CN107823650A - 葡萄糖修饰的新型脑靶向磁性纳米粒的制备 - Google Patents
葡萄糖修饰的新型脑靶向磁性纳米粒的制备 Download PDFInfo
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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Abstract
发明公开了一种以葡萄糖修饰的新型脑靶向磁性纳米粒的制备,为通式(I)所示结构或其药学上可接受的盐或水合物:,其中:X代表一端羧基化的聚乙二醇PEG,可以是三甘醇、四甘醇或聚乙二醇PEG分子量为200、400、600、800、1000、1500、2000、4000等;Y代表‑(CH2)a‑、‑C(O)‑(CH2)a‑C(O)‑或‑O‑(CH2)b‑、‑NH‑(CH2)b‑、‑C(O)‑(CH2)b‑、‑C(O)‑(CH2)b‑C(O)‑,a表示0~6,b表示1~4;MNPs代表Fe3O4、γ‑Fe2O3、MnFe2O4、CoFe2O4和ZnFe2O4等;Drug代表可作用于中枢神经系统的药物。本发明提供一种以葡萄糖修饰的新型脑靶向磁性纳米粒的制备方法,可作为载体用于中枢神经系统疾病的治疗,既有四氧化三铁纳米粒的磁靶向作用,还有葡萄糖的主动脑靶向作用。
Description
技术领域
本发明涉及一种新型脑靶向磁性纳米粒的制备方法,属于医药技术领域。
背景技术
据统计,全球约有1/5的人口患有不同种类和程度的中枢神经系统(CNS)疾病,这些疾病包括脑肿瘤、急性或慢性疼痛综合症、癫痫、脑炎,脑缺血以及神经衰退性疾病(如:阿尔茨海默症、帕金森氏症等)。随着世界人口的老龄化,这一趋势将会更加严重,并且会对人类的健康造成严重的影响。血脑屏障(BBB)的存在对人类中枢神经系统起到了一定的保护作用,但同时也限制了许多物质从血液中进入脑部。几乎所有大分子和95%的小分子药物都不能有效进入大脑及中枢神经系统,这使得对CNS有效的药物很难进入CNS病灶部位并呈现有效的药物浓度从而达到治疗效果。
据报道非甾体抗炎药(Non-Steroidal Anti-Inflammatory Drugs,NSAIDs)如布洛芬、萘普生等神经保护剂已经被广泛用于治疗CNS疾病,也可用作慢性摄入型非甾体抗炎药。例如,布洛芬能够降低CNS疾病的风险,甚至能够延缓CNS疾病的发病,所以布洛芬在治疗CNS紊乱方面具有广阔发展前景。但是,由于布洛芬的低渗透性,在CNS中的分布有限,有效的治疗浓度低,为了达到较好的治疗效果需要增加药物的剂量,使药物在体内达到一个较高的浓度,但与此同时其它器官的药物浓度也会增加,毒副反应也随之增加,对身体产生更大的危害。长期使用这些药物,便会产生不同程度的胃肠道不适,头晕,头痛,甚至肾毒性等的不良反应。这些不良反应主要是由于药物在体内的分布,当药物在外周器官分布较多时,容易产生各种毒副反应,同时也降低了其在脑组织中的分布比例,所以布洛芬的临床应用受到了很大限制。因此,为了治疗CNS疾病,需要找到一种有效的策略以提高布洛芬的在大脑中的输运能力。
血-脑屏障(blood-brain barrier,BBB)是存在于血-脑,血-脑脊液(BCB)及脑-脑脊液之间选择性控制进入脑脊液和脑的物质,作为血液与中枢神经系统之间的调节界面,对维持中枢神经系统内的环境恒定有至关重要的作用。这使得对CNS有效的药物很难进入CNS 病灶部位并呈现有效的药物浓度从而达到治疗效果。因此对跨BBB给药方式的研究已经成为治疗CNS疾病的关键。研究表明,这些特异性转运蛋白具有较高的选择性,通常特定的载体蛋白只能转运特定的底物。
葡萄糖是哺乳动物细胞的主要能源来源之一,大脑尽管只有体重的2%,却占据了约人体消耗葡萄糖总量的30%。研究显示,血脑屏障上葡萄糖转运蛋白(GLUT1)数量很多,大约每个脑血管内皮细胞含有6×106个GLUT1分子,是BBB上所有转运蛋白中数量最多的。GLUT1一级结构显示,它有12个跨膜螺旋结构,形成了贯穿双层脂质膜的亲水性的通道,允许D-葡萄糖和其他己糖通过。在BBB上高度表达的GLUT1转运效率非常高,其每分钟转运的葡萄糖质量是自身质量的十倍,因此成为目前脑靶向药物修饰时经常考虑的靶点。研究发现,当葡萄糖6位与药物连接时,其与GLUT1的亲和力最强,说明药物与6位羟基连接能够最大程度的保留葡萄糖与GLUT1的亲和活性。葡萄糖修饰后的CNS类药物也表现出比母体药物更好的活性,如抗惊厥药7-Cl-Kyn、非甾体抗炎药布洛芬、帕金森综合症治疗药物多巴胺与葡萄糖偶合后其在脑内的分布都明显提高,这些结果都表明以葡萄糖为载体、 GLUT1为靶点的前药是脑靶向药物设计的有效手段。
磁靶向给药系统(magnetic targeting drug delivery system,MTDDS)是指将药物和磁性物质共同包裹于聚合物载体中制成的,应用于体内后利用外加磁场的效应引导药物在体内定向移动和定位集中,在磁场区释放药物,从而起到靶区局部浓集作用或靶区截流作用的药物制剂。20世纪70年代Widder等提出磁控靶向药物传递系统的概念,并首先开展了载药磁性微粒的研究。1994年,德国Lǜbbe等第一次将磁性靶向治疗应用于临床。磁性材料如铁、铁氧化物、镍、钴等通过有机或无机材料的表面修饰、包覆等作用,形成了具有特定功能的复合粒子并广泛用于生物医学领域。氧化铁纳米粒,因具有良好的生物相容性和简易的合成方法,目前已被广泛的研究并应用于生物医学领域,如细胞标记、细胞分离和净化、靶向药物传输、核磁共振成像、肿瘤细胞的磁热治疗等,最具有代表性的氧化铁纳米粒为Fe3O4和γ-Fe2O3,可以在人体组织中通过降解贮存或排出体外,具有良好的生物安全性,是目前临床应用和研究最广泛的磁性纳米粒子。当今国际上报道的用于治疗脑部疾病的磁靶向治疗药物或载体有磁靶向作用,但只能靠扩散作用,而不能特异性的靶向透过BBB,进入脑中发挥治疗作用。如果将磁性纳米粒应用到葡萄糖修饰的材料上,即形成葡萄糖介导的脑靶向磁性纳米粒。这类药物不仅克服了磁性纳米粒的无脑靶向性的难题,同时也增加了药物在血脑屏障附近的药物浓度,有利于药物通过葡萄糖转运进入脑,有望增加药物在脑中的浓度,从而提供更为有效的治疗。
发明内容
本发明的目的是提出一种新型的基于葡萄糖修饰的具有主动脑靶向的磁性纳米药物载体,以提高药物的脑靶向性,增加药物的中枢浓度,从而增强药物疗效,同时降低了药物在外周器官的分布,减少了药物的毒副作用。因此,我们设计了如通式(I)所示的一类磁性纳米粒,旨在设计并制备这类脑靶向的磁性纳米粒。
本发明提供一类通式(I)所示结构的化合物或其药学上可接受的盐或水合物:
其中:
X代表一端羧基化的聚乙二醇PEG,可以是三甘醇、四甘醇或聚乙二醇PEG分子量为200、400、600、800、1000、1500、2000、4000等;
Y代表-(CH2)a-、-C(O)-(CH2)a-C(O)-或-O-(CH2)b-、-NH-(CH2)b-、-C(O)-(CH2)b-、-C(O)- (CH2)b-C(O)-,a表示0~6,b表示1~4;
MNPs代表Fe3O4、γ-Fe2O3、MnFe2O4、CoFe2O4和ZnFe2O4等;
Drug代表可作用于中枢神经系统的药物。
通式(I)所示化合物的具体制备方法如下所示:
具体实施方法
但以下实施例旨在说明本发明而不是对本发明的进一步限定。
实施例1
油酸包裹的Fe3O4磁性纳米粒(MNPs-OA)的制备
精密称取4.00g FeCl3·6H2O,1.47g FeCl2·4H2O加入到120ml的去离子水中,在氮气保护作用下,搅拌溶解完全,然后迅速加入40ml的25%的氨水,溶液从黄色变成黑色。向溶液中加入1ml的油酸(OA),搅拌5min,再加入到80℃油浴中反应1h。反应结束后待溶液冷却至室温,离心得黑色沉淀,并用正己烷、甲醇洗涤,得到油酸包裹的Fe3O4磁性纳米粒(MNPs-OA)。
实施例2
多巴胺功能化的Fe3O4磁性纳米粒(MNPs-APS)的制备
称取0.21g前面制备的MNPs-OA纳米颗粒加入10ml甲苯中,并加入3-氨丙基三甲氧基硅烷(0.2ml)和三乙胺(0.2ml),室温下搅拌反应12小时。磁铁分离,并用甲苯和二氯甲烷洗涤,60℃干燥即得MNPs-APS。
实施例3
化合物2的制备
冰浴下,将三甲基氯硅烷(128ml,1mol)和六甲基二硅烷胺(105ml,0.5mol)的混合溶液缓慢滴加至D-葡萄糖(30g,0.167mol)吡啶溶液(230ml)中,室温搅拌过夜。减压除去溶剂,加水,乙酸乙酯萃取水层,有机层依次用1N HCl溶液、饱和食盐水洗涤,无水Na2SO4干燥,浓缩后得黄色油状物87.3g,收率96.6%,产品可不经纯化直接进行下一步反应。MS(m/z):491.5[M+Na]+。
实施例4
化合物3的制备
冰浴下,向化合物12(20g,37mmol)的丙酮/甲醇(50ml/80ml)溶液中缓慢滴加乙酸(4.2ml, 74mmol)的丙酮/甲醇(5ml/8ml)溶液,约8min滴毕。将反应移至室温反应2h后,减压除去溶剂得粗品。柱层析纯化,得白色半固体13.04g,收率75.2%。
实施例5
化合物5的制备
将丁二酸单苄酯(5.00g,24.01mmol)溶于二氯甲烷(50ml)中,加入DCC(7.42g,36.02mmol)和DMAP(0.59g,4.80mmol),于-5℃下活化30min后,加入四甘醇(18.65g,96.06mmol),移至室温继续搅拌反应2h。过滤,滤液浓缩,残留物经柱层析纯化得到无色油状物7.66g,收率83%。1H NMR(600MHz,CDCl3)δH(ppm)2.06(br,1H),2.69(s,4H), 3.60-3.73(m,14H),4.24(t,2H,J=4.8Hz),5.14(s,2H),7.32-7.38(m,5H)。
实施例6
化合物6的制备
将Fmoc-L-谷氨酸-γ-叔丁酯(2.00g,4.70mmol)溶解于30ml二氯甲烷,置于-5℃下,加入DCC(1.93g,9.40mmol)和DMAP(0.11g,0.94mmol),搅拌30min后,加入化合物5 (2.00g,7.05mmol),移至室温搅拌20h。过滤,除去白色固体,滤液浓缩,经柱层析纯化得到白色固体2.08g,收率56%。1H NMR(600MHz,CDCl3)δH(ppm)1.45(s,9H),1.94- 2.00(m,1H),2.15-2.20(m,1H),2.28-2.39(m,2H),2.68(s,4H),3.62-3.71(m,12H),4.22(dd,4H, J=8.4,4.8Hz),4.30-4.43(m,4H),5.13(s,2H),5.56(d,1H,J=7.8Hz),7..30-7.41(m,9H),7.60(t, 2H,J=6.6Hz),7.76(d,2H,J=7.2Hz)。
实施例7
化合物7的制备
将化合物6(1.12g,1.41mmol)溶于15ml二氯甲烷,加入DBU(0.64ml,4.23mmol),室温搅拌15min。反应液用饱和碳酸氢钠溶液洗涤,有机层用无水硫酸钠干燥,浓缩,经柱层析纯化得到无色油状物0.73g,收率88%。1H NMR(600MHz,CDCl3)δH(ppm)1.44(s,9H), 1.78-1.85(m,3H),2.01-2.07(m,1H),2.37(t,2H,J=1.8Hz),2.68(s,4H),,3.49-3.53(m,1H),3.60-3.73(m,12H),4.24(t,2H,J=4.8Hz),4.28(t,2H,J=4.8Hz),5.13(s,2H),7.32-7.38(m,5H)。
实施例8
化合物8的制备
将布洛芬(0.23g,1.11mmol)溶解于10ml二氯甲烷,置于-10℃下,加入IBCF(0.17g,1.21mmol)和NMM(0.12g,1.21mmol),搅拌30min后,加入化合物7(0.58g,1.01 mmol),移至室温搅拌过夜。过滤,除去白色固体,滤液浓缩,经柱层析纯化得到无色油状物0.54g,收率70%。1H NMR(400MHz,CDCl3)δH(ppm)0.89(d,6H,J=6.8Hz),1.40(s, 9H),1.49(d,3H,J=7.2Hz),1.78-1.88(m,2H),2.04-2.20(m,3H),2.45(d,2H,J=7.2Hz),2.68(s, 4H),3.56(q,1H,J=7.2Hz),3.65-3.68(m,12H),4.22-4.28(m,4H),4.54-4.59(m,1H),5.13(s,2H),6.16(d,1H,J=7.6Hz),7.10(d,2H,J=8.0Hz),7.20(d,2H,J=8.0Hz),7.31-7.38(m,5H)。
实施例9
化合物9的制备
将化合物8(0.29g,0.38mmol)溶于5ml二氯甲烷,加入三氟乙酸(3ml),室温搅拌1h。反应液浓缩,得到无色油状物0.26g,收率97%。1H NMR(600MHz,CDCl3)δH(ppm)0.89 (dd,6H,J=9.2,6.8Hz),1.49(d,3H,J=7.2Hz),1.78-2.21(m,3H),2.29-2.50(m,4H),2.66(s,4H),3.55-3.84(m,14H),4.14-4.28(m,4H),4.58(q,1H,J=6.8Hz),5.12(s,2H),6.33(d,1H,J=7.2Hz), 7.10(d,2H,J=7.6Hz),7.19(d,2H,J=7.6Hz),7.30-7.35(m,5H)。
实施例10
将化合物9(0.16g,0.23mmol)溶于15ml二氯甲烷,加入EDCI(87mg,0.45mmol)、 DMAP(56mg,0.45mmol)和DIPEA(0.12g,0.91mmol),室温下搅拌30min后,加入化合物3(0.21g,0.45mmol),继续室温搅拌过夜。过滤,滤液浓缩,经柱层析纯化得到无色油状物50mg,收率70%。1H NMR(400MHz,CDCl3)δH(ppm)0.06-0.14(m,36H),0.88(d, 6H,J=6.6Hz),1.48(dd,3H,J=7.2,3.0Hz),1.81-1.91(m,2H),2.10-2.35(m,3H),2.43(d,2H, J=7.2Hz),2.67(s,4H),3.34-3.41(m,2H),3.55(q,1H,J=7.2Hz),3.61-3.66(m,12H),3.77(t,1H, J=9.0Hz),3.86-3.89(m,1H),3.95-4.00(m,1H),4.21-4.30(m,5H),4.54-4.60(m,1H),4.99(t,1H, J=3.6Hz),5.12(s,2H),6.16(dd,1H,J=20.8,5.2Hz),7.08-7.36(m,9H)。
实施例11
化合物11的制备
将化合物10(80mg,0.07mmol)溶于5ml二氯甲烷,加入三氟乙酸(3ml),室温搅拌2h。反应液浓缩,得到无色油状物57mg,收率95%。1H NMR(600MHz,CDCl3)δH(ppm)0.86 (d,6H,J=6.4Hz),1.21-1.36(m,4H),1.40(d,3H,J=6.8Hz),1.76-1.92(m,2H),2.08-2.30(m,4H),2.42(d,2H,J=8.0Hz),2.64(s,4H),3.60-3.67(m,14H),3.86-3.99(m,1H),4.12-4.47(m,7H), 5.06-5.10(m,3H),7.06-7.33(m,9H),8.20-8.30(m,1H)。
实施例12
化合物12的制备
向化合物11(64mg,0.074mmol)的THF/CH3OH(5:1,6ml)溶液加入Pd/C(10%,20mg),在0.4MPa H2下室温反应2h。滤去Pd/C,浓缩,经柱层析纯化得到无色油状物50mg,收率88%。1HNMR(400MHz,CD3OD)δH(ppm)0.88(d,6H,J=6.4Hz),1.43(t,3H,J=7.2Hz), 1.77-2.04(m,4H),2.14-2.62(m,9H),3.12-3.24(m,1H),3.30-3.72(m,15H),3.94-4.02(m,1H), 4.14-4.26(m,4H),4.33-4.52(m,2H),5.08-5.14(m,1H),7.09(d,2H,,J=8.0Hz),7.25(d,2H, J=8.0Hz)。
实施例13
葡萄糖修饰的Fe3O4磁性纳米粒(MNPs-APS-Glu)的制备
将化合物12(37mg,0.048mmol)溶解于7ml CH2Cl2中,依次分别加入NHS(9mg,0.08mmol)、DCC(15mg,0.073mmol)、DMAP(2mg,0.016mmol)和MNPs-APS(20mg),室温搅拌24小时,磁铁分离并用CH2Cl2洗涤,30℃真空干燥即可得到葡萄糖修饰的Fe3O4磁性纳米粒(MNPs-APS-Glu)。
实施例14
脑靶向磁性纳米粒(MNPs-APS-Glu)的红外表征
Fe3O4磁性纳米粒(MNPs-OA,MNPs-APS和MNPs-APS-Glu)的红外光谱参见图2。 MNPs-OA的红外光谱中,577cm-1处有很强的吸收峰,归属为Fe3O4中的Fe-O振动吸收峰, 2844cm-1和2924cm-1处较强的吸收峰分别归属于油酸的CH2-对称伸缩及不对称伸缩振动峰,以上证明了MNPs-OA合成的成功。MNPs-APS的红外光谱中,1015cm-1和1113cm-1处有很强的吸收峰,归属为Si-O伸缩振动峰,3426cm-1处N-H的伸缩振动进一步说明APS成功在Fe3O4表面聚合形成MNPs-APS。MNPs-APS-Glu的红外光谱中,1634cm-1处C=O伸缩振动证明了化合物12与MNPs-APS之间酰胺键的缩合成功。
实施例15
脑靶向磁性纳米粒(MNPs-APS-Glu)的粒径大小与分布
扫描电镜下观察脑靶向磁性纳米粒的大小及形状,结果参见图3。MNPs-OA和MNPs-APS-Glu都呈近似圆球形,颗粒较为规则,分散性较好,未见明显团聚现象发生。另取适量,用动态光散射分析仪测定纳米粒的粒径大小与分布,测定结果表明,MNPs-OA和MNPs-APS- Glu的粒径大小与扫描电镜结果一致,即MNPs-APS-Glu相对于MNPs-OA,有一个轻微变大的平均粒径。此外,MNPs-APS-Glu和MNPs-OA的分散系数分别为0.125和0.140,表明制备得到的葡萄糖修饰的脑靶向磁性纳米粒大小均匀性良好。
实施例16
脑靶向磁性纳米粒(MNPs-APS-Glu)的磁性表征
磁力学性质测定,结果参见图4。合成的MNPs-OA正己烷溶液具有磁流体的性质,在磁场的作用下,磁溶液向磁场方向定位。精密称取实施例中所得的Fe3O4磁性纳米粒(MNPs-OA,MNPs-APS和MNPs-APS-Glu),放置于JDM-13D磁性测定仪中,随着外磁场的变化,测定纳米粒磁矩的变化情况,并绘制对应的磁滞回线:曲线为过原点的单一曲线,即当外加磁性为0时,没有剩磁;当有外加磁性存在时,产生剩磁。其最大磁饱和强度分别为68emu/g、 37emu/g和32emu/g。
实施例17
脑靶向磁性纳米粒(MNPs-APS-Glu)的细胞毒性考察
将bEnd.3细胞(小鼠脑微血管内皮细胞)复苏后,用含10%胎牛血清的DMEM培养基, 37℃,5%CO2的环境下培养两周,每隔一天换液一次。用培养基分别将Fe3O4磁性纳米粒(MNPs-OA,MNPs-APS和MNPs-APS-Glu)和化合物12逐步稀释为6.125μg/ml、12.5μg/ml、25μg/ml、50μg/ml、100μg/ml和200μg/ml的溶液备用。将C6细胞以2×103个/孔的密度接种于96孔板内,培养24h后,分别加入上述系列浓度的载多西紫杉醇的脂质体或多西紫杉醇溶液继续孵育24h。孵育结束后,弃去培养基,向细胞孔内加入20μl 5mg/ml的MTT溶液,于37℃条件下孵育4h后,小心吸去上层培养基,加入150μl DMSO,于37℃恒温空气摇床中缓慢振摇30min后,置酶标仪中测定490nm波长处的吸光度值A测定。以DMSO的吸光度值A空白作为空白,以未加药处理的细胞孔同法操作测得的吸光度值A对照作为对照,计算各孔细胞的存活率,存活率(%)=(A测定-A空白)/(A对照-A空白)×100%。结果表明,所有的材料在0-200μg/ml的浓度下,均未见明显毒性。
实施例18
脑靶向磁性纳米粒(MNPs-APS-Glu)的释药行为
精密称取实施例中所得的葡萄糖修饰的脑靶向磁性纳米粒(MNPs-APS-Glu),分别加入到不同的释放介质中(pH 2.5、5.0、7.4和8.0的磷酸盐缓冲液,以及小鼠血浆和脑匀浆),于预定的时间点取样,分别通过HPLC检测布洛芬的含量。结果表明,在pH7.4的缓冲液中,布洛芬释放最为缓慢,从而保证了药物在生理环境下的稳定以及有足够的时间到达靶部位。此外,在血浆和脑匀浆的释放行为表明,磁性纳米粒在脑匀浆的释放要快于血浆,从而避免磁性纳米粒在脑部的过度蓄积。
附图说明
图1本发明实施例12中化合物12结构的1H-NMR谱图
图2本发明实施例14中磁性纳米粒的红外光谱图
图3本发明实施例15中磁性纳米粒的扫描电镜图与粒径分布
图4本发明实施例16中磁性纳米粒的磁性表征
图5本发明实施例17中磁性纳米粒的细胞毒性
图6本发明实施例18中磁性纳米粒在不同体系中的释药行为。
Claims (5)
1.一种以葡萄糖修饰的具有脑靶向的磁性纳米粒,为通式(I)所示结构或其药学上可接受的盐或水合物:
。
其中:
X代表一端羧基化的聚乙二醇PEG,可以是三甘醇、四甘醇或聚乙二醇PEG分子量为200、400、600、800、1000、1500、2000、4000等;
Y代表-(CH2)a-、-C(O)-(CH2)a-C(O)-或-O-(CH2)b-、-NH-(CH2)b-、-C(O)-(CH2)b-、-C(O)-(CH2)b-C(O)-,a表示0~6,b表示1~4;
MNPs代表Fe3O4、γ-Fe2O3、MnFe2O4、CoFe2O4和ZnFe2O4等;
Drug代表可作用于中枢神经系统的药物。
2.根据权利要求1所述的以葡萄糖修饰的新型脑靶向磁性纳米粒,其特征在于X为一端羧基化的PEG,一端与氨基通过酰胺键相连,另一端与谷氨酸的羧基以酯键相连;Y的一端以酯键与谷氨酸的氨基相连或通过C-N键直接与氨基相连,另一端以酯键或醚键或酰胺键同药物相连。
3.根据权利要求1所述的以葡萄糖修饰的新型脑靶向磁性纳米粒,其特征在于将葡萄糖的脑靶向特性和磁性纳米粒的磁靶向特性结合起来,形成双重脑靶向磁性纳米粒。
4.根据权利要求1所述的以葡萄糖修饰的新型脑靶向磁性纳米粒,其特征在于MNPs可以是但不限于Fe3O4、γ-Fe2O3、MnFe2O4、CoFe2O4和ZnFe2O4等,优选Fe3O4。
5.根据权利要求1所述的以葡萄糖修饰的新型脑靶向磁性纳米粒,其特征在于药物可以是但不限于萘普生、布洛芬、文拉法辛、美金刚胺等可作用于中枢神经系统的药物。
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