的制备
(1)制备PEAL:TIBA=1:5(摩尔比)的碘代PEAL材料,其中PEAL分子量为1×105g/mol:称取0.3g的PEAL,0.01gEDC及0.006gNHS,加入到100mL烧瓶中,在氮气保护下抽排3次后,加入烧瓶中,将0.025g的2,3,5-三碘苯甲酸(TIBA)溶解二氯甲烷中,在氮气抽排3次后反应12h。旋蒸除去二氯甲烷,之后加3mLDMF溶解,转移到透析袋透析48h,冻干后备用。
(2)微流控制备碘代PEAL显影载药微球(图3):配制制备微球所需的分散相、连续相、接收浴。分散相为15wt%的碘代PEAL的有机相溶液,连续相和接收浴为1wt%的PVA水溶液。搭建微流控装置,使用微流控技术制备碘代PEAL显影微球。微流控管道选择聚四氟乙烯管搭建,两相交汇处及收集处通道内径为400μm,使用单个微流控芯片时分散相与连续相流速分别为50μL/min与350μL/min(分散相:连续相=1:7),得到粒径为180μm,孔径为50-500nm的碘代PEAL微球。制备过程结束后,静置48小时,收集微球。使用去离子水清洗3次,冷冻干燥后备用。
使用时,配制成浓度为0.5g/mL的微球悬液,并向2mL的含有显影微球的水中加入0.2g的阿霉素后使用(药物所占比重为20%)。
实施例4载miRNA-376c的碘代PEAL微球的制备
(1)制备PEAL:TIBA=1:10(摩尔比)的碘代PEAL材料,其中PEAL分子量为3×105g/mol:称取0.3g的PEAL,0.02gEDC及0.012gNHS,加入到100mL烧瓶中,在氮气保护下抽排3次后,加入烧瓶中,将0.05g的2,3,5-三碘苯甲酸(TIBA)溶解二氯甲烷中,在氮气抽排3次后反应12h。旋蒸除去二氯甲烷,之后加3mL DMF溶解,转移到透析袋透析48h,冻干后备用。
(2)微流控制备碘代PEAL显影载药微球:配制制备微球所需的分散相、连续相、接收浴。分散相为20wt%的碘代PEAL的有机相溶液,连续相和接收浴为4wt%的泊洛沙姆水溶液。搭建微流控装置,使用微流控技术制备碘代PEAL显影微球。微流控管道选择聚四氟乙烯管搭建,两相交汇处及收集处通道内径为600μm,使用单个微流控芯片时分散相与连续相流速分别为60μL/min与360μL/min(分散相:连续相=1:6),得到粒径为150μm,孔径为50-400nm的碘代PEAL微球。制备过程结束后,静置48小时,收集微球。使用去离子水清洗3次,冷冻干燥后备用(图4)。
使用时,配制成浓度为0.5g/mL的微球悬液,向3mL的含有显影微球的水中加入50nmol的miRNA-376c后使用。
实施例5载抗PD-L1抗体的碘代PEAL微球的制备
(1)制备PEAL:TIBA=1:50(摩尔比)的碘代PEAL材料,其中PEAL分子量为3×106g/mol:称取0.3g的PEAL,0.04gEDC及0.023gNHS,加入到100mL烧瓶中,在氮气保护下抽排3次后,加入烧瓶中,将0.25g的2,3,5-三碘苯甲酸(TIBA)溶解二氯甲烷中,在氮气抽排3次后反应12h。旋蒸除去二氯甲烷,之后加3mL DMF溶解,转移到透析袋透析48h,冻干后备用。
(2)微流控制备碘代PEAL显影载药微球:配制制备微球所需的分散相、连续相、接收浴。分散相为20wt%的碘代PEAL的有机相溶液,连续相和接收浴为3wt%的PVA水溶液。搭建微流控装置,使用微流控技术制备碘代PEAL显影微球。微流控管道选择聚四氟乙烯管搭建,两相交汇处及收集处通道内径为500μm,使用单个微流控芯片时分散相与连续相流速分别为70μL/min与560μL/min(分散相:连续相=1:8),得到粒径为150μm,孔径为80-450nm的碘代PEAL微球。制备过程结束后,静置48小时,收集微球。使用去离子水清洗3次,冷冻干燥后备用(图5)。
使用时,配制成浓度为0.5g/mL的微球悬液,并向2mL的含有显影微球的水中加入100μg抗PD-L1抗体后使用。
实施例6载细胞的碘代PEAL微球的制备
(1)制备PEAL:TIBA=1:1(摩尔比)的碘代PEAL材料,其中分子量为3×106g/mol:称取0.3g的PEAL,0.002gEDC及0.0012gNHS,加入到100mL烧瓶中,在氮气保护下抽排3次后,加入烧瓶中,将0.005g的2,3,5-三碘苯甲酸(TIBA)溶解二氯甲烷中,在氮气抽排3次后反应12h。旋蒸除去二氯甲烷,之后加3mL DMF溶解,转移到透析袋透析48h,冻干后备用。
(2)微流控制备碘代PEAL显影载药微球:配制制备微球所需的分散相、连续相、接收浴。分散相为15wt%的碘代PEAL的有机相溶液,连续相和接收浴为2wt%的卡巴浦尔水溶液。搭建微流控装置,使用微流控技术制备碘代PEAL显影微球。微流控管道选择聚四氟乙烯管搭建,两相交汇处及收集处通道内径为500μm,使用单个微流控芯片时分散相与连续相流速分别为50μL/min与500μL/min(分散相:连续相=1:10),得到粒径为150μm,孔径为80-400nm的碘代PEAL微球。制备过程结束后,静置48小时,收集微球。使用去离子水清洗3次,冷冻干燥后备用(图6)。
使用时,配制成浓度为0.5g/mL的微球悬液,并向2mL的含有显影微球的水中加入104-105个细胞,培养12-72h后使用。
实施例7载利多卡因的碘代PEAL微球的制备
(1)制备PEAL:TIBA=1:5(摩尔比)的碘代PEAL材料其中PEAL分子量为3×106g/mol:称取0.3g的PEAL,0.01g EDC及0.006gNHS,加入到100mL烧瓶中,在氮气保护下抽排3次后,加入烧瓶中,将0.025g的2,3,5-三碘苯甲酸(TIBA)溶解二氯甲烷中,在氮气抽排3次后反应12h。旋蒸除去二氯甲烷,之后加3mL DMF溶解,转移到透析袋透析48h,冻干后备用。
(2)微流控制备碘代PEAL显影载药微球:配制制备微球所需的分散相、连续相、接收浴。分散相为20wt%的碘代PEAL的有机相溶液,连续相和接收浴为1wt%的PVA水溶液。搭建微流控装置,使用微流控技术制备碘代PEAL显影微球。微流控管道选择聚四氟乙烯管搭建,两相交汇处及收集处通道内径为500μm,使用单个微流控芯片时分散相与连续相流速分别为60μL/min与480μL/min(分散相:连续相=1:8),得到粒径为200μm,孔径为50-450nm的碘代PEAL微球。制备过程结束后,静置48小时,收集微球。使用去离子水清洗3次,冷冻干燥后备用。
使用时,配制成浓度为0.5g/mL的微球悬液,向伤口上涂覆载有利多卡因的200mg显影微球。
实施例8老鼠体内栓塞显影微球成像实验
常规准备下,在小鼠腹腔注射戊巴比妥钠溶液,麻醉小鼠。使用手术器械,开小鼠左右后腿部位,将碘代PEAL显影微球使用注射器包埋到左右后腿肌肉间隙中(图7)。然后缝合小鼠左右后腿。使用CT查看小鼠显影栓塞微球在小鼠左右后腿部位的显影情况。
实施例9健康试验兔肾动脉栓塞
常规准备下,兔耳缘静脉注射注射盐酸氯胺酮(3.5-4mg/kg)行静脉麻醉后,开后腿,沿后腿动脉内侧引入2根套扎线,远端结扎,近端向上牵拉止血后,将动脉剪一小口后插入24G静脉留置软管进入肾动脉内,行DSA造影确定肾动脉及分支显影后再经导管注射含有碘代PEAL微球1.5mL(图8),复查造影见肾动脉段以下细小分支完全性栓塞后,拔管、包扎缝合伤口,结束手术。术后4周取肾部(图9),H&E染色(图10)观察。
Claims (7)
1.一种碘代聚乙二醇单甲醚-聚乳酸羟基乙酸-聚赖氨酸(PEAL)的显影多孔微球,所述的PEAL分子量为1.0×103-9.0×106,聚乙二醇单甲醚/乳酸的摩尔比为1-50∶50-100,乳酸/羟基乙酸的摩尔比为1-100∶1-100,羟基乙酸/赖氨酸的摩尔比为50-100∶1-50,其特征是所述微球中PEAL与碘代分子的摩尔比为1:1-1:50;微球孔径大小为10-1000nm;微球中含有相对于微球的质量分数为0-30wt%的药物;所述的碘代分子选自2,3,5-三碘苯甲酸(TIBA)、3-氨基-2,4,6-三碘苯甲酸(ATBA)、一定量的2,3,5-三碘苯甲基醛(TBA)或2,3,5-三碘苯甲酰氯(TBC),所述催化选自二环己基碳二亚胺、4-二甲氨基吡啶、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺、N-羟基丁二酰亚胺(NHS)。
2.如权利要求1所述的碘代聚乙二醇单甲醚-聚乳酸羟基乙酸-聚赖氨酸的显影多孔微球,其特征是所述药物选自临床常见药、抗肿瘤基因、抗肿瘤药物或分子靶向药物或放射性核素。
3.一种如权利要求1所述的碘代聚乙二醇-聚乳酸羟基乙酸-聚赖氨酸(PEAL)显影多孔微球的微流控制备方法,其特征是:
(1)碘代PEAL的合成:
在有催化剂和无催化剂的反应条件下,PEAL与2,3,5-三碘苯甲酸(TIBA)、3-氨基-2,4,6-三碘苯甲酸(ATBA)或2,3,5-三碘苯甲基醛(TBA)或2,3,5-三碘苯甲酰氯(TBC)按一定比例搅拌溶解,反应完成之后纯化;PEAL与碘代分子的摩尔比为1:1-1:50;
(2)微流控法制备碘代PEAL显影微球:将方法(1)获得的1-40wt%碘代PEAL的有机相溶液作为分散相,1-10wt%的表面活性剂水溶液作为连续相和接收浴;搭建微流控装置,该装置微通道由微通道和连续相微通道交叉组成,将单组芯片并联可得微流控芯片组,获得微球;使用去离子水清洗,最后冷冻干燥备用;
(3)加入相对于微球的质量分数为0-30wt%的药物成分。
4.根据权利要求3所述的制备方法,其特征在于有机相选自二氯甲烷、三氯甲烷、丙酮、四氢呋喃、石油醚、乙酸乙酯。
5.权利要求3述的制备方法,其特征在于所述的方法(1)所述的纯化方法是透析、过滤、水洗、冷冻干燥或重结晶。
6.据权利要求2所述的制备方法,其特征在于,方法(2)中所述的玻璃毛细管内径为20μm~1000μm,聚四氟乙烯管道内径为40μm~3mm,分散相与连续相的流速比为1:6-1:10。
7.权利要求1所述的碘代聚乙二醇-聚乳酸羟基乙酸-聚赖氨酸的影多孔微球在制备疾病治疗药物或者治疗疾病的器件。
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