CN113069558B - 一种可用于类风湿性关节炎的诊疗一体化纳米探针的制备及应用 - Google Patents
一种可用于类风湿性关节炎的诊疗一体化纳米探针的制备及应用 Download PDFInfo
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Abstract
本发明属于生物与医学纳米材料技术领域,具体涉及一种可用于类风湿性关节炎的诊疗一体化纳米探针的制备及应用,本发明先用mPEG连接可用于CT造影成像的TIPA,再通过MMP酶响应多肽KGPLGVRK连接抗风湿性药物MTX而制成第一种两亲性聚合物;然后将可靶向IL‑6受体的TCZ单抗共价连接于Pal‑GGGGHHHHD上而制成第二种两亲性聚合物;最后由上述两种两亲性聚合物自组装形成聚合物纳米胶束,并在纳米胶束上螯合Gd3+离子制备得到。所得的诊疗一体化纳米探针集MR/CT双模态成像与单抗主动靶向、酶响应释药于一体,不仅能在RA病灶部位靶向MR/CT双模态成像,而且可提升RA药物治疗效果。
Description
技术领域
本发明属于生物与医学纳米材料技术领域,具体涉及一种可用于类风湿性关节炎(rheumatoid arthritis,RA)的诊疗一体化纳米探针的制备及应用。
背景技术
多模态成像是指将两种或两种以上的成像技术相结合,使各成像模态的优点得到充分展现,对目标进行高精度和高分辨率的成像。多模态成像同时具有多种成像功能,可弥补单一成像技术的缺点,同时发挥各自成像技术的优势以获得更全面的诊断信息。多模态成像技术是分子影像技术的重要发展方向之一,其关键在于多种成像造影剂的融合。
近年来,多/双模态成像探针在类风湿性关节炎(rheumatoid arthritis,RA)诊断中的应用被广泛研究。目前已开发的用于RA诊断的双模态成像探针的组合模式有MR/NIR、FL/PA、FL/MR和US/PA等,这些组合模式主要是将光学成像与MR成像相结合,从而克服光学成像的弱穿透性和MR成像的低灵敏度,进而达到更好的RA诊断效果。然而这些成像模式都主要是对RA的软组织进行成像,但难以对RA病程评估中表现出的骨侵蚀情况做出准确诊断。
CT成像作为检测RA骨侵蚀等钙化组织破坏的黄金标准,对用于RA诊断的多模态成像探针的构建具有重要意义。通过构建MR/CT双模态成像探针可同时对RA部位的滑膜炎症和骨侵蚀情况做出准确诊断。此外,由于被动靶向的纳米载体特异性差,导致其到达病灶部位的药物较少,而主动靶向的载药系统可提高病灶部位药物的有效浓度,提升药物的治疗效果;同时,能针对病灶部位微环境选择性释药的载药系统,还可以有效提高药物的利用率,实现精准治疗。可见,集成诊断与治疗功能的诊疗一体化纳米探针,在个性化医疗、实时监测治疗过程和反馈治疗效果等方面均优于单一的诊断或治疗手段。因此,研制可用于RA的诊疗一体化纳米探针具有重要的应用价值。
发明内容
为了克服上述现有技术的不足,本发明提出了一种可用于RA的诊疗一体化纳米探针制备方法,制备所得的诊疗一体化纳米探针集MR/CT双模态成像与单抗主动靶向、酶响应释药于一体,应用于治疗类风湿性关节炎,可提升病灶部位的药物有效浓度,增强治疗效果并减少毒副作用。
为了实现上述目的,本发明所采用的技术方案是:
本发明提供了一种诊疗一体化纳米探针的制备方法,包括以下步骤:
S1、第一种两亲性聚合物mPEG-TIPA-KGPLGVRK-MTX的制备:用生物相容性优异的mPEG(氨基聚乙二醇)连接可用于CT造影成像的TIPA(5-氨基-2,4,6-三碘间苯二甲酸),再通过MMP酶(基质金属蛋白酶-2)响应多肽KGPLGVRK连接抗风湿性药物MTX(甲氨蝶呤)而制成;
S2、第二种两亲性聚合物Pal-GGGGHHHHD-TCZ的制备:将可靶向IL-6(白介素-6)受体的TCZ(妥珠单抗)共价连接于两亲性聚多肽【Pal-GGGGHHHHD,Pal为Palmitic acid(山嵛酸)】上而制成;
S3、诊疗一体化纳米探针的制备:将mPEG-TIPA-KGPLGVRK-MTX和Pal-GGGGHHHHD-TCZ自组装形成聚合物纳米胶束,再在聚合物纳米胶束上螯合Gd3+离子即得。
作为本发明的一个优选实施方式,上述的一种诊疗一体化纳米探针的制备方法,包括以下步骤:
S1、第一种两亲性聚合物mPEG-TIPA-KGPLGVRK-MTX的制备:
S11、mPEG-TIPA的合成:在EDC【1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐】和NHS【N-羟基琥珀酰亚胺】的催化作用下,将化合物mPEG和过量TIPA避光搅拌反应后制得;
S12、mPEG-TIPA-KGPLGVRK的合成:在EDC和NHS的催化作用下,将步骤S11制得的mPEG-TIPA和MMP响应性多肽KGPLGVRK避光搅拌反应后制得;
S13、mPEG-TIPA-KGPLGVRK-MTX的合成:在EDC和NHS的催化作用下,将步骤S12制得的mPEG-TIPA-KGPLGVRK加入到MTX的DMSO溶液中,避光搅拌反应后制得;
S2、第二种两亲性聚合物Pal-GGGGHHHHD-TCZ的制备:在EDC和NHS的催化作用下,将化合物Pal-GGGGHHHHD和TCZ避光搅拌反应后制得;
S3、诊疗一体化纳米探针的制备:以mPEG-TIPA-KGPLGVRK-MTX和Pal-GGGGHHHHD-TCZ为原料,用溶剂溶解后于水中透析自组装形成聚合物纳米胶束,再加入氯化钆GdCl3·5H2O(Pal-GGGGHHHHD的组氨酸上的咪唑基团可有效螯合Gd3+离子),经搅拌反应后在水中透析去除未螯合的Gd3+,即制得诊疗一体化纳米探针。
本发明首先合成了共价连接CT成像造影剂TIPA和类风湿关节炎治疗药物MTX的mPEG-TIPA-KGPLGVRK-MTX以及共价连接白介素6抗体的Pal-GGGGHHHHD-TCZ两种两亲性聚合物,然后将两种两亲性聚合物通过自组装形成复合纳米胶束,并将钆离子螯合于纳米胶束表面,最终制备得到一种诊疗一体化纳米探针。该探针结合了CT对类风湿性关节炎关节面骨质破坏、骨质硬化、关节间隙的检测能力和MRI(Pal-GGGGHHHHD的组氨酸上的咪唑基团可有效螯合Gd3+离子从而可作为MRI造影剂)对关节滑膜病变,骨水肿,软骨破坏的检测能力,不仅可对早期类风湿性关节炎做出准确诊断,而且可以实现对病程发展的全面评估和预后监测,可尽早确定疾病并加以治疗,进而降低致残率。同时,在探针上引入的TCZ单抗,对RA部位具有主动靶向作用从而有效提高探针在病灶部位的聚集率,能够实时、精确诊断病情并为随后的治疗提供影像指导。在探针上引入的抗风湿药物MTX和MMP响应性多肽,可针对类风湿性关节炎微环境进行选择性释药,从而提高药物利用率,减少耐药性和毒副作用,为类风湿性关节炎的精准治疗提供有效的方法。可见,本发明的诊疗一体化纳米探针集MR/CT双模态成像与单抗主动靶向、酶响应释药于一体,有望应用于制备造影剂或者治疗类风湿性关节炎的药物。
优选地,在步骤S11中,mPEG的相对分子质量为1000-5000,TIPA与mPEG的摩尔比为1:(0.01-1),TIPA、EDC与NHS之间的摩尔比为1:(1-5):(1-5)。进一步地,mPEG的相对分子质量为2000,TIPA与mPEG的摩尔比为1:0.1;TIPA、EDC与NHS之间的摩尔比为1:2.5:2.5。
优选地,在步骤S11中,先将TIPA、EDC和NHS溶于溶剂得到溶液1,搅拌避光反应0.5h以活化-COOH;然后将mPEG用溶剂溶解得到溶液2,溶液1与溶液2混合后继续搅拌反应。
进一步地,在步骤S11中,TIPA在溶液1中的浓度为4mg/mL,mPEG在溶液2中的浓度为(0.4-40)mg/mL;反应温度为25-50℃,继续搅拌反应的时间为12-48h,搅拌转速为400-800rpm/min;溶液1和溶液2的溶剂均为甲醇或DMSO。
具体地,在步骤S11中,mPEG在溶液2中的浓度为4mg/mL;反应温度为25℃,继续搅拌反应的时间为24h,搅拌转速为600rpm/min;溶液1和溶液2的溶剂均为甲醇。
优选地,在步骤S11中,反应后,收集反应液并在水(一般为超纯水)中透析后冻干得到产物,透析时间为2-4d。进一步地,透析时间为3d。
优选地,在步骤S12中,KGPLGVRK与mPEG-TIPA的质量比为1:(1-5),mPEG-TIPA、EDC与NHS之间的摩尔比为1:(1-5):(1-5)。进一步地,KGPLGVRK与mPEG-TIPA的质量比为1:2.5,mPEG-TIPA、EDC与NHS之间的摩尔比为1:2.5:2.5。
优选地,在步骤S12中,先将步骤S11制得的mPEG-TIPA与EDC、NHS溶于溶剂中得到溶液1,搅拌避光反应0.5h以活化-COOH,然后将MMP酶响应多肽KGPLGVRK用溶剂溶解得到溶液2,溶液1与溶液2混合后继续搅拌反应。
进一步地,在步骤S12中,mPEG-TIPA在溶液1中的浓度为2.5mg/mL,MMP酶响应多肽KGPLGVRK在溶液2中的浓度为(5-25)mg/mL;反应温度为25-50℃,继续搅拌反应的时间为12-48h,搅拌转速为400-800rpm/min;溶液1和溶液2的溶剂均为DMSO。
具体地,在步骤S12中,MMP酶响应多肽KGPLGVRK在溶液2中的浓度为10mg/mL;反应温度为25℃,继续搅拌反应的时间为24h,搅拌转速为600rpm/min。
优选地,在步骤S13中,MTX与mPEG-TIPA的质量比为1:(1-5),MTX、EDC与NHS之间的摩尔比为1:(1-5):(1-5)。进一步地,MTX与mPEG-TIPA的质量比为1:2.5;MTX、EDC与NHS之间的摩尔比为1:2.5:2.5。
优选地,在步骤S13中,先将MTX、EDC与NHS溶于溶剂中得到溶液1,搅拌避光反应0.5h以活化-COOH;然后将步骤S12制得的mPEG-TIPA-KGPLGVRK以溶液的形式直接与MTX的DMSO溶液混合得到溶液2,溶液1与溶液2混合后继续避光搅拌反应。
优选地,在步骤S13中,MTX在溶液1中的浓度为(0.5-2.5)mg/mL,mPEG-TIPA-KGPLGVRK溶液与MTX的DMSO溶液的体积比为(11-15):(5-25);反应温度为25-50℃,反应时间为12-48h,搅拌转速为600-1000rpm/min;溶液1的溶剂为DMSO,MTX的DMSO溶液中MTX的浓度为1mg/mL。
具体地,在步骤S13中,MTX在溶液1中的浓度为1mg/mL,mPEG-TIPA-KGPLGVRK溶液与MTX的DMSO溶液的体积比为6:5;反应温度为25℃,反应时间为24h,搅拌转速为800rpm/min。
优选地,在步骤S13中,反应后,收集反应液并在水(一般为超纯水)中透析后冻干得到产物,透析时间为2-4d。进一步地,透析时间为3d。
优选地,在步骤S2中,TCZ与两亲性聚多肽(Pal-GGGGHHHHD)的质量比为1:(500-2000),Pal-GGGGHHHHD、EDC与NHS之间的摩尔比为1:(1-5):(1-5)。进一步地,TCZ与Pal-GGGGHHHHD的质量比为1:1000,Pal-GGGGHHHHD、EDC与NHS之间的摩尔比为1:2.5:2.5。
优选地,在步骤S2中,将Pal-GGGGHHHHD、EDC与NHS溶解于溶剂中,搅拌避光反应0.5h以活化-COOH;再加入TCZ继续搅拌反应。
进一步地,在步骤S2中,Pal-GGGGHHHHD在溶剂中的浓度为1mg/mL;反应温度为25-50℃,继续搅拌反应的时间为12-48h,搅拌转速为400-800rpm/min;反应体系的溶剂为DMSO。
具体地,在步骤S2中,反应温度为25℃,继续搅拌反应的时间为24h,搅拌转速为600rpm/min。
优选地,在步骤S2中,反应后,收集反应液并在水(一般为超纯水)中透析后冻干得到产物,透析时间为2-4d。进一步地,透析时间为3d。
优选地,在步骤S3中,Pal-GGGGHHHHD-TCZ与mPEG-TIPA-KGPLGVRK-MTX的质量比为1:(1-10)。进一步地,Pal-GGGGHHHHD-TCZ与mPEG-TIPA-KGPLGVRK-MTX的质量比为1:4。
优选地,在步骤S3中,溶剂为DMSO,溶剂的加入量使mPEG-TIPA-KGPLGVRK-MTX的浓度为2mg/mL;搅拌反应的时间为4h,拌速为400-800rpm/min;两次透析的时间均为2-4d。进一步地,拌速为600rpm/min;第一次透析的时间为2d,第二次透析的时间为3d。
优选地,在步骤S3中,GdCl3·5H2O的浓度为10mg/mL,GdCl3·5H2O的加入量为(100uL-1mL)/10mL溶剂。进一步地,GdCl3·5H2O的加入量为500uL/10mL溶剂。
本发明还提供了采用上述的制备方法制备得到的诊疗一体化纳米探针。
本发明还提供了上述的诊疗一体化纳米探针在制备造影剂中的应用。
本发明还提供了上述的诊疗一体化纳米探针在制备类风湿性关节炎治疗药物中的应用。
与现有技术相比,本发明的有益效果是:
本发明提供了一种诊疗一体化纳米探针的制备方法,先用生物相容性优异的mPEG连接可用于CT造影成像的TIPA,再通过MMP酶响应多肽KGPLGVRK连接抗风湿性药物MTX而制成第一种两亲性聚合物mPEG-TIPA-KGPLGVRK-MTX;然后将可靶向IL-6受体的TCZ单抗共价连接于两亲性聚多肽(Pal-GGGGHHHHD)上而制成第二种两亲性聚合物Pal-GGGGHHHHD-TCZ;最后由上述两种两亲性聚合物自组装形成聚合物纳米胶束,并在纳米胶束上螯合Gd3+离子制备得到。所得的纳米探针尺寸合适、均一性好、生物相容性高,弥补了单一影像技术造影的不足,结合CT对类风湿性关节炎关节面骨质破坏、骨质硬化、关节间隙的检测能力和MRI(Pal-GGGGHHHHD的组氨酸上的咪唑基团可有效螯合Gd3+离子从而可作为MRI造影剂)对关节滑膜病变,骨水肿,软骨破坏的检测能力,不仅可对早期类风湿性关节炎做出准确诊断,而且可以实现对病程发展的全面评估和预后监测,可尽早确定疾病并加以治疗,进而降低致残率;同时可利用TCZ抗体对炎症因子白介素6受体的特异识别以及类风湿性关节炎微环境MMP酶含量高表达的特点,从而对类风湿性关节炎的病灶部位选择性释药,可提升病灶部位的药物有效浓度,增强类风湿性关节炎的治疗效果并减少毒副作用。因此,本发明的诊疗一体化纳米探针集MR/CT双模态成像与单抗主动靶向、酶响应释药于一体,不仅具有MR/CT双模态成像功能,且可有效治疗类风湿性关节炎,可应用于制备造影剂或者治疗类风湿性关节炎的药物。
附图说明
图1为诊疗一体化纳米探针的合成路径;
图2为诊疗一体化纳米探针的TEM图(图中左上角部分为粒度分布图);
图3为小鼠的爪厚度统计图;
图4为小鼠的临床评分曲线;
图5为小鼠的MR和CT成像图。
具体实施方式
下面对本发明的具体实施方式作进一步说明。在此需要说明的是,对于这些实施方式的说明用于帮助理解本发明,但并不构成对本发明的限定。此外,下面所描述的本发明各个实施方式中所涉及的技术特征只要彼此之间未构成冲突就可以相互组合。
下述实施例中的实验方法,如无特殊说明,均为常规方法,下述实施例中所用的试验材料,如无特殊说明,均为可通过常规的商业途径购买得到的。
实施例1诊疗一体化纳米探针的制备
其合成途径如图1所示,具体的制备方法包括以下步骤:
(1)mPEG-TIPA的合成:于50mL烧瓶中称量TIPA40 mg、EDC 34mg、NHS 48mg,加入10mL甲醇溶解,在搅拌器上常温避光反应0.5h以活化-COOH(转速为600rpm/min);将4mgmPEG2000用1mL甲醇溶解后与上述溶液混合,继续搅拌反应24h(转速为600rpm/min),收集反应液并在超纯水中透析3d,经冻干后得到产物mPEG-TIPA。
(2)mPEG-TIPA-KGPLGVRK的合成:于50mL烧瓶中称量步骤(1)制得的mPEG-TIPA25mg、EDC 5mg、NHS 7mg,加入10mLDMSO溶解,在搅拌器上常温避光反应0.5h以活化-COOH(转速为600rpm/min)。称量MMP酶响应多肽KGPLGVRK 10mg于2mL EP管中,加入2mLDMSO溶解,然后缓慢滴加到上述烧瓶中,常温下搅拌反应24h(转速为600rpm/min),得到mPEG-TIPA-KGPLGVRK溶液。
(3)mPEG-TIPA-KGPLGVRK-MTX的合成:于50mL烧瓶中称量MTX 10mg、EDC 10mg、NHS15mg,加入10mLDMSO溶解,在搅拌器上常温避光反应0.5h以活化-COOH(转速为800rpm/min);将步骤(2)制得的mPEG-TIPA-KGPLGVRK溶液(12mL)缓慢滴加于10mLMTX的DMSO溶液(MTX的浓度为1mg/mL)中,常温避光搅拌反应24h(转速为800rpm/min),收集反应液并在超纯水中透析3d,经冻干后得到产物mPEG-TIPA-KGPLGVRK-MTX。
(4)Pal-GGGGHHHHD-TCZ的合成:于50mL烧瓶中称量两亲性聚多肽(Pal-GGGGHHHHD)10mg、EDC 5mg、NHS 7mg,加入10mL DMSO溶解,在搅拌器上常温避光反应0.5h以活化-COOH(转速为600rpm/min);再在上述溶液中加入TCZ 10μg,继续搅拌反应24h(转速为600rpm/min),收集反应液并在超纯水中透析3d,经冻干后得到产物Pal-GGGGHHHHD-TCZ。
(5)自组装形成诊疗一体化探针:于4mL EP管中称量步骤(3)制得的mPEG-TIPA-KGPLGVRK-MTX 20mg、步骤(4)制得的Pal-GGGGHHHHD-TCZ 5mg,加入10mLDMSO溶解并转移到透析袋(MW1000)中,在超纯水中缓慢搅拌透析2d;将上述透析溶液转移到棕色西林瓶中,边搅拌(转速为600rpm/min)边向其中逐滴缓慢滴加500μLGdCl3·5H2O(10mg/mL),常温避光搅拌反应4h(转速为600rpm/min),收集反应液并在超纯水中透析3d后得到最终产物。
用粒度仪和透射电镜(TEM)对上述所得的诊疗一体化纳米探针进行观察,如图2所示的TEM图,该探针呈均匀球形,平均粒径为70-120nm,尺寸合适、均一性好,良好的生物相容性。
实施例2诊疗一体化纳米探针的制备
其合成途径如图1所示,具体的制备方法包括以下步骤:
(1)mPEG-TIPA的合成:于50mL烧瓶中称量TIPA40 mg、EDC 13mg、NHS 19mg,加入10mL甲醇溶解,在搅拌器上常温避光反应0.5h以活化-COOH(转速为400rpm/min);将40mgmPEG1000用1mL甲醇溶解后与上述溶液混合,继续搅拌反应12h(转速为400rpm/min),收集反应液并在超纯水中透析2d,经冻干后得到产物mPEG-TIPA。
(2)mPEG-TIPA-KGPLGVRK的合成:于50mL烧瓶中称量步骤(1)制得的mPEG-TIPA25mg、EDC 3mg、NHS 4mg,加入10mLDMSO溶解,在搅拌器上常温避光反应0.5h以活化-COOH(转速为400rpm/min)。称量MMP酶响应多肽KGPLGVRK 5mg于2mL EP管中,加入1mL DMSO溶解,然后缓慢滴加到上述烧瓶中,常温下搅拌反应12h(转速为400rpm/min),得到mPEG-TIPA-KGPLGVRK溶液。
(3)mPEG-TIPA-KGPLGVRK-MTX的合成:于50mL烧瓶中称量MTX 25mg、EDC 10mg、NHS15mg,加入25mLDMSO溶解,在搅拌器上常温避光反应0.5h以活化-COOH(转速为600rpm/min);将步骤(2)制得的mPEG-TIPA-KGPLGVRK溶液(11mL)缓慢滴加于25mLMTX的DMSO溶液(MTX的浓度为1mg/mL)中,常温避光搅拌反应12h(转速为600rpm/min),收集反应液并在超纯水中透析2d,经冻干后得到产物mPEG-TIPA-KGPLGVRK-MTX。
(4)Pal-GGGGHHHHD-TCZ的合成:于50mL烧瓶中称量两亲性聚多肽(Pal-GGGGHHHHD)10mg、EDC 2mg、NHS 3mg,加入10mLDMSO溶解,在搅拌器上常温避光反应0.5h以活化-COOH(转速为400rpm/min);再在上述溶液中加入TCZ 5μg,继续搅拌反应12h(转速为400rpm/min),收集反应液并在超纯水中透析2d,经冻干后得到产物Pal-GGGGHHHHD-TCZ。
(5)自组装形成诊疗一体化探针:于4mL EP管中称量步骤(3)制得的mPEG-TIPA-KGPLGVRK-MTX 20mg、步骤(4)制得的Pal-GGGGHHHHD-TCZ 2mg,加入10mLDMSO溶解并转移到透析袋(MW1000)中,在超纯水中缓慢搅拌透析2d;将上述透析溶液转移到棕色西林瓶中,边搅拌(转速为400rpm/min)边向其中逐滴缓慢滴加100μLGdCl3·5H2O(10mg/mL),常温避光搅拌反应4h(转速为400rpm/min),收集反应液并在超纯水中透析3d后得到最终产物。
实施例3诊疗一体化纳米探针的制备
其合成途径如图1所示,具体的制备方法包括以下步骤:
(1)mPEG-TIPA的合成:于50mL烧瓶中称量TIPA40 mg、EDC 68mg、NHS 97mg,加入10mL甲醇溶解,在搅拌器上常温避光反应0.5h以活化-COOH(转速为800rpm/min);将0.4mgmPEG5000用1mL甲醇溶解后与上述溶液混合,继续搅拌反应48h(转速为800rpm/min),收集反应液并在超纯水中透析4d,经冻干后得到产物mPEG-TIPA。
(2)mPEG-TIPA-KGPLGVRK的合成:于50mL烧瓶中称量步骤(1)制得的mPEG-TIPA25mg、EDC 4mg、NHS 6mg,加入10mLDMSO溶解,在搅拌器上常温避光反应0.5h以活化-COOH(转速为800rpm/min)。称量MMP酶响应多肽KGPLGVRK 25mg于2mL EP管中,加入5mLDMSO溶解,然后缓慢滴加到上述烧瓶中,常温下搅拌反应48h(转速为800rpm/min),得到mPEG-TIPA-KGPLGVRK溶液。
(3)mPEG-TIPA-KGPLGVRK-MTX的合成:于50mL烧瓶中称量MTX 5mg、EDC 2mg、NHS3mg,加入5mL DMSO溶解,在搅拌器上常温避光反应0.5h以活化-COOH(转速为1000rpm/min);将步骤(2)制得的mPEG-TIPA-KGPLGVRK溶液(15mL)缓慢滴加于5mL MTX的DMSO溶液(MTX的浓度为1mg/mL)中,常温避光搅拌反应48h(转速为1000rpm/min),收集反应液并在超纯水中透析4d,经冻干后得到产物mPEG-TIPA-KGPLGVRK-MTX。
(4)Pal-GGGGHHHHD-TCZ的合成:于50mL烧瓶中称量两亲性聚多肽(Pal-GGGGHHHHD)10mg、EDC 10mg、NHS 13mg,加入10mL DMSO溶解,在搅拌器上常温避光反应0.5h以活化-COOH(转速为800rpm/min);再在上述溶液中加入TCZ 20μg,继续搅拌反应48h(转速为800rpm/min),收集反应液并在超纯水中透析4d,经冻干后得到产物Pal-GGGGHHHHD-TCZ。
(5)自组装形成诊疗一体化探针:于4mL EP管中称量步骤(3)制得的mPEG-TIPA-KGPLGVRK-MTX 20mg、步骤(4)制得的Pal-GGGGHHHHD-TCZ 20mg,加入10mLDMSO溶解并转移到透析袋(MW1000)中,在超纯水中缓慢搅拌透析2d;将上述透析溶液转移到棕色西林瓶中,边搅拌(转速为800rpm/min)边向其中逐滴缓慢滴加1mL GdCl3·5H2O(10mg/mL),常温避光搅拌反应4h(转速为800rpm/min),收集反应液并在超纯水中透析3d后得到最终产物。
实验例1诊疗一体化纳米探针在MR/CT成像介导下治疗类风湿性关节炎中的应用
(1)关节炎小鼠(CIA)模型的建立:取6周龄雄性DBA/1小鼠(体重16-20g,购自北京维通利华实验动物技术有限公司)6只,于尾部皮下注射50μLⅡ型胶原蛋白(CⅡ-A)和弗氏完全佐剂(A-A)乳化液(体积比1:1),21天后再次注射50μL牛II型胶原和弗氏不完全佐剂乳化液(体积比1:1)加强免疫,建立得到胶原蛋白诱导的关节炎小鼠(CIA)模型。
(2)分组给药及疗效观察:将上述CIA小鼠随机分为两组,每组3只,治疗组自第28天起每3天经尾静脉注射100μL实施例1制备的诊疗一体化纳米探针(10mg/mL,用生理盐水稀释),共治疗7次,对照组注射生理盐水;每3天记录一次各组小鼠的爪厚度和临床评分,第49天在治疗后2h,分别对两组小鼠进行MR和CT成像以评估各组小鼠的关节炎发展情况。
如图3和图4所示,治疗开始后,治疗组小鼠的爪厚度和临床评分曲线的上升速度均较缓慢,而对照组则迅速上升(说明炎症急剧恶化);图5的MR和CT图像也显示出治疗组小鼠的关节炎症状明显减轻,而对照组出现了严重的炎症和骨侵蚀。说明本发明的诊疗一体化纳米探针不仅可以主动靶向关节炎部位且具有良好的CT成像造影功能,而且可通过MMP响应释药对类风湿性关节炎具有良好的治疗效果,即同时具有IL-6单抗靶向,MMP响应释药和CT/MR双模态成像的功能。
以上对本发明的实施方式作了详细说明,但本发明不限于所描述的实施方式。对于本领域的技术人员而言,在不脱离本发明原理和精神的情况下,对这些实施方式进行多种变化、修改、替换和变型,仍落入本发明的保护范围内。
序列表
<110> 中山大学
<120> 一种可用于类风湿性关节炎的诊疗一体化纳米探针的制备及应用
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> MMP酶响应多肽
<400> 1
Lys Gly Pro Leu Gly Val Arg Lys
1 5
<210> 2
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Pal-GGGGHHHHD
<220>
<223> 两亲性聚多肽:Pal-GGGGHHHHD
<400> 2
Gly Gly Gly Gly His His His His Asp
1 5
Claims (10)
1.一种诊疗一体化纳米探针的制备方法,其特征在于,包括以下步骤:
S1、第一种两亲性聚合物mPEG-TIPA-KGPLGVRK-MTX的制备:用生物相容性优异的mPEG连接可用于CT造影成像的TIPA,再通过MMP酶响应多肽KGPLGVRK连接抗风湿性药物MTX而制成;
S2、第二种两亲性聚合物Pal-GGGGHHHHD-TCZ的制备:将可靶向IL-6受体的TCZ共价连接于两亲性聚多肽Pal-GGGGHHHHD上而制成;
S3、诊疗一体化纳米探针的制备:将mPEG-TIPA-KGPLGVRK-MTX和Pal-GGGGHHHHD-TCZ自组装形成聚合物纳米胶束,再在聚合物纳米胶束上螯合Gd3+离子即得。
2.根据权利要求1所述的一种诊疗一体化纳米探针的制备方法,其特征在于,包括以下步骤:
S1、第一种两亲性聚合物mPEG-TIPA-KGPLGVRK-MTX的制备:
S11、mPEG-TIPA的合成:在EDC和NHS的催化作用下,将化合物mPEG和过量TIPA避光搅拌反应后制得;
S12、mPEG-TIPA-KGPLGVRK的合成:在EDC和NHS的催化作用下,将步骤S11制得的mPEG-TIPA和MMP响应性多肽KGPLGVRK避光搅拌反应后制得;
S13、mPEG-TIPA-KGPLGVRK-MTX的合成:在EDC和NHS的催化作用下,将步骤S12制得的mPEG-TIPA-KGPLGVRK加入到MTX的DMSO溶液中,避光搅拌反应后制得;
S2、第二种两亲性聚合物Pal-GGGGHHHHD-TCZ的制备:在EDC和NHS的催化作用下,将化合物Pal-GGGGHHHHD和TCZ避光搅拌反应后制得;
S3、诊疗一体化纳米探针的制备:以mPEG-TIPA-KGPLGVRK-MTX和Pal-GGGGHHHHD-TCZ为原料,用溶剂溶解后于水中透析自组装形成聚合物纳米胶束,再加入GdCl3·5H2O,经搅拌反应后在水中透析去除未螯合的Gd3+,即制得诊疗一体化纳米探针。
3.根据权利要求2所述的一种诊疗一体化纳米探针的制备方法,其特征在于,在步骤S11中,mPEG的相对分子质量为1000-5000,TIPA与mPEG的摩尔比为1:(0.01-10),TIPA、EDC与NHS之间的摩尔比为1:(1-5):(1-5)。
4.根据权利要求2所述的一种诊疗一体化纳米探针的制备方法,其特征在于,在步骤S12中,KGPLGVRK与mPEG-TIPA的质量比为1:(1-5),mPEG-TIPA、EDC与NHS之间的摩尔比为1:(1-5):(1-5)。
5.根据权利要求2所述的一种诊疗一体化纳米探针的制备方法,其特征在于,在步骤S13中,MTX与mPEG-TIPA的质量比为1:(1-5),MTX、EDC与NHS之间的摩尔比为1:(1-5):(1-5)。
6.根据权利要求2所述的一种诊疗一体化纳米探针的制备方法,其特征在于,在步骤S2中,TCZ与Pal-GGGGHHHHD的质量比为1:(500-2000),Pal-GGGGHHHHD与EDC和NHS的总量之间的摩尔比为1:(1-5)。
7.根据权利要求2所述的一种诊疗一体化纳米探针的制备方法,其特征在于,在步骤S3中,Pal-GGGGHHHHD-TCZ与mPEG-TIPA-KGPLGVRK-MTX的质量比为1:(1-10)。
8.采用权利要求1-7任一项所述的制备方法制备得到的诊疗一体化纳米探针。
9.权利要求8所述的诊疗一体化纳米探针在制备造影剂中的应用。
10.权利要求8所述的诊疗一体化纳米探针在制备类风湿性关节炎治疗药物中的应用。
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"英夫利西单抗联合甲氨蝶呤治疗类风湿性关节炎的Meta分析";苏妍等;《实用医学杂志》;20141231;第30卷(第13期);第2142-2147页 * |
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