CN116715805B - 一种富含双膦酸基团多功能凝胶微球及其制备方法和应用 - Google Patents
一种富含双膦酸基团多功能凝胶微球及其制备方法和应用 Download PDFInfo
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- CN116715805B CN116715805B CN202310954779.XA CN202310954779A CN116715805B CN 116715805 B CN116715805 B CN 116715805B CN 202310954779 A CN202310954779 A CN 202310954779A CN 116715805 B CN116715805 B CN 116715805B
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Abstract
本发明属于放射性药物领域,具体涉及一种富含双膦酸基团多功能凝胶微球及其制备方法和应用。本发明以丙烯酰胺,N‑丙烯酰氧基琥珀酰亚胺,和帕米膦酸二钠为原料,通过乳液聚合或微流控方法,经自由基氧化聚合制备富含双膦酸的凝胶微球,然后通过双膦酸基团对金属核素强效的螯合作用,将核素稳定的标记至该微球上,制备具有治疗、成像或成像治疗一体化的放射栓塞微球。同时,该凝胶微球含有丰富的三维孔隙结构,为化疗药物的装载提供了空间,可装载药物,制备一种可同时快速、稳定标记放射性核素,装载化疗药物的多功能治疗微球,可进行肝癌精准、有效、低毒的联合治疗与微球体内定位分布监测。
Description
技术领域
本发明属于放射性药物领域,具体涉及一种富含双膦酸基团多功能凝胶微球及其制备方法和应用。
背景技术
肝癌是常见的恶性肿瘤之一,严重危害人类健康。手术切除是肝癌最有效的治疗手段。然而,由于早期症状隐匿、病程发展快,多数患者确诊时已处于中晚期,失去了手术的指征。化疗是中晚期肝癌临床治疗的主要手段,但是肝癌细胞对化疗药物具有固有耐受性,且全身性化疗常会引起剧烈的副作用,严重影响患者的生活质量。因为肝癌细胞对放射线比较敏感,所以放疗也是中晚期肝癌有效的治疗手段之一。然而正常的肝脏细胞对放射线更敏感,外照射剂量累计达到43Gy尚不能完全抑制肿瘤细胞增殖,但会造成正常肝组织功能衰竭。基于放射栓塞微球的内照射治疗(经肝动脉化疗栓塞,TARE),即将装载能量高、射程短(主要是β核素)放射性核素的放射栓塞微球,使用介入手段注入肝癌的供血血管,通过核素衰变产生的高能射线,近距离杀伤肿瘤细胞。据悉,TARE治疗后,患者肿瘤局部剂量可达150Gy,远超肿瘤的耐受剂量。同时因为装载的核素射程短,对正常肝脏组织损伤较小,因此,相比与传统的外照射治疗,基于放射栓塞微球的内照射治疗,有效性与安全性更佳。近年来,TARE治疗在美国、欧洲等地区广泛的开展临床实践,并取得了良好的疗效,逐渐成为中晚期肝癌治疗的主要手段之一。2022年,基于放射栓塞微球的TARE治疗被写入《原发性肝癌诊疗指南(2022版)》,将为中晚期肝癌有效治疗带来新的希望。
放射栓塞微球是TARE治疗的核心,目前上市的商业化微球有三种,其中两种是装载发射纯β射线的钇90微球:BTG International Canada生产的Thera-Spheres 90Y玻璃微球和Sirtex Medical推出的SIR-Sphere 90Y树脂微球。另外一种是荷兰Terumo公司推出商品名为QuiremSpheres,装载166Ho的聚乳酸微球。三种微球均具有各自的优势,并取得良好的临床疗效,然而各自均存在明显的缺陷。90Y玻璃微球在生产过程中,将非放射性的89Y装载于玻璃微球中,再使用反应堆照射活化,制备90Y玻璃微球。该微球单球活度高,可达2500Bq/球,且放射性核素装载稳定,不易脱落。但是该种微球生产设备需求极高,需使用反应堆,且在反应堆活化的过程中,会产生其他高毒性的放射性副产物。此外,90Y玻璃微球比重较大,为3.3g/mL,故微球易沉积,不易注射。相比于90Y树脂微球,90Y树脂微球,具有生产设备需求低,且微球比重适宜(1.6g/mL)等优势。2022年2月9日Sirtex 90Y树脂微球获药品监督管理局批准,获得上市许可。但是该微球单球活度进50Bq,为达到理想的治疗效果,微球使用量大,有造成反流性异位栓塞的风险,此外,90Y树脂微球,通过离子交换将核素装载至微球表面,在复杂的生物环境中,核素易解离浸出,对正常组织造成放射性损伤。166Ho的聚乳酸微球生产过程亦需要反应堆轰击,且反应堆轰击会对微球节后造成一定的破坏。
发明内容
虽然绝大多数肝癌患者可从TARE治疗中获益,但是其疗效仍有提高的空间。研究证实化疗药物联合外照射与局部内照射治疗,可以显著降低肝癌细胞对射线的耐受性,提高肝癌治疗的疗效。因此,研发一种比重适宜,可快速、稳定标记放射性核素、且可高效装载化疗药物,实现肝癌TARE-TACE(肝动脉化疗栓塞)联合有效治疗的多功能微球具有重要的应用价值与临床意义。
为了解决上述存在的技术问题,本申请提供如下技术方案:
本发明提供一种富含双膦酸基团多功能凝胶微球的制备方法,包括如下步骤:
S11:将帕米膦酸二钠和N-丙烯酰氧基琥珀酰亚胺溶解于水中,调节pH至碱性后,反应,得到混合产物;
S12:将所述混合产物加入乙醇中,得到沉淀物;
S13:将所述沉淀物洗涤,干燥,得到丙烯酰胺双膦酸酯单体;
S14:将内相(分散相)和外相(连续相)通过微流控装置制备得到微球后紫外固化,得到所述富含双膦酸基团多功能凝胶微球;所述内相由丙烯酰胺双膦酸酯单体、丙烯酰胺、N,N'-亚甲基双丙烯酰胺、光引发剂溶于水得到;所述外相由矿物油和司盘80组成。
优选的,所述帕米膦酸二钠和N-丙烯酰氧基琥珀酰亚胺的重量比为100-800:100-1000。
优选的,所述步骤S11中,调节pH的方法为用氢氧化钠将pH调至7.5-10。
优选的,所述步骤S11中,反应的方法为室温(25±5℃)搅拌12-72h。
优选的,所述步骤S13中,洗涤的方法为乙醇洗涤2-4次。
优选的,所述步骤S13中,干燥的时间为40-50h。
优选的,按重量份计,所述内相由50-400份丙烯酰胺双膦酸酯单体、500-1600份丙烯酰胺、30-200份N,N'-亚甲基双丙烯酰胺、5-80份光引发剂溶于4000-5000份水得到。
优选的,所述外相的流速为500-1000μL/h,内相的流速为100-200μL/h。
优选的,所述司盘80的浓度为1-8wt%。
优选的,所述步骤S14中,紫外固化后用吐温80和水进行清洗。
优选的,所述吐温80的浓度为0.5-3wt%。
优选的,所述步骤S14中,紫外固化的条件为:紫外强度为30-200mw/cm2,固化时间为10-90s。
本发明还提供一种上述制备方法制备得到的富含双膦酸基团多功能凝胶微球。
本发明还提供上述富含双膦酸基团多功能凝胶微球在放射性标记和药物装载的应用,包括如下步骤:
S21:将富含双膦酸基团多功能凝胶微球加入含有金属核素的弱酸性溶液中,混合,分离,得到放射性标记微球;
S22:将所述放射性标记微球加入含有药物的水溶液中,混合,得到标记核素的载药微球。
优选的,所述弱酸性溶液选自醋酸钠、醋酸钾或含有0.0001-0.01mM/L盐酸的水溶液。
优选的,所述药物选自阿霉素、伊立替康、表柔比星、吡柔比星、三氧化二砷、吉西他滨、博来霉素、奥沙利铂、索拉非尼或仑伐替尼。
优选的,所述金属核素为90Y(钇)、166Ho(钬)、177Lu(镥)、188Re(铼)、99mTc(锝)、68Ga(镓)或64Cu(铜)。
优选的,所述含有非放射性镥的醋酸钠水溶液中,镥含量为35-45pmol/mL。
优选的,所述含有非放射性镥的醋酸钠水溶液的pH为5-6。
优选的,所述步骤S21中,混合的方法为:在35-40℃温度,700-900rpm转速的条件下,振荡25-35min。
优选的,所述步骤S21中,分离的方法为:800-1200rpm离心2-4min,去除上清。
优选的,所述盐酸阿霉素的水溶液中,溶质的浓度为0.8-1.2mg/mL。
本发明的技术方案相比现有技术具有以下优点:
本发明以丙烯酰胺,丙烯酸,丙烯酸-2-羟乙基酯,N-丙烯酰氧基琥珀酰亚胺和帕米膦酸二钠为原料,通过乳液聚合或微流控方法,经自由基氧化聚合制备富含双膦酸的凝胶微球,然后通过双膦酸基团对金属核素强效的螯合作用,将90Y、166Ho、177Lu、188Re、99mTc、68Ga、64Cu等核素稳定的标记至该微球上,制备具有治疗、成像或成像治疗一体化的放射栓塞微球。同时,该凝胶微球含有丰富的三维孔隙结构,为化疗药物的装载提供了空间,可装载阿霉素、伊立替康、表柔比星、吡柔比星、三氧化二砷、吉西他滨、博来霉素、奥沙利铂、索拉非尼和仑伐替尼等化疗或靶向药物,制备一种可同时快速、稳定标记放射性核素,装载化疗药物的多功能治疗微球,可进行肝癌精准、有效、低毒的TARE-TACE联合治疗与微球体内定位分布监测。
附图说明
图1为富含双膦酸凝胶微球的形貌与特征。
图2为体外分析凝胶微球的生物相容性图。
图3为凝胶微球金属核素标记验证与177Lu核素标记稳定性结果图。
图4为凝胶微球装载盐酸阿霉素的表征与装载性能图。
图5为凝胶微球装载177Lu核素与盐酸阿霉素对肝癌细胞的联合杀伤效果评价图。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明,以使本领域的技术人员可以更好地理解本发明并能予以实施,但所举实施例不作为对本发明的限定。
实施例1
(1)丙烯酰胺双膦酸酯单体合成
将600mg帕米膦酸二钠和200mgN-丙烯酰氧基琥珀酰亚胺一起溶解在去离子水中;用氢氧化钠将反应溶液调至pH为8,室温(25±5℃)搅拌42h;反应结束后,将最终产物溶液滴入无水乙醇中,得到沉淀产物;收集沉淀产物,用乙醇洗涤三次;沉淀物在真空烘箱中干燥2天,得到丙烯酰胺双膦酸酯单体。
(2)微球合成
称取100mg制备得到的丙烯酰胺双膦酸酯、900mg丙烯酰胺、100mg N-N亚甲基双丙烯酰胺、40mg光引发剂溶于4mL水中,作为内相(分散相);以矿物油和4%司盘80作为外相(连续相);两相分别注入注射器,通过注射泵调节注射器不同微通道内液体的流速;泵启动后,内相和外相分别注入微流控装置,其中外相流速550μL/h;内相流速150μL/h;收集微球后,紫外固化(紫外强度100mw/cm2,固化时间20s);用2%吐温80和去离子水反复清洗,并收集固化的微球,得到富含双膦酸基团多功能凝胶微球。
实施例2
(1)丙烯酰胺双膦酸酯单体合成
将369mg帕米膦酸二钠和169mg N-丙烯酰氧基琥珀酰亚胺一起溶解在去离子水中;用氢氧化钠将反应溶液调至pH为8.5,室温搅拌24h;反应结束后,将最终产物溶液滴入无水乙醇中,得到沉淀产物;收集沉淀产物,用乙醇洗涤三次;沉淀物在真空烘箱中干燥2天,得到丙烯酰胺双膦酸酯单体。
(2)微球合成
称取50mg制备得到的丙烯酰胺双膦酸酯、500mg丙烯酰胺、50mg N-N亚甲基双丙烯酰胺、20mg光引发剂溶于4mL水中,作为内相(分散相);以矿物油和1%司盘80作为外相(连续相);两相分别注入注射器,通过注射泵调节注射器不同微通道内液体的流速;泵启动后,内相和外相分别注入微流控装置,其中外相流速500μL/h;内相流速100μL/h;收集微球后,紫外固化(紫外强度30mw/cm2,固化时50s);用0.5%吐温80和去离子水反复清洗,并收集固化的微球,得到富含双膦酸基团多功能凝胶微球。
实施例3
(1)丙烯酰胺双膦酸酯单体合成
将800mg帕米膦酸二钠和200mgN-丙烯酰氧基琥珀酰亚胺一起溶解在去离子水中;用氢氧化钠将反应溶液调至pH 9,室温搅拌72h;反应结束后,将最终产物溶液滴入无水乙醇中,得到沉淀产物;收集沉淀产物,用乙醇洗涤三次;沉淀物在真空烘箱中干燥2天,得到丙烯酰胺双膦酸酯单体。
(2)微球合成
称取400mg制备得到的丙烯酰胺双膦酸酯、1600mg丙烯酰胺、200mgN-N亚甲基双丙烯酰胺、80mg光引发剂溶于10mL水中,作为内相(分散相);以矿物油和8%span 80作为外相(连续相);两相分别注入注射器,通过注射泵调节注射器不同微通道内液体的流速;泵启动后,内相和外相分别注入微流控装置,其中外相流速1000μL/h;内相流速200μL/h;收集微球后,紫外固化(紫外强度200mw/cm2,固化时间15s);用3%吐温80和去离子水反复清洗,并收集固化的微球,得到富含双膦酸基团多功能凝胶微球。
实施例4
(1)核素标记、纯化
取5mg实施例1、实施例2和实施例3制备得到的富含双膦酸基团多功能凝胶微球,加入500μL醋酸钠缓充液液(pH=5.6);在37℃,800rpm条件下震荡30min,标记结束后用去离子水清洗3次以除去游离Lu。通过放射性活度计测量沉淀和总的放射性活度来计算标记率。
标记率=沉淀放射性活度/总放射性活度*100;
(2)放射性标记稳定性
在室温环境下,将少量标记核素的微球分别静置于1.2mL的PBS和10%FBS中,各三组重复样。每间隔一定时间使用γ放射计数仪测1mL上清放射性计数和沉淀放射性计数。
标记稳定性=(沉淀放射性计数-0.2上清放射性计数)/(沉淀放射性计数+沉淀放射性计数)*100;
(3)药物装载
取3mg微球,加入500μL含非放射性镥的醋酸钠溶液(pH=5.6;镥含量=40pmol/mL);在37℃,800rpm条件下,振荡30min);标记后,1000rpm离心3min,去除上清;加入1mL盐酸阿霉素水溶液(1mg/mL),同样条件下振荡;每隔5min,取10μL上清,测紫外吸光度,计算药物的包封率与装载率。
包封率=微球装载药物的质量/微球总质量*100;
装载率=微球装载药物的质量/投入药物的总质量*100;
在室温环境下,将少量标记放射性177Lu的载药微球分别静置于1.2mLPBS缓冲液和10%FBS(胎牛血清)中,各三组重复样,每间隔一定时间使用γ放射计数仪测1mL上清和沉淀放射性计数,进而计算装载药物对核素标记稳定性的影响。
效果评价1
图1中,(a)为光学显微镜观察的微球形貌及微球的粒径统计;(b)为扫描电子显微镜观察凝胶微球的形貌;(c)为扫描电镜下局部放大的微球胶孔;(d)为通过扫描电镜能谱分析观测凝胶微球碳、氧、磷元素的含量与定位。
图2为不同浓度凝胶微球处理肝癌细胞Hepa1-6(a)和脐静脉血管内皮细胞HUVEC(b)24和48h后,使用CCK-8分析细胞存活率。
图3中,扫描电镜能谱分析检测双膦酸凝胶微球标记非放射性钇(a)、钬(b)和镥(c)元素;(d)γ计数仪分析凝胶微球标记177Lu核素后,在磷酸盐缓冲液(PBS)与胎牛血清溶液(FBS)中的核素标记稳定性。
图4中,(a)为凝胶微球(左)与装载盐酸阿霉素的凝胶微球(右)颜色对比;(b)为荧光显微镜观察装载盐酸阿霉素的凝胶微球;(c)为凝胶微球装载盐酸阿霉素的包封率与药物装载率;(d)为凝胶微球装载盐酸阿霉素后对其核素标记稳定性的影响。
图5中,装载177Lu和盐酸阿霉素的凝胶微球处理肝癌细胞Hepa1-6的联合疗效。
显然,上述实施例仅仅是为清楚地说明所作的举例,并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (8)
1.一种富含双膦酸基团多功能凝胶微球的制备方法,其特征在于,包括如下步骤:
S11:将帕米膦酸二钠和N-丙烯酰氧基琥珀酰亚胺溶解于水中,调节pH至碱性后,反应,得到混合产物;
S12:将所述混合产物加入乙醇中,得到沉淀物;
S13:将所述沉淀物洗涤,干燥,得到丙烯酰胺双膦酸酯单体;
S14:将内相和外相通过微流控装置制备得到微球后紫外固化,得到所述富含双膦酸基团多功能凝胶微球;按重量份计,所述内相由50-400份丙烯酰胺双膦酸酯单体、500-1600份丙烯酰胺、30-200份N,N'-亚甲基双丙烯酰胺、5-80份光引发剂溶于4000-5000份水得到;所述外相由矿物油和司盘80组成;所述外相的流速为500-2000 μL/h,内相的流速为100-200μL/h。
2.如权利要求1所述的制备方法,其特征在于,所述帕米膦酸二钠和N-丙烯酰氧基琥珀酰亚胺的重量比为100-800:100-1000。
3.如权利要求1所述的制备方法,其特征在于,所述步骤S11中,反应的方法为室温搅拌12-72 h。
4.如权利要求1所述的制备方法,其特征在于,所述步骤S14中,紫外固化的条件为:紫外强度为30-200 mw/cm2,固化时间为10-90 s。
5.一种权利要求1-4中任一项所述制备方法制备得到的富含双膦酸基团多功能凝胶微球。
6.权利要求5所述富含双膦酸基团多功能凝胶微球在放射性标记和药物装载中的应用,其特征在于,包括如下步骤:
S21:将富含双膦酸基团多功能凝胶微球加入含有金属核素的弱酸性溶液中,混合,分离,得到放射性标记微球;
S22:将所述放射性标记微球加入含有药物的水溶液中,混合,得到标记核素的载药微球。
7.如权利要求6所述的应用,其特征在于,所述药物选自阿霉素、伊立替康、表柔比星、吡柔比星、三氧化二砷、吉西他滨、博来霉素、奥沙利铂、索拉非尼或仑伐替尼。
8.如权利要求6所述的应用,其特征在于,所述金属核素为90Y、166Ho、177Lu、188Re、99mTc、68Ga或64Cu。
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