CN107224590A - 一种可降解聚合物磁性纳米粒子及其制备方法 - Google Patents
一种可降解聚合物磁性纳米粒子及其制备方法 Download PDFInfo
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Abstract
一种可降解聚合物磁性纳米粒子及其制备方法,是以含双乙烯基二硫键的化合物作为偶联剂,将多巴胺、抗肿瘤药物基团、靶向功能基团通过共价键连接的方式与偶联剂主链相连,聚合制成可降解外壳,再将可降解外壳化学包裹在四氧化三铁纳米粒子外表面上,可降解外壳上的多巴胺能够与四氧化三铁纳米粒子表面通过配位键结合,制成可降解聚合物磁性纳米粒子。本发明聚合物外壳可降解,且与磁性纳米粒子通过配位键结合稳定,药物的负载稳定性好,具有靶向功能以及造影效果好的特点。
Description
技术领域
本发明属于可降解聚合物磁性纳米粒子及其制备技术领域,具体涉及一种在磁性纳米粒子外壳包裹可降解聚合物材料作为药物载体及其制备方法,特别涉及一种在磁性纳米粒子外壳包裹可降解聚合物材料作为具有靶向功能的药物载体及其制备方法。
背景技术
近年来,基于Fe3O4的磁性纳米粒子具有超顺磁性、细胞毒性小等优点,在药物传递(治疗)以及磁共振成像(医学诊断)一体化研究方面得到了广泛的应用。为提高磁性纳米粒子的稳定性,本领域技术人员通常采用的技术解决手段是在磁性纳米粒子包裹一层聚合物材料外壳来制备聚合物磁性纳米粒子。该外壳不仅可保护Fe3O4内核不受外部化学环境的氧化或酸蚀等影响;同时也防止了磁性纳米粒子发生聚集。然而,随着对聚合物磁性纳米粒子的深入研究,发现其在实现诊断治疗过程中还存在一些制约磁性纳米粒子大规模临床应用的缺陷:
(1)聚合物外壳无法降解。用聚合物材料作为外壳包裹磁性纳米粒子来形成聚合物磁性纳米粒子的技术,虽然具有方法简单,纳米粒子结构清楚等优点,但其形成的聚合物外壳一般无降解功能,很容易在人体中发生聚集,从而引起对肝、肾等器官的毒性(FangC.,Kievit F.M.,Veiseh O.,Stephen Z.R.,Wang T.,Lee D.,Ellenbogen R.G.,ZhangM.Fabrication of magnetic nanoparticles with controllable drug loading andrelease through a simple assembly approach.Journal of ControlledRelease.2012,162:233–241)。
(2)纳米粒子稳定性不足。传统技术一般是利用聚合物材料与磁性纳米粒子之间的非共价键作用来形成聚合物磁性纳米粒子。这一技术虽然简便,但是由于形成的非共价键作用本身不够稳定,使得所制备的聚合物磁性纳米粒子会在人体体液稀释作用下,在温度、离子浓度、pH值等影响因素下易崩解,使聚合物外壳与磁性纳米粒子容易分离,稳定性很差,不能实现其在人体内长期循环的要求。另一方面,传统技术中一般采取透析法,利用聚合物的亲疏水性、氢键等弱作用力来包裹药物,实现对药物分子的传递。由于这种技术手段所形成的药物与聚合物之间的相互作用力较弱,药物的负载稳定性也较差,常常会在正常组织和细胞处将较多的药物提前释放,故此类磁性纳米粒子普遍存在对正常组织细胞的毒副作用(Chen J.,Shi M.,Liu P.,Ko A.,Zhong W.,Liao W.,Xing M.,M.Q.Reduciblepolyamidoamine-magnetic iron oxide self-assembled nanoparticles fordoxorubicin delivery.Biomaterials,2014,35:1240–1248)。
(3)无靶向功能,使载药后聚合物磁性纳米粒子不能进行准确释药。由于传统上一般是采用聚乙二醇、聚(N-异丙基丙烯酰胺)等亲水性聚合物作为聚合物磁性纳米粒子的外壳,从而保持其在溶液中的稳定性。虽然该技术具有制备方法简单的优点,但其制备的聚合物磁性纳米粒子无靶向功能,不能将聚合物磁性纳米粒子有效传递进入靶向细胞,释药杀伤肿瘤细胞。因此,载药的聚合物磁性纳米粒子在正常组织和细胞处易发生聚集,存在毒副作用的风险(尚乐,周庆翰.多功能磁性纳米药物载体的制备及表征.西南民族大学学报(自然科学版),2016,42(5):531-537)。
(4)造影效果不佳。传统技术制备的聚合物磁性纳米粒子,因聚合物材料与磁性纳米粒子之间的相互作用力较弱(如疏水键、氢键等非共价键力),其包裹的磁性纳米粒子含量偏少,导致橫向弛豫性能(r2)偏低,造影效果不佳,影响了聚合物磁性纳米粒子作为磁性造影的临床应用(Liu Y.,Yang K.,Cheng L.,Zhu J.,Ma X.,Xu H.,Li Y.,Guo L.,Gu H.,Liu Z.PEGylated FePt@Fe2O3core-shell magnetic nanoparticles:Potentialtheranostic applications and in vivo toxicity studies.Nanomedicine:Nanotechnology,Biology,and Medicine,2013,9:1077–1088)。
发明内容
本发明的目的是针对上述现有聚合物磁性纳米粒子存在的问题,提供一种可降解聚合物磁性纳米粒子,即其聚合物外壳可降解,且与磁性纳米粒子通过配位键结合稳定,药物的负载稳定性好,具有靶向功能以及造影效果好的特点。
本发明另一目的是提供上述可降解聚合物磁性纳米粒子的制备方法。
本发明提供的一种可降解聚合物磁性纳米粒子,该纳米粒子是以含双乙烯基二硫键的化合物作为偶联剂,将多巴胺、抗肿瘤药物基团、靶向功能基团通过共价键连接的方式与该偶联剂主链相连,并聚合制成可降解外壳,再通过可降解外壳上的多巴胺与四氧化三铁纳米粒子表面进行配位键结合,将可降解外壳化学包裹在四氧化三铁纳米粒子外表面上,该可降解聚合物磁性纳米粒子最高载药量为857μg抗肿瘤药物每毫克铁,且在加入谷胱甘肽(GSH)的条件下药物累计释放量最高为79.1%。
上述含双乙烯基二硫键的化合物为N,N'-双(丙稀酰)胱胺(BACy)。
上述抗肿瘤药物基团为盐酸阿霉素(DOX)基团。
上述靶向功能基团为叶酸聚乙二醇(FA-PEG-NH2)基团。
本发明提供的制备上述可降解聚合物磁性纳米粒子方法的工艺步骤和条件如下:
(1)参照现有技术制备得四氧化三铁纳米粒子;
(2)按质量份数计,将含双乙烯基二硫键的偶联剂5~15份,盐酸多巴胺(DA)2~10份,抗肿瘤药物2~10份,氨基聚乙二醇(mPEG-NH2)10~50份,靶向修饰剂2~10份混合均匀,同时将三乙胺溶解于溶剂I中配置成体积浓度为0.5~1%的三乙胺溶液,然后再将三乙胺溶液滴加入上述混合物中,并在氮气保护下于20~50℃反应20~48小时,所得粗产物用溶剂I洗涤沉淀,沉淀物溶解于去离子水中透析,冷冻干燥得到的暗红色固体即为可降解聚合物;
(3)按质量份数计,将步骤(2)所得可降解聚合物10~20份溶解在溶剂II中配置成质量体积浓度为0.05~0.10g/L的溶液,并加入2~10份步骤(1)所得四氧化三铁纳米粒子混合,然后将混合物溶解于四氢呋喃形成以可降解聚合物质量计浓度为0.6~1.4mg/mL的溶液,于氮气保护下,室温避光搅拌反应24~48小时,离心分离混合溶液得到粗产品,利用去离子水对粗产品进行洗涤、透析,冷冻干燥后得到可降解聚合物磁性纳米粒子;
其中,所述的溶剂I为N,N-二甲基甲酰胺(DMF)、四氢呋喃(THF)、二甲基亚砜(DMSO)、乙酸乙酯、二氯甲烷或乙醚中的任一种;
其中,所述的溶剂II为N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺或二甲基亚砜(DMSO)中的任一种。
上述步骤(1)中所述参照现有技术制备得四氧化三铁纳米粒子具体是参照文献(陈亭汝,孙瑾.Fe3O4磁性纳米粒子的共沉淀法制备研究[J].应用化工,2009,38(2):227-228.)中所记载的方法制备的,为了适应本发明,调整其工艺参数如下:
将FeCl3·6H2O和FeSO4按照摩尔比为1:(1~10)混合,并溶解于去离子水中配制成0.5~2g/mL的溶液,然后在氮气气氛且温度为50~90℃下,边搅拌边加入以去离子水体积计2~10%的碱液,反应30~60min,再加入以去离子水体积计2~6%的油酸,继续反应3~6h,所得粗产品经磁铁收集后,再用去离子水洗涤、离心分离、干燥即得四氧化三铁纳米粒子。其中所用碱液为市售浓度为25~28%的浓氨水或配制的浓度为10%的氢氧化钠溶液。
上述步骤(2)中所述的含双乙烯基二硫键的偶联剂为N,N'-双(丙稀酰)胱胺(BACy),其是参考文献(Pan Y.J.,Chen Y.Y.,Wang D.R.,Wei C.,Guo J.,Lu D.R.,ChuC.C.,Wang C.C.Redox/pH dual stimuli-responsive biodegradable nanohydrogelswith varying responses to dithiothreitol and glutathione for controlled drugrelease.Biomaterials,2012,33:6570–6579)所公开的方法制备的。
上述步骤(2)中所述的抗肿瘤药物为盐酸阿霉素(DOX)。
上述步骤(2)中所述的靶向修饰剂为叶酸聚乙二醇(FA-PEG-NH2)。
本发明具有以下有益效果:
(1)由于本发明制备工艺中所采用含双乙烯基二硫键偶联剂是由胱胺二盐酸盐与丙烯酰氯进行缩合反应而制得,其不仅可作为直链式偶联剂,在磁性粒子聚合物外壳上形成主链,并与DOX、叶酸聚乙二醇进行链接,而且因其上含有二硫键结构,还可在谷胱甘肽(GSH)作用下被还原成-SH基,因而可使得其制成的聚合物外壳既能同时承载药物和靶向修饰剂,又具有还原响应性,解决了传统聚合物磁性纳米粒子载药体在人体内难以降解的问题。
(2)由于本发明在制备可降解聚合物外壳的技术方案中,其合成原理是采用的麦克尔(Michael)加成反应技术,即是直接将多巴胺与聚合物主链进行链接,而链接的多巴胺又能够与四氧化三铁纳米粒子表面通过配位键进行牢固结合,因而使得聚合物外壳与磁性纳米粒子的联结具有良好的稳定性,解决了传统聚合物磁性纳米粒子在人体体液稀释、温度、离子浓度、pH值等影响因素下容易崩解、诊断效率低的问题。
(3)由于本发明能够通过麦克尔加成反应技术,将药物盐酸阿霉素(DOX)与聚合物主链通过共价键进行链接,因而使得药物负载稳定性较高,不仅在正常生理条件下聚合物外壳负载的药物不释放,且当聚合物磁性纳米粒子进入细胞后就可在谷胱甘肽(GSH)作用下降解,快速释放盐酸阿霉素(DOX),杀伤肿瘤细胞,解决了传统聚合物磁性纳米粒子载药稳定性差、提前释药的问题。
(4)由于本发明通过麦克尔加成反应技术还能将叶酸聚乙二醇与聚合物主链进行链接,而叶酸基团可与肿瘤细胞表面的叶酸受体结合,因而使得聚合物磁性纳米粒子能够有效传递进入靶向肿瘤细胞,解决了现有技术中聚合物磁性纳米粒子无靶向功能,易在正常组织和细胞处发生聚集,存在毒副作用的问题。
(5)由于本发明制备方法能将可降解聚合物与四氧化三铁纳米粒子二者间利用配体交换反应技术制备得到可降解聚合物磁性纳米粒子,这不仅使四氧化三铁纳米粒子可在聚合物外壳包裹作用下形成磁性粒子簇,进而发生磁耦合现象,因而可有效提高其作为磁共振成像造影剂的橫向弛豫性能(r2),解决了传统聚合物磁性纳米粒子磁共振成像造影效果不佳的问题。
(6)由本发明提供方法制备所得的聚合物磁性纳米粒子不仅载药量可达857μgDOX每毫克铁,优于同类产品,且在GSH条件下药物累计释放量最高可达79.1%,也高于同类产品。
(7)本发明提供的制备方法简单,条件温和,可控性强,易于操作,便于推广应用。
附图说明
图1是用胱胺二盐酸盐和丙烯酰氯制备得到的含双乙烯基二硫键偶联剂的核磁氢谱图。其中,δ(ppm):6.6(c:酰胺键上的氢),δ(ppm):6.2(b:双键中靠近羰基的碳上的氢),δ(ppm):5.6和6.4(a:双键中远离羰基的碳上的氢),δ(ppm):2.9(靠近二硫键亚甲基上的氢),δ(ppm):3.6(靠近酰胺亚甲基上氢)。结果表明所制备的偶联剂与预期一致。
图2是用盐酸多巴胺,盐酸阿霉素,偶联剂,甲氧基聚乙二醇氨基和叶酸聚乙二醇氨基制备得到的可降解聚合物的核磁氢谱图。其中,δ(ppm):8.5-8.8(多巴胺上酚羟基氢),δ(ppm):8.2(多巴胺上氨基氢),δ(ppm):7-7.8(叶酸苯环上的氢),δ(ppm):6.3-6.6(b、c:多巴胺苯环上的氢),δ(ppm):5.4(阿霉素上酚羟基氢),δ(ppm):4.0(阿霉素上甲氧基上的氢)δ(ppm):3.5(聚乙二醇上的氢),δ(ppm):3.3(多巴胺上氨基相邻碳氢),δ(ppm):2.7(偶联剂二硫键旁碳上的氢)。结果表明所制备的可降解聚合物与预期一致。
图3是含双乙烯基二硫键的偶联剂、四氧化三铁纳米粒子和可降解聚合物磁性纳米粒子的红外光谱谱图。在可降解聚合物磁性纳米粒子的谱图中1650cm-1附近出现的明显酰胺键-羰基特征吸收峰,表明已成功制备可降解聚合物磁性纳米粒子。在可降解聚合物磁性纳米粒子的谱图中580cm-1附近有明显的Fe-O键的特征吸收峰,结果表明已成功制备可降解聚合物磁性纳米粒子。
图4是可降解聚合物磁性纳米粒子在10mM的GSH作用下降解后的粒径变化图。由图可以看出,加入GSH后,其粒径呈现出先逐渐增大的趋势,这是因为GSH使聚合物中的二硫键断裂,纳米粒子发生溶胀,粒径增大。结果表明所制备的可降解聚合物磁性纳米粒子对GSH具有很好的还原响应性。
图5为实施例1中可降解聚合物磁性纳米粒子在室温、pH=7.4条件下,用动态光散射(DLS)测得的一周内粒径变化图。结果表明,随着时间的增加,胶束的粒径没有明显变化,说明该纳米粒子在室温下结构稳定。
图6为可降解聚合物磁性纳米粒子在水中的透射电镜照片,从照片中可见纳米粒子呈球形分布,其平均粒径约120nm左右。结果表明所制备的可降解聚合物磁性纳米粒子在水中分散良好,符合本发明中对纳米粒子的要求。
图7为可降解聚合物磁性纳米粒子在阿霉素/PBS(ph=7.4)/GSH环境下的药物释放曲线图。从图中可见在PBS缓冲液中,载药的可降解聚合物磁性纳米粒子的药物累计释放量只有25.4%,加入GSH后药物累计释放量最高可达79.1%。结果表明,载药的可降解聚合物磁性纳米粒子在GSH作用下,能够快速高效释药。
具体实施方式
下面给出实施例以对本发明作进一步说明。有必要在此指出的是以下实施例不能理解为对本发明保护范围的限制,如果该领域的技术熟练人员根据上述本发明内容对本发明作出一些非本质的改进和调整,仍属于本发明保护范围。
特别说明的是,以下实施例中产品所用表征与处理方法:(1)红外表征所用傅里叶转换红外光谱仪(FTIR)型号为Thermo公司的Nicolet is50,测试时用KBr磨成粉,压片,测试范围400~4000cm-1。(2)核磁表征所用核磁共振谱仪(NMR)的型号为BRUKER-400MHz,测试时以TMS为内标,氘代氯仿(CDCl3)或氘代DMSO为溶剂。(3)动态光散射(DLS)所用仪器型号为Nano-zs90,测量时温度25℃。紫外可见光光度计(UV-Vis):TU1950,测量波长为480nm。透射电子显微镜(TEM)为日立H-600,加速电压为75kv,纳米粒子浓度2mg/mL。(4)处理和分析数据所用软件为ChemDraw,MestReNova,Origin等。(5)以下实施例中所用的浓氨水为浓度25~28%的市售浓氨水,所述氢氧化钠溶液为配制的浓度为10%的氢氧化钠溶液。
实施例1
将摩尔比为1:2的FeCl3·6H2O和FeSO4,加入50mL去离子水中配制成0.7g/mL的溶液,通入氮气并在80℃下进行机械搅拌,然后加入5mL浓氨水反应50min后,再加入油酸1mL,继续反应6h。所得粗产品经磁铁收集后,再用去离子水洗涤、离心分离、干燥即得产品四氧化三铁纳米粒子。
将含双乙烯基二硫键的偶联剂130mg、DA 72mg、DOX 70mg、mPEG-NH2 328mg、FA-PEG-NH2 52mg混合均匀,同时将50μL三乙胺溶解于10mL DMSO配置成体积浓度为0.5%的溶液,再滴加入上述混合物中,并在氮气保护下于20℃反应20小时。反应结束后粗产品用乙醚洗涤沉淀,沉淀物溶解于去离子水中透析,冷冻干燥得到暗红色固体即为可降解聚合物。
将可降解聚合物20mg溶解于200μL DMSO中,并加入2mg四氧化三铁纳米粒子混合,然后将混合物溶解于20mL的THF中,于氮气保护下,室温避光搅拌反应24小时,离心分离得到粗产品,利用去离子水对粗产品进行洗涤、透析、冷冻干燥后得到可降解聚合物磁性纳米粒子。
实施例2
将摩尔比为1:3的FeCl3·6H2O和FeSO4,加入50mL去离子水中配制成0.5g/mL的溶液,通入氮气并在50℃下进行机械搅拌,然后加入4mL浓氨水反应40min后,再加入油酸1mL,继续反应4h。所得粗产品经磁铁收集后,再用去离子水洗涤、离心分离、干燥即得产品四氧化三铁纳米粒子。
将含双乙烯基二硫键的偶联剂50mg、DA20mg、DOX20mg、mPEG-NH2 100mg、FA-PEG-NH2 20mg混合均匀,同时将80μL三乙胺溶解于10mL DMSO配置成体积浓度为0.8%的溶液,再滴加入上述混合物中,并在氮气保护下于30℃反应48小时。反应结束后粗产品用乙醚洗涤沉淀,沉淀物溶解于去离子水中透析,冷冻干燥得到暗红色固体即为可降解聚合物。
将可降解聚合物10mg溶解于200μL DMSO中,并加入10mg四氧化三铁纳米粒子混合,然后将混合物溶解于14mL的THF中,于氮气保护下,室温避光搅拌反应48小时,离心分离得到粗产品,利用去离子水对粗产品进行洗涤、透析、冷冻干燥后得到可降解聚合物磁性纳米粒子。
实施例3
将摩尔比为1:4的FeCl3·6H2O和FeSO4,加入50mL去离子水中配制成1g/mL的溶液,通入氮气并在90℃下进行机械搅拌,然后加入1mL氢氧化钠溶液反应30min后,再加入油酸3mL,继续反应5h。所得粗产品经磁铁收集后,再用去离子水洗涤、离心分离、干燥即得产品四氧化三铁纳米粒子。
将含双乙烯基二硫键的偶联剂150mg、DA 100mg、DOX 100mg、mPEG-NH2 500mg、FA-PEG-NH2 100mg混合均匀,同时将90μL三乙胺溶解于10mL DMF配置成体积浓度为0.9%的溶液,再滴加入上述混合物中,并在氮气保护下于50℃反应36小时。反应结束后粗产品用乙醚洗涤沉淀,沉淀物溶解于去离子水中透析,冷冻干燥得到暗红色固体即为可降解聚合物。
将可降解聚合物14mg溶解于200μL DMF中,并加入5mg四氧化三铁纳米粒子混合,然后将混合物溶解于10mL的THF中,于氮气保护下,室温避光搅拌反应36小时,离心分离得到粗产品,利用去离子水对粗产品进行洗涤、透析、冷冻干燥后得到可降解聚合物磁性纳米粒子。
实施例4
将摩尔比为1:1的FeCl3·6H2O和FeSO4,加入50mL去离子水中配制成1.5g/mL的溶液,通入氮气并在70℃下进行机械搅拌,然后加入3mL氢氧化钠溶液反应30min后,再加入油酸2mL,继续反应3h。所得粗产品经磁铁收集后,再用去离子水洗涤、离心分离、干燥即得产品四氧化三铁纳米粒子。
将含双乙烯基二硫键的偶联剂110mg、DA36mg、DOX35mg、mPEG-NH2 164mg、FA-PEG-NH2 26mg混合均匀,同时将100μL三乙胺溶解于10mL DMF配置成体积浓度为1.0%的溶液,再滴加入上述混合物中,并在氮气保护下于40℃反应40小时。反应结束后粗产品用乙醚洗涤沉淀,沉淀物溶解于去离子水中透析,冷冻干燥得到暗红色固体即为可降解聚合物。
将可降解聚合物12mg溶解于200μL DMSO中,并加入8mg四氧化三铁纳米粒子混合,然后将混合物溶解于20mL的THF中,于氮气保护下,室温避光搅拌反应40小时,离心分离得到粗产品,利用去离子水对粗产品进行洗涤、透析、冷冻干燥后得到可降解聚合物磁性纳米粒子。
实施例5
将摩尔比为1:10的FeCl3·6H2O和FeSO4,加入50mL去离子水中配制成2g/mL的溶液,通入氮气并在60℃下进行机械搅拌,然后加入1mL氢氧化钠溶液反应60min后,再加入油酸3mL,继续反应6h。所得粗产品经磁铁收集后,再用去离子水洗涤、离心分离、干燥即得产品四氧化三铁纳米粒子。
将含双乙烯基二硫键的偶联剂130mg、DA56mg、DOX65mg、mPEG-NH2 204mg、FA-PEG-NH2 66mg混合均匀,同时将50μL三乙胺溶解于10mLTHF配置成体积浓度为0.5%的溶液,再滴加入上述混合物中,并在氮气保护下于50℃反应24小时。反应结束后粗产品用乙醚洗涤沉淀,沉淀物溶解于去离子水中透析,冷冻干燥得到暗红色固体即为可降解聚合物。
将可降解聚合物18mg溶解于200μL DMSO中,并加入6mg四氧化三铁纳米粒子混合,然后将混合物溶解于20mL的THF中,于氮气保护下,室温避光搅拌反应24小时,离心分离得到粗产品,利用去离子水对粗产品进行洗涤、透析、冷冻干燥后得到可降解聚合物磁性纳米粒子。
Claims (9)
1.一种可降解聚合物磁性纳米粒子,其特征在于该纳米粒子是以含双乙烯基二硫键的化合物作为偶联剂,将多巴胺、抗肿瘤药物基团、靶向功能基团通过共价键连接的方式与该偶联剂主链相连,并聚合制成可降解外壳,再通过可降解外壳上的多巴胺与四氧化三铁纳米粒子表面进行配位键结合,将可降解外壳化学包裹在四氧化三铁纳米粒子外表面上,该可降解聚合物磁性纳米粒子最高载药量为857μg抗肿瘤药物每毫克铁,且在加入谷胱甘肽(GSH)的条件下药物累计释放量最高为79.1%。
2.根据权利要求1所述可降解聚合物磁性纳米粒子,其特征在于所述含双乙烯基二硫键的化合物为N,N'-双(丙稀酰)胱胺。
3.根据权利要求1或2所述可降解聚合物磁性纳米粒子,其特征在于所述抗肿瘤药物基团为盐酸阿霉素基团。
4.根据权利要求1或2所述可降解聚合物磁性纳米粒子,其特征在于所述靶向功能基团为叶酸聚乙二醇基团。
5.一种可降解聚合物磁性纳米粒子的制备方法,其特征在于该方法的工艺步骤和条件如下:
(1)参照现有技术制备得四氧化三铁纳米粒子;
(2)按质量份数计,将含双乙烯基二硫键的偶联剂5~15份,盐酸多巴胺(DA)2~10份,抗肿瘤药物2~10份,氨基聚乙二醇10~50份,靶向修饰剂2~10份混合均匀,同时将三乙胺溶解于溶剂I中配置成体积浓度为0.5~1%的三乙胺溶液,然后再将三乙胺溶液滴加入上述混合物中,并在氮气保护下于20~50℃反应20~48小时,所得粗产物用溶剂I洗涤沉淀,沉淀物溶解于去离子水中透析,冷冻干燥得到的暗红色固体即为可降解聚合物;
(3)按质量份数计,将步骤(2)所得可降解聚合物10~20份溶解在溶剂II中配置成质量体积浓度为0.05~0.10g/L的溶液,并加入2~10份步骤(1)所得四氧化三铁纳米粒子混合,然后将混合物溶解于四氢呋喃形成以可降解聚合物质量计浓度为0.6~1.4mg/mL的溶液,于氮气保护下,室温避光搅拌反应24~48小时,离心分离混合溶液得到粗产品,利用去离子水对粗产品进行洗涤、透析,冷冻干燥后得到可降解聚合物磁性纳米粒子;
其中,所述的溶剂I为N,N-二甲基甲酰胺、四氢呋喃、二甲基亚砜、乙酸乙酯、二氯甲烷或乙醚中的任一种;
其中,所述的溶剂II为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲基亚砜中的任一种。
6.根据权利要求5所述可降解聚合物磁性纳米粒子的制备方法,其特征在于该方法步骤(1)中所述参照现有技术制备得四氧化三铁纳米粒子,是将FeCl3·6H2O和FeSO4按照摩尔比为1:(1~10)混合,并溶解于去离子水中配制成0.5~2g/mL的溶液,然后在氮气气氛且温度为50~90℃下,边搅拌边加入以去离子水体积计2~10%的碱液,反应30~60min,再加入以去离子水体积计2~6%的油酸,继续反应3~6h,所得粗产品经磁铁收集后,再用去离子水洗涤、离心分离、干燥即得四氧化三铁纳米粒子。其中所用碱为市售浓度为25~28%的浓氨水或浓度为10%的氢氧化钠。
7.根据权利要求5或6所述可降解聚合物磁性纳米粒子的制备方法,其特征在于该方法步骤(2)中所述含双乙烯基二硫键的偶联剂为N,N'-双(丙稀酰)胱胺。
8.根据权利要求5或6所述可降解聚合物磁性纳米粒子的制备方法,其特征在于该方法步骤(2)中所述抗肿瘤药物为盐酸阿霉素;所述靶向修饰剂为叶酸聚乙二醇。
9.根据权利要求7所述可降解聚合物磁性纳米粒子的制备方法,其特征在于该方法步骤(2)中所述抗肿瘤药物为盐酸阿霉素;所述靶向修饰剂为叶酸聚乙二醇。
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