CN111921003B - 一种磁响应热疗可控降解栓塞微球及其制备方法与应用 - Google Patents
一种磁响应热疗可控降解栓塞微球及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种磁响应热疗可控降解栓塞微球,这种磁响应热疗可控降解栓塞微球中以卡拉胶和明胶等可降解材料做混合胶,以粒径200‑500nm氧化铁作为高效磁热显影剂。这是一种集栓塞,核磁成像,磁热,可控降解为一体,可用于治疗肿瘤等疾病的新型微球。本发明还公开了所述微球的制备方法,通过油包水或者水包油的方式,选取饱和磁化强度较好,制备工艺中抗氧化能力最强,磁热升温表现优异的粒径范围200‑500nm的磁性氧化铁包载到栓塞微球中,实现了显影和栓塞同步,提高栓塞操作精准度,且在磁场作用下,通过磁热效应升温到40‑45℃,可以起到热疗协同杀伤肿瘤病灶的作用,提高治疗效果,当治疗达到预期后,通过磁热效应使微球温度提升到49‑55℃,可以加快栓塞微球降解,达到栓塞再疏通,减小对正常组织损伤。
Description
技术领域
本发明属于生物与医学纳米材料技术,特别是涉及一种磁响应热疗可控降解栓塞微球及其制备方法及应用。
背景技术
2019年1月,国家癌症中心发布了最新一期的全国癌症统计数据报告。报告指出,2015年全国恶性肿瘤发病约392.9万人,死亡约233.8万人。即平均每天超过1万人、每分钟7.5个人被确诊为癌症,近10多年来,我国的恶性肿瘤发病率每年保持约3.9%的增幅,死亡率每年保持2.5%的增幅。国人每年花费在肿瘤治疗上的费用高达上千亿。
治疗肿瘤的方式有很多,对于不同阶段的肿瘤也有相应的对策。传统手段手术切除局限于良性肿瘤,放疗和化疗易对全身正常组织,器官和免疫系统造成损伤。在上个世纪八十年代,日本科学家提出了“经导管动脉栓塞”的治疗方法,这种治疗方法是通过将栓塞剂注射到靠近肿瘤处的肝动脉及其分支动脉中,阻断机体对癌细胞的供给,实现饿死癌细胞的效果。这一治疗对肝肿瘤格外有效,原因在于肝肿瘤细胞与正常肝细胞依赖的供给途径不同,前者更依赖肝动脉,而后者更依赖门静脉。
除了介入医生的临床操作外,栓塞剂的性能最大程度上决定了最终的治疗效果,越来越多的生物医学研究者着手开发更多性能的微球来实现更好的效果。很多各种新型功能的栓塞剂被研发出来,可降解,载药,可造影等一种或多种功能的组合微球。
临床上,栓塞治疗中当病灶处达到治愈效果后,继续栓塞易造成病灶周围正常组织的缺血性坏死,这时可降解的栓塞微球就有了临床需求。但是因病患病症轻重不一,个体差异较大,栓塞治疗康复周期长短不一,重症病患需要长降解周期的栓塞微球治疗,轻症患者则需要短降解周期的栓塞微球治疗。现有的可降解栓塞微球在体内降解周期不可控,如PLA栓塞微球在体内降解周期长达一年,而明胶栓塞微球在体内降解周期短到几周,每个临床治疗康复时间个体差异很大,因此为了提升病患的愈后质量,临床亟需一种可根据病人栓塞治疗进程不同选择性控制降解的栓塞微球。
发明内容
发明目的:针对上述现有技术,本发明提供了一种集栓塞、核磁成像、磁热、可控降解为一体,可用于治疗肿瘤等疾病的新型栓塞微球及其制备方法与应用。技术方案:本发明所述的一种磁响应热疗可控降解栓塞微球,其以卡拉胶-明胶微球包载磁热显影剂磁性氧化铁,其中,磁性氧化铁粒径200-500nm。
本发明还公开了所述磁响应热疗可控降解栓塞微球的制备方法,包括以下步骤:
(1)将卡拉胶、明胶、磁性氧化铁溶于水中作为水相,液体石蜡作为油相1,往油相1中滴加表面活性剂,搅匀,得油相2;
(2)在高温和高剪切条件下,油相2逐滴滴加到水相中,制成初乳;
(3)将上述初乳从高温高剪切条件换成低温高剪切,继续反应,制成固化乳液;
(4)往上述固化乳液中滴加交联剂,继续反应,制成交联乳液;
(5)将上述交联乳液静置,洗涤,抽滤,干燥,获得磁响应热疗可控降解栓塞微球.
进一步的,步骤(1)中,卡拉胶和明胶质量比为2:1~1:6,水的质量是卡拉胶和明胶混胶质量的5~15倍,卡拉胶和明胶混胶溶胀温度为50-90℃,时间为15~25min。
步骤(1)中,磁性氧化铁粒径为200-500nm,其质量为卡拉胶和明胶混胶的1%~20%。
步骤(1)中,所述的油相2和水相的体积比为1:10~10:1;所述表面活性剂是司班80,其体积占油相2的0.01‰~10‰。
步骤(2)中,所述的高温高剪切条件,温度为50~90℃,转速为200~1000rpm,时间为10~60min。
步骤(3)中,所述的低温高剪切条件,温度为0~10℃,转速为200~1000rpm,时间为10~60min。
步骤(4)中,所述的交联剂为戊二醛,体积百分比为水相的0.1%~10%,反应温度为0~10℃,时间为10~60min。
步骤(5)中,所述的静置时间为10~60min,洗涤条件为加入质量体积比为10~50倍的异丙醇,洗涤时间为10~120min;干燥条件为37℃烘箱干燥0.5~5小时。
本发明还公开了所述磁响应热疗可控降解栓塞微球在制备治疗血管丰富的肿瘤的栓塞、核磁共振成像、热疗辅助剂中的应用。
进一步的,所述磁响应热疗可控降解栓塞微球通过磁热效应升温到40-45℃,热疗协同杀伤肿瘤病灶;当治疗达到预期后,通过磁热效应使微球温度提升到49-55℃,加快栓塞微球降解。
有益效果:相比较于现有技术,本发明具有以下优势:
1.目前科研人员研究的载铁微球,磁性氧化铁的粒径范围都在100nm以下,这种小粒径的磁性氧化铁饱和磁化强度相对于粒径100nm以上的磁性氧化铁较弱,且在微球制备过程种磁性氧化铁易被氧化成氧化铁,大大降低了磁性氧化铁的饱和磁化强度。本发明将栓塞微球粒径范围200-500nm的磁性氧化铁装载到栓塞微球上作为磁热显影剂,提高了饱和磁化强度和抗氧化能力。
2.本发明将磁性氧化铁和卡拉胶-明胶栓塞微球结合起来,利用磁性纳米材料的磁热效应达到热疗协同治疗效果,实现了栓塞与热疗同步,提高病灶治疗效果。
3.本发明制备的载铁微球在栓塞和热疗协同治疗达到预期后,通过磁热效应使温度短期高于49℃,可以加速微球降解,通过调控磁热降解温度时间可以控制栓塞微球降解速率,解决了现有可降解微球降解速率不可调控的不足,使治疗后血管快速恢复供血状态,减少对正常组织的损伤,有效提升了病患的愈后质量。
附图说明
图1中a和b分别是粒径10nm和300nm磁性氧化铁相同参数下的磁滞回线;
图2中a和b分别为实施例2载10nm的磁性氧化铁卡拉胶-明胶栓塞微球与实施例6载300nm磁性氧化铁卡拉胶-明胶栓塞微球的显微成像图;
图3中a和b分别为栓塞前后兔肾碘海醇造影x-ray成像图;
图4中a和b分别为栓塞前后兔肾核磁共振成像。
具体实施方式
下面结合具体实施例对本申请作出详细说明。
实施例1
粒径为10、50、100、200、300、400、500、600nm的磁性氧化铁磁滞回线测定
分别称取上述规格的磁性氧化铁颗粒8mg,用振动样品磁强计(VSM)测样品的磁滞回线,结果如表1所示:
表1
根据表1可见,磁性氧化铁的饱和磁化强度跟粒径相关,整体呈现出粒径越大,饱和磁化强度越强,粒径在200-500nm范围,磁性氧化铁饱和磁化强度大于80emu/g。其中,粒径10nm和300nm磁性氧化铁磁滞回线如图1所示,根据图示可见,10nm粒径的磁性氧化铁饱和磁化强度为57emu/g,300nm粒径的磁性氧化铁饱和磁化强度为85emu/g。
实施例2
采用乳化交联法制备载10nm级规格磁性氧化铁卡拉胶-明胶栓塞微球
称取0.6g明胶、0.6g卡拉胶和50mg 10nm级磁性氧化铁粉末,将粉末缓缓撒在装有10mL纯水中,55℃溶胀20min,制成水相。量取50mL液体石蜡,滴加0.4gSpan80,置于于55℃预热,制成油相。将油相缓缓注入水相中,55℃、800rpm搅拌30min,形成初乳。搅拌冷却30min,滴加25%戊二醛溶液1.5mL,继续搅拌交联1h。最后加入30mL异丙醇搅拌脱水15min,再用异丙醇、水和无水乙醇分次洗涤,抽滤,60℃烘箱干燥30min,研磨分选即得微球。干燥微球呈棕黄色,粒径均匀,取10mg,粒径50±10μm的微球,用纯水浸润1h,制备成微球显微观察装片,在显微镜下观察,显微成像如图2a所示,微球颜色呈棕黄色,粒径100μm左右,微球中间有微小的黑色颗粒,磁性氧化铁是黑色的,制备的微球最终是棕黄色的,在此微球制备工艺下,10nm的磁性氧化铁易发生氧化。。
实施例3
采用乳化交联法制备载50nm级规格磁性氧化铁卡拉胶-明胶栓塞微球
称取0.6g明胶、0.6g卡拉胶和50mg 50nm级磁性氧化铁粉末,将粉末缓缓撒在装有10mL纯水中,55℃溶胀20min,制成水相。量取50mL液体石蜡,滴加0.4g Span80,置于于55℃预热,制成油相。将油相缓缓注入水相中,55℃、800rpm搅拌30min,形成初乳。搅拌冷却30min,滴加25%戊二醛溶液1.5mL,继续搅拌交联1h。最后加入30mL异丙醇搅拌脱水15min,再用异丙醇、水和无水乙醇分次洗涤,抽滤,60℃烘箱干燥30min,研磨分选即得微球。干燥微球呈棕黄色,粒径均匀,取10mg,粒径50±10μm的微球,用纯水浸润1h,制备成微球显微观察装片,在显微镜下观察,微球颜色呈棕黄色,粒径100μm左右,微球中间有微小的黑色颗粒,磁性氧化铁是黑色的,制备的微球最终是棕黄色的,在此微球制备工艺下,50nm的磁性氧化铁易发生氧化。
实施例4
采用乳化交联法制备载100nm级规格磁性氧化铁卡拉胶-明胶栓塞微球
称取0.6g明胶、0.6g卡拉胶和50mg 100nm级磁性氧化铁粉末,将粉末缓缓撒在装有10mL纯水中,55℃溶胀20min,制成水相。量取50mL液体石蜡,滴加0.4g Span80,置于于55℃预热,制成油相。将油相缓缓注入水相中,55℃、800rpm搅拌30min,形成初乳。搅拌冷却30min,滴加25%戊二醛溶液1.5mL,继续搅拌交联1h。最后加入30mL异丙醇搅拌脱水15min,再用异丙醇、水和无水乙醇分次洗涤,抽滤,60℃烘箱干燥30min,研磨分选即得微球。干燥微球呈深棕色,粒径均匀,取10mg,粒径50±10μm的微球,用纯水浸润1h,制备成微球显微观察装片,在显微镜下观察,微球颜色呈深棕色,粒径100μm左右,微球中间有微小的黑色颗粒,磁性氧化铁是黑色的,制备的微球最终是深棕色的,在此微球制备工艺下,100nm的磁性氧化铁部分被氧化。
实施例5
采用乳化交联法制备载200nm级规格磁性氧化铁卡拉胶-明胶栓塞微球
称取0.6g明胶、0.6g卡拉胶和50mg 200nm级磁性氧化铁粉末,将粉末缓缓撒在装有10mL纯水中,55℃溶胀20min,制成水相。量取50mL液体石蜡,滴加0.4g Span80,置于于55℃预热,制成油相。将油相缓缓注入水相中,55℃、800rpm搅拌30min,形成初乳。搅拌冷却30min,滴加25%戊二醛溶液1.5mL,继续搅拌交联1h。最后加入30mL异丙醇搅拌脱水15min,再用异丙醇、水和无水乙醇分次洗涤,抽滤,60℃烘箱干燥30min,研磨分选即得微球。干燥微球呈黑色,粒径均匀,取10mg,粒径50±10μm的微球,用纯水浸润1h,制备成微球显微观察装片,在显微镜下观察,微球颜色呈浅黑色,粒径100μm左右,微球中间有微小的黑色颗粒,磁性氧化铁是黑色的,制备的微球最终是浅黑色的,在此微球制备工艺下,200nm的磁性氧化铁抗氧化能力较好。
实施例6
采用乳化交联法制备载300nm级规格磁性氧化铁卡拉胶-明胶栓塞微球
称取0.6g明胶、0.6g卡拉胶和50mg 300nm级规格磁性氧化铁粉末,将粉末缓缓撒在装有10mL纯水中,55℃溶胀20min,制成水相。量取50mL液体石蜡,滴加0.4g Span80,置于于55℃预热,制成油相。将油相缓缓注入水相中,55℃、800rpm搅拌30min,形成初乳。搅拌冷却30min,滴加25%戊二醛溶液1.5mL,继续搅拌交联1h。最后加入30mL异丙醇搅拌脱水15min,再用异丙醇、水和无水乙醇分次洗涤,抽滤,60℃烘箱干燥30min,研磨分选即得微球。干燥微球呈黑色,粒径均匀,取10mg,粒径50±10μm的微球,用纯水浸润1h,制备成微球显微观察装片,在显微镜下观察,显微成像如图2b所示,微球颜色呈浅黑色,粒径100μm左右,微球中间有微小的黑色颗粒,磁性氧化铁是黑色的,制备的微球最终是浅黑色的,在此微球制备工艺下,300nm的磁性氧化铁抗氧化能力较好。
实施例7
采用乳化交联法制备载400nm级规格磁性氧化铁卡拉胶-明胶栓塞微球
称取0.6g明胶、0.6g卡拉胶和50mg 400nm级磁性氧化铁粉末,将粉末缓缓撒在装有10mL纯水中,55℃溶胀20min,制成水相。量取50mL液体石蜡,滴加0.4g Span80,置于于55℃预热,制成油相。将油相缓缓注入水相中,55℃、800rpm搅拌30min,形成初乳。搅拌冷却30min,滴加25%戊二醛溶液1.5mL,继续搅拌交联1h。最后加入30mL异丙醇搅拌脱水15min,再用异丙醇、水和无水乙醇分次洗涤,抽滤,60℃烘箱干燥30min,研磨分选即得微球。干燥微球呈黑色,粒径均匀,取10mg,粒径50±10μm的微球,用纯水浸润1h,制备成微球显微观察装片,在显微镜下观察,微球颜色呈浅黑色,粒径100μm左右,微球中间有微小的黑色颗粒,磁性氧化铁是黑色的,制备的微球最终是浅黑色的,在此微球制备工艺下,400nm的磁性氧化铁抗氧化能力较好。
实施例8
采用乳化交联法制备载500nm级规格磁性氧化铁卡拉胶-明胶栓塞微球
称取0.6g明胶、0.6g卡拉胶和50mg 500nm级磁性氧化铁粉末,将粉末缓缓撒在装有10mL纯水中,55℃溶胀20min,制成水相。量取50mL液体石蜡,滴加0.4g Span80,置于于55℃预热,制成油相。将油相缓缓注入水相中,55℃、800rpm搅拌30min,形成初乳。搅拌冷却30min,滴加25%戊二醛溶液1.5mL,继续搅拌交联1h。最后加入30mL异丙醇搅拌脱水15min,再用异丙醇、水和无水乙醇分次洗涤,抽滤,60℃烘箱干燥30min,研磨分选即得微球。干燥微球呈黑色,粒径均匀,取10mg,粒径50±10μm的微球,用纯水浸润1h,制备成微球显微观察装片,在显微镜下观察,微球颜色呈浅黑色,粒径100μm左右,微球中间有微小的黑色颗粒,磁性氧化铁是黑色的,制备的微球最终是浅黑色的,在此微球制备工艺下,500nm的磁性氧化铁抗氧化能力较好。
实施例9
采用乳化交联法制备载600nm级规格磁性氧化铁卡拉胶-明胶栓塞微球
称取0.6g明胶、0.6g卡拉胶和50mg 600nm级磁性氧化铁粉末,将粉末缓缓撒在装有10mL纯水中,55℃溶胀20min,制成水相。量取50mL液体石蜡,滴加0.4g Span80,置于于55℃预热,制成油相。将油相缓缓注入水相中,55℃、800rpm搅拌30min,形成初乳。搅拌冷却30min,滴加25%戊二醛溶液1.5mL,继续搅拌交联1h。最后加入30mL异丙醇搅拌脱水15min,再用异丙醇、水和无水乙醇分次洗涤,抽滤,60℃烘箱干燥30min,研磨分选即得微球。干燥微球呈浅黑色,粒径均匀,取10mg,粒径50±10μm的微球,用纯水浸润1h,制备成微球显微观察装片,在显微镜下观察,微球颜色呈浅黑色,粒径100μm左右,微球中间有较大块的黑色颗粒,磁性氧化铁是黑色的,制备的微球最终是浅黑色的,在此微球制备工艺下,600nm的磁性氧化铁抗氧化能力较好,但易聚集成大块,造成微球中存在大粒径的磁性氧化铁。
实施例10
磁响应热疗可控降解栓塞微球进行磁热升温定量评价
从实施例2-9中所制备的微球中分别称取300mg磁微球,加入到2mL纯水中,浸泡2h,期间偶尔轻轻摇动混合液,用一次性滴管吸取多余的水,即得湿微球。定量评估它们在交变磁场下(390kHz、12A)的磁热升温性能。用温度光纤对微球的磁热升温追踪结果如表2所示:
表2
实施例 | 磁性氧化铁的粒径/nm | 温度差/℃ |
2 | 10 | 12.4 |
3 | 50 | 12.7 |
4 | 100 | 13.9 |
5 | 200 | 21.5 |
6 | 300 | 23.8 |
7 | 400 | 24.4 |
8 | 500 | 26.5 |
9 | 600 | 15.8 |
由表2可知,在实施例2-实施例9中,10nm、50nm、100nm、200nm、300nm、400nm、500nm、600nm磁性氧化铁制备的微球在在5min内的升温分别为12.4、12.7℃、13.9℃、21.5℃、23.8℃、24.4℃、26.5℃、15.8℃,其中磁性氧化铁粒径范围在200-500nm时,5min内升温超过20℃,表现出较好的磁热效应。
实施例11
模拟栓塞微球热疗加速降解
从实施例6所制备的微球中称取2100mg微球,分成七组,分别编号为A组、B组、C组、D组、E组、F组和G组,每组300mg,每组微球加入到4mL纯水中,浸泡2h,期间偶尔轻轻摇动混合液,即得含微球水溶液。五组微球水溶液放在37℃培养箱一周,每日换水溶液,其中A组-G组每天分别升温至37℃、40℃、43℃、46℃、49℃、52℃、55℃半小时。一周后,离心,60℃烘箱干燥2h,称量,计算微球降解率。如表3所示表明,A组-G组,微球分别降解了7%、9%、12%、12%、53%、57%和65%。结果表明载铁卡拉胶-明胶微球每天半小时高于49℃的升温可以有效快速的提升微球的降解速率。
表3
组别 | 升温温度/℃ | 微球降解/% |
A | 37 | 7 |
B | 40 | 9 |
C | 43 | 12 |
D | 46 | 12 |
E | 49 | 53 |
F | 52 | 57 |
G | 55 | 65 |
实施例1可知,磁性氧化铁粒径范围200-500nm表现出更高的饱和磁化强度,从实施例2-实施例9可以看出,采用粒径范围200-500nm的磁性氧化铁在文中介绍的制备工艺下表现出更好的抗氧化能力,且在微球内部聚集形成的颗粒较小。实施例10表明采用粒径范围200-500nm的磁性氧化铁制备的微球磁热升温效应比较好。综合而言,粒径范围200-500nm的磁性氧化铁制备的微球在磁学性质,抗氧化能力和磁热升温等三个方面比其他粒径由更好的表现。实施例11表明微球热疗升温到高于49℃情况下可以有效的加速微球的降解。
实施例12
兔肾栓塞实验
从实施例6所制备的微球中称取300mg微球,加入到4mL溶液(碘海醇/生理盐水=1:1,v/v)中,浸泡2h,期间偶尔轻轻摇动混合液,即得含微球悬浮溶液。在X射线CT引导下,通过兔耳中动脉穿刺,对兔右肾主动脉进行栓塞,栓塞操作结束二十分钟后,用碘海醇再造影,观察栓塞情况。兔肾主动脉栓塞前后X-CT如图3a和3b所示,栓塞成功后兔肾碘海醇造影x-ray成像,黑色圈内为实施栓塞实验的兔一侧肾,根据图示可见,3a中介入栓塞成功前,整个肾呈现出碘海醇造影的黑色,说明栓塞前肾主动脉血流供给是通畅的,没有缺血现象,3b中介入栓塞后,肾主动脉栓塞前端是碘海醇造影成功的,而整个肾是造影不成功的,呈普通组织的浅灰色,这个说明没有血流进入栓塞的那只肾,栓塞成功,前后对比表明这个工艺制备的栓塞微球可以有效的完成介入栓塞实验。
实施例13
兔肾栓塞核磁共振成像实验
在实施例12中,用核磁共振成像对兔肾主动脉栓塞前和栓塞后分别进行成像。兔肾栓塞前后核磁共振成像如图4a和4b所示,栓塞成功后兔肾核磁共振成像,黑色圈内为实施栓塞实验的兔一侧肾,根据图示可见,相较于栓塞手术前,兔肾主动脉微球介入栓塞后的核磁共振成像表现出明显的黑色造影信号区,表明载铁的栓塞微球在栓塞手术后可以有效的在体内环境下进行核磁共振成像,且表现出较好的,较明显的造影信号区。
实施例14
荷瘤鼠模型构建
培养Hepa1-6肿瘤细胞,离心,用生理盐水制细胞悬液,在大鼠后腿外侧肌肉内接种Hepa1-6肿瘤细胞构建荷瘤鼠模型,每只模型鼠接种细胞量为107个,待到肿瘤体积长到4cm3待用。
实施例15
磁性氧化铁卡拉胶-明胶栓塞微球栓塞-热疗辅助治疗肝癌
选取实施例14中荷瘤鼠9只,分为A,B,C三组,每组三只荷瘤鼠。A组作为对照组不做任何治疗处理。B组和C组实体瘤注射实施例6的微球,微球按照实施例12进行前处理,其中C组每天在磁场作用下热疗三十分钟,热疗温度控制在40-45℃,一个月后,三组荷瘤鼠处死,取出瘤体,清洗,测量瘤体体积,结果显示A组的肿瘤平均体积最大,C组的肿瘤平均体积最小,微球栓塞-热疗辅助治疗可以有效提高肝癌的治疗效果
实施例12-15表现出我们制备的磁响应热疗可控降解栓塞微球在制备治疗血管丰富的肿瘤的栓塞、核磁共振成像、热疗辅助剂中有很好的应用。
Claims (9)
1.一种磁响应热疗可控降解栓塞微球,其特征在于,以卡拉胶-明胶微球包载磁热显影剂磁性氧化铁,其中,磁性氧化铁粒径200-500 nm。
2.权利要求1所述磁响应热疗可控降解栓塞微球的制备方法,其特征在于,包括以下步骤:
(1)将卡拉胶、明胶、磁性氧化铁溶于水中作为水相,液体石蜡作为油相1,往油相1中滴加表面活性剂,搅匀,得油相2;
(2)在高温和高剪切条件下,油相2逐滴滴加到水相中,制成初乳;
(3)将上述初乳从高温高剪切条件换成低温高剪切,继续反应,制成固化乳液;
(4)往上述固化乳液中滴加交联剂,继续反应,制成交联乳液;
(5)将上述交联乳液静置,洗涤,抽滤,干燥,获得磁响应热疗可控降解栓塞微球。
3.根据权利要求2所述的磁响应热疗可控降解栓塞微球的制备方法,其特征在于,步骤(1)中,卡拉胶和明胶质量比为2:1~1:6,水的质量是卡拉胶和明胶混胶质量的5~15倍,卡拉胶和明胶混胶溶胀温度为50-90°C,时间为15~25 min。
4.根据权利要求2所述的磁响应热疗可控降解栓塞微球的制备方法,其特征在于,步骤(1)中,磁性氧化铁粒径为200-500 nm,其质量为卡拉胶和明胶混胶的1%~20%。
5.根据权利要求2所述的磁响应热疗可控降解栓塞微球的制备方法,其特征在于,步骤(1)中,所述的油相2和水相的体积比为1:10~10:1;所述表面活性剂是司班80,其体积占油相2的0.01‰~10‰。
6.根据权利要求2所述的磁响应热疗可控降解栓塞微球的制备方法,其特征在于,步骤(2)中,所述的高温高剪切条件,温度为50~90°C,转速为200~1000 rpm,时间为10~60min。
7.根据权利要求2所述的磁响应热疗可控降解栓塞微球的制备方法,其特征在于,步骤(3)中,所述的低温高剪切条件,温度为0~10°C,转速为200~1000 rpm,时间为10~60min。
8.根据权利要求2所述的磁响应热疗可控降解栓塞微球的制备方法,其特征在于,步骤(4)中,所述的交联剂为戊二醛,体积百分比为水相的0.1%~10%,反应温度为0~10°C,时间为10~60 min。
9.根据权利要求2所述的磁响应热疗可控降解栓塞微球的制备方法,其特征在于,步骤(5)中,所述的静置时间为10~60 min,洗涤条件为加入质量体积比为10~50倍的异丙醇,洗涤时间为10~120 min;干燥条件为37℃烘箱干燥0.5~5小时。
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