CN105693807A - 新型脑靶向脂质材料及其在药物传递系统中的应用 - Google Patents
新型脑靶向脂质材料及其在药物传递系统中的应用 Download PDFInfo
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- CN105693807A CN105693807A CN201610046800.6A CN201610046800A CN105693807A CN 105693807 A CN105693807 A CN 105693807A CN 201610046800 A CN201610046800 A CN 201610046800A CN 105693807 A CN105693807 A CN 105693807A
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- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
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Abstract
本发明公开了两种新型脂质材料,用于实现延长循环时间的脑部肿瘤靶向药物传递以及脑部肿瘤靶向药物锁定功能。其中一种脂质材料以聚乙二醇为桥连,一侧连接胆固醇,一侧连接维生素C,该脂质材料具有脑部靶向功能,并且由于PEG的加入,可以延长循环时间;另一种材料是在第一种材料的基础上用TDS修饰,增加脑部锁定功能,弥补维生素C转运体具有的双向转运性质,改善维生素C修饰的脂质体存在的入脑后外排的现象。该新型脂质材料可用于脂质体、纳米粒、胶束等在内的不同剂型,所制成的载多烯紫杉醇脂质体具有明显的脑靶向锁住功能,拥有广阔的应用前景。
Description
技术领域
本发明涉及两种新型脂质材料及其在药物传递系统中的应用,其中一种是具有延长体内循环和脑部靶向药物传递功能的新型脂质材料维生素C聚乙二醇胆固醇聚合物,另一种是在第一种材料的基础上用TDS修饰的具有锁定功能的脑部靶向脂质材料,包括此两种材料的制备,及其作为药物载体在药物传递中的应用,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。
维生素C(简称AA),又名抗坏血酸,具有许多生物学功能,包括:参与氨基酸代谢;神经递质、胶原蛋白和组织细胞间质的合成,增加对感染的抵抗能力,降低毛细血管的通透性,加速血液凝固,并有抗组胺及阻止致癌物质生成的作用等。维生素C在脑内的浓度是其它器官的10倍以上,这源于大脑中葡萄糖转运蛋白1(GLUT1)、钠离子依赖的维生素C转运蛋白2(SVCT2)和少量的钠离子依赖的维生素C转运蛋白1(SVCT1)。钠离子依赖的维生素C转运蛋白2(SVCT2)是转运维生素C的特异性载体,在脑脊液神经内皮细胞和脑胶质瘤细胞中均有大量表达。据报道,哌啶甲酸、犬尿酸、等药物在修饰抗坏血酸后,均可被SVCT2所识别,并递送相应药物到脑中。因此,以SVCT2为靶标,通过连接维生素C改善脑屏障穿透性能,可以提高药物在脑的靶向性,从而使药物在脑内可以维持在一个相对较高的水平。因此,可以将维生素C作为药物脑靶向给药的载体,如维生素C修饰的脂质体。然而仅仅靠维生素C转运的脂质体,其脑靶向性虽然有提高,但总体提高还是不尽人意。其原因可能在于维生素C转运体具有双向转运性质,那么维生素C修饰的脂质体也可能存在入脑后外排的现象。
日本学者Ishikura提出了硫胺素类脑靶向传递系统(TDS)。TDS是基于维生素B1母核设计的药物传递系统,药物与硫胺素类化合物偶联后形成的TDS偶联物亲脂性增加,可自由扩散并通过BBB。进入中枢后,分子中的二硫键被脑中还原型谷胱甘肽以及NAD+-NADH辅酶系统共同还原,进而分子自身环合为噻唑季铵盐形式,极性和水溶性得到极大的增加,使该类偶联物被“锁定”在脑中,然后逐渐释放出药物,达到治疗作用。如果将TDS应用到脂质体配体的合成上,也可制备维生素C转运体介导的具有“锁定”功能的新型脑靶向脂质体。
常规包含磷脂和胆固醇的脂质体具有较高的系统清除率,静脉注射后很快会被肝、脾、骨髓等组织的巨噬细胞吞噬。因此,可以对组成脂质体的磷脂或者胆固醇进行结构修饰,如将其与PEG连接可以延长脂质体体内循环时间;将其与靶头连接,可赋予脂质体脑靶向的性质。
综上所述,通过维生素C修饰,可以得到两种新型脑靶向脂质材料:其中一种脂质材料以聚乙二醇为桥连,一侧连接胆固醇,一侧连接维生素C,该脂质材料具有脑部靶向功能;另一种材料是在第一种材料的基础上进一步用硫胺素类化合物修饰,增加脑部锁定功能,提高药物的中枢浓度。两种新型脂质材料可用于脂质体、纳米粒、胶束等在内的不同剂型,同时具有长循环、脑靶向、脑部锁定、以及降低毒性的功能,将此两种新型脂质材料应用于药物传递系统,将具有很大的应用前景,依此两种脂质材料所制成的载多烯紫杉醇脂质体具有明显的脑靶向锁住功能。
发明内容
本发明的目的在于提供了两种新型脑靶向脂质材料:一种是具有延长体内循环和脑靶向药物传递功能的新型脂质材料A:维生素C-聚乙二醇-胆固醇聚合物(Vc-PEG-L);另外一种是在第一种材料的基础上用TDS修饰的具有脑靶向锁定功能的脂质材料B:TDS-维生素C-聚乙二醇-胆固醇聚合物(TDS-Vc-PEG-L)。
所述的脂质材料TDS-Vc-PEG-L为硫胺素类化合物,药物与硫胺素类化合物偶联后形成的TDS偶联物亲脂性增加,可自由扩散并通过BBB。进入中枢后,分子中的二硫键被脑中还原型谷胱甘肽以及NAD+-NADH辅酶系统共同还原,进而分子自身环合为噻唑季铵盐形式,极性和水溶性得到极大的增加,使该类偶联物被“锁定”在脑中,然后逐渐释放出药物,可以防止维生素C修饰的脂质体存在的入脑后外排现象,提高脑中药物浓度,达到治疗作用。
本发明的第二个目的在于提供上述多功能的新型脂质材料A和B的制备方法。
本发明的第三个目的在于提供上述多功能的新型脂质材料A和B在药物制剂中的应用。
本发明通过以下技术方案实现上述目的:
所述的新型脂质材料A的结构通式如下:
其中:m表示2~4;
所述的新型脂质材料B的结构通式如下:
其中:
X代表但并不仅限于-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2-C6H5等;n表示2~4,或者代表所用的PEG的分子量等于但并不仅限于200、400、600、800、1000、1500、2000、4000等。
所述的新型脂质材料A,其特征在于采用以下方法制备:
。
所述的新型脂质材料B,其特征在于采用以下方法制备:
。
本发明所述的新型脂质材料A和B可以作为载体用于制备脑靶向锁定功能脂质体。
所述脂质体其特征在于包含磷脂、胆固醇、Vc-PEG-L、TDS-Vc-PEG-L及活性剂。
所述脂质体主要由膜材与活性剂组成,其膜材为磷脂双分子层,由卵磷脂,胆固醇以及脂质体配体组成,其中,各组分配比关系如下:胆固醇和磷脂的摩尔比为1~2:1~10,脂质体配体的摩尔含量为胆固醇和磷脂的总摩尔数的1~25%。本发明所述的活性剂优选治疗剂或显影剂,如本领域所知的,活性剂的剂量可以依据包含在甾体中的活性剂来调整,其中按重量百分数计算,活性剂占总脂质的0.1%~50%。
所述的脂质体中的磷脂包括所有类型的磷脂,包括但不限于大豆磷脂、卵磷脂、磷脂酰乙醇胺、磷酯酰丝氨酸、磷脂酰肌醇、磷脂酰甘油、二磷脂酰甘油;优选卵磷脂。
所述的脂质体中的活性剂可以是抗肿瘤药物,包括但不限于烷化剂、抗代谢物、抗肿瘤抗生素、蒽环类抗生素、植物生物碱、紫杉醇衍生物、拓朴异构酶抑制剂、单克隆抗体、光敏剂、激酶抑制剂和含铂化合物。抗癫痫药物,包括但不限于巴比妥类、乙丙酰脲类、双链脂肪酸类、琥珀酰亚胺类、苯甲二氮卓类、亚氨基苷类、磺胺类、恶唑烷双酮类、胡椒碱类、皮质激素类、免疫球蛋白等。抗抑郁药物,包括但不限于去甲肾上腺素再摄取抑制剂、单胺氧化酶抑制剂、5-羟色胺再摄取抑制剂。
本发明所述的脑靶向锁定功能脂质体的制备方法,包括以下步骤:
(一)称取磷脂、胆固醇、多烯紫杉醇于茄型烧瓶中,用适量溶剂溶解,加入相应比例的脂质体配体(空白脂质体不加),于20-40℃恒温水浴旋转蒸发除去有机溶剂;
(二)再将茄型瓶置于真空干燥器中真空干燥过夜除去残余溶剂;
(三)向茄型瓶中加入磷酸盐缓冲液或硫酸铵溶液等水化液,用37-60℃恒温空气浴摇床水化约1-5小时后,冰水浴探头超声,用挤压过膜或超声等方法将脂质体粒径控制在100nm左右。
优选的步骤(一)中的多烯紫杉醇:脂质材料比为1:40。
优选的步骤(二)中的溶剂为氯仿,脂质摩尔比1:2(胆固醇:大豆磷脂)。
优选的步骤(三)中的水化液为pH6.5的0.02M磷酸盐缓冲液(PBS)。
本发明通过以下技术方案实现上述目的:
具体实施方法
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。下面参照实施例进一步详细阐述本发明,但本发明并不限于这些实施例以及使用的制备方法。而且,本领域技术人员根据本发明的描述可以对本发明进行等同替换、组合、改良或修饰,但这些都将包括在本发明的范围内。
所述的新型脂质材料A、B具体由以下步骤制备:
实施例1
化合物11的制备
将化合物10苄溴(3.42g,20mmol)的乙醇溶液(40ml)加至硫代硫酸钠五水合物(5g,20mmol)的水溶液中(40ml),将混合液置于外温80°C的条件下回流14h。反应完全后减压蒸干溶剂,得淡白色固体苄基硫代硫酸钠4.2g。
实施例2
化合物2的制备
将化合物1(3g,17mmol)溶于二氯甲烷(50ml)中,滴加N,N-二异丙基乙胺(3.96g,30ml),将反应液置于-5℃条件下搅拌15min,缓慢滴加2-甲氧基乙氧基甲基氯(3.8g,30mmol),在冰浴条件下搅拌2h,反应完全后加入饱和食盐水溶液(50ml),分出有机层,用无水Na2SO4固体干燥,浓缩后用柱层析纯化得淡黄色油状物2.1g,收率38.9%。
实施例3
化合物4的制备
将胆固醇(40g,103mmol)溶于重蒸过的吡啶(330ml)中,慢慢加入TsCl,此时反应液呈淡粉色澄清溶液。将反应在外温50℃条件下搅拌10h后停止反应,旋去吡啶,得淡粉色固体,产品在水中(500ml)搅拌至细白色悬浮液,静置过夜。将悬浮液过滤得到白色固体,置于红外灯下干燥,得白色固体55.1g,收率98.6%。m.p.:132-133℃。
实施例4
化合物5的制备
将化合物4(55.1g,102mmol)溶于二氧六环中,将反应液升温至90℃时溶解,为淡黄色澄清溶液。将三甘醇(69ml)加入上述溶液中,升温至120℃,回流8h。反应完全后,旋去溶剂,得冻状物,用二氯甲烷溶解后,依次用水和饱和食盐水溶液洗涤二氯甲烷层,用无水Na2SO4固体干燥,旋干得浅棕色冻状物。将产物用柱层析纯化(石油醚:丙酮=25:1-10:1),得纯品30.3g,收率58.4%。目标产物结构表征:1HNMR(400MHzCDCl3):δ0.66(s,3H),0.85(d,6H,J=6.4Hz),0.91(d,3H,J=6.4Hz),0.99(s,3H),0.67-2.38(remainingcholesterolprotons),3.20(m,1H),3.59-3.75(m,12H),5.34(m,1H)。
实施例5
化合物6的制备
将化合物5(10.3g,19.85mmol)溶于甲苯(70ml)中,加入50%NaOH(aq.,50ml),溶液分层,微放热,冷却后加入溴乙酸叔丁酯(4.8ml,29.78mmol)/n-Bu4N+HSO4 -,室温搅拌下使反应过夜。次日,反应完全后,分出甲苯层,用乙醚萃取浓稠水层4次,合并有机层,用无水Na2SO4固体干燥,浓缩得浅褐色浓稠油状物14g,用柱层析纯化(石油醚:丙酮=15:1),得纯品10.1g,收率80.4%。目标产物结构表征:1HNMR(400MHz,CDCl3):δ0.66(s,3H),0.85(d,6H,J=6.4Hz),0.91(d,3H,J=6.6Hz),0.99(s,3H),0.64-2.39(remainingcholesterolprotons),1.47(s,9H),3.20(m,1H),3.58-3.79(m,12H),4.02(s,2H),5.34(m,1H)。
实施例6
化合物7的制备
将化合物6(4.5g,7.11mmol)溶于甲苯(50ml)中,加入TsOH(0.24g,1.4mmol),将反应置于外温110℃条件下回流,反应液变为可乐色,4h后停止反应。外温60℃旋去甲苯,浓缩得粘稠油状物。将产品用柱层析纯化(石油醚:丙酮=5:1-4:1),得淡黄色油状物3.77g,收率91.9%。目标产物结构表征:1HNMR(400MHz,CDCl3):δ0.66(s,3H),0.86(d,6H,J=6.4Hz),0.92(d,3H,J=6.6Hz),0.99(s,3H),0.66-2.39(remainingcholesterolprotons),3.20(m,1H),3.61-3.81(m,12H),4.17(s,2H),5.35(m,1H)。
实施例7
化合物8的制备
将化合物7(3g,3.1mmol)用二氯甲烷溶解,缓慢加入HClO4(0.5ml)的二氯甲烷溶液,反应液呈淡黄色,室温搅拌7h后溶液变为玫瑰红色,反应完全后旋去溶剂,将反应物用柱层析纯化(CH2Cl2:CH3OH=100:1-50:1),得淡黄色油状物1.8g,收率64.2%。
实施例8
化合物9的制备
将化合物8(1.8g,2.0mmol)溶于50ml二氯甲烷中,置于-5℃条件下搅拌,加入1,3-二环己基碳化二亚胺(DCC,0.6g,2.9mmol)和4-N,N-二甲基吡啶(0.05g,0.41mmol),溶液变浑浊,继续搅拌1h进行活化,将化合物2(0.7g,2.0mmol)快速加入反应液中,移至室温条件下反应过夜,反应完全后过滤除去不溶物,浓缩后用柱层析纯化(CH2Cl2:CH3OH=100:1),得淡黄色油状物1.5g,收率61.0%。
实施例9
化合物12的制备
将化合物7(1.38g,2.4mmol)溶于二氯甲烷(40ml)中,置于-15℃下搅拌,滴加N-甲基吗啉(0.49g,3.6mmol)与氯甲酸异丁酯(0.36g,3.6mmol),活化30min后滴加化合物A(0.42g,2.9mmol),搅拌约2h,反应完全后,用饱和碳酸氢钠溶液洗涤二氯甲烷层,无水Na2SO4固体干燥,浓缩后用柱层析纯化(CH2Cl2:CH3OH=100:1),得纯品1.2g,收率71.9%。
实施例10
化合物13的制备
将化合物12(4g,5.6mmol)溶于乙醇(50ml)中,滴加溴乙酸叔丁酯(1.65g,8.5mmol),将反应液于外温90℃条件下回流过夜,浓缩后用柱层析纯化(CH2Cl2:CH3OH=20:1),得纯品2.1g,收率41.2%。
实施例11
化合物14的制备
将化合物13(1.8g,2mmol)溶于水(20ml)中,缓慢滴入NaOH(0.16g,4mmol)的水溶液(10ml),搅拌30min。加入苄基硫代硫酸钠(0.9g,4mmol),有黄色油状沉淀产生。加入乙酸乙酯(20ml),室温条件下搅拌过夜。分离出有机相,用乙酸乙酯萃取水层,合并有机层,用饱和食盐水洗涤有机层,无水Na2SO4固体干燥,浓缩后用柱层析纯化(石油醚:丙酮=5:1),得纯品2.1g,收率41.2%。
实施例12
化合物15的制备
将化合物14(3g,3.1mmol)用DCM溶解,缓慢加入HClO4(0.5ml)的DCM溶液,反应液呈淡黄色,室温搅拌7h后溶液变为玫瑰红色,旋去溶剂,柱层析纯化(CH2Cl2:CH3OH=100:1-50:1),得纯品1.8g,收率64.2%。1HNMR(400MHz,,CDCl3):δ0.67(s,3H),0.86(d,6H,J=6.4Hz),0.91(d,3H,J=6.6Hz),0.99(s,3H),0.67-2.37(remainingcholesterolprotons),1.91(s,3H),2.74(t,2H,J=6.0Hz),3.19(m,1H),3.43(m,2H),3.62-3.70(m,12H),3.90(s,2H),3.92(s,2H),4.22(s,2H),5.33(m,1H),7.27-7.33(m,5H),8.05(s,1H)。
实施例13
化合物16的制备
将化合物15(1.8g,2.0mmol)溶于50ml二氯甲烷中,置于-5℃条件下搅拌,加入1,3-二环己基碳化二亚胺(0.6g,2.9mmol)和4-N,N-二甲基吡啶(0.05g,0.41mmol),溶液变浑浊,继续搅拌1h进行活化,将化合物2(0.7g,2.0mmol)快速加入反应液中,移至室温条件下反应过夜,反应完全后过滤除去不溶物,浓缩后用柱层析纯化(CH2Cl2:CH3OH=100:1),得淡黄色油状物1.5g,收率61.0%。目标产物结构表征:1HNMR(400MHz,CDCl3):δ0.67(s,3H),0.86(d,6H,J=6.4Hz),0.91(d,3H,J=6.6Hz),0.99(s,3H),0.67-2.37(remainingcholesterolprotons),1.99(s,3H),2.69(t,2H,J=6.0Hz),3.18(m,1H),3.37(s,6H),3.56(m,2H),3.58-3.66(m,14H),3.81-3.85(m,4H),3.95(s,2H),4.01(s,2H),4.08(s,2H),4.17-4.32(m,2H),4.39-4.44(m,1H),4.72(s,1H),5.25(s,2H),5.33(m,1H),5.25(s,2H),5.38(d,1H,J=6.0Hz),5.74(d,1H,J=6.0Hz),7.29-7.31(m,5H),7.97(s,1H)。
实施例14
化合物17的制备
将化合物16(0.1g,0.08mmol)溶于溶于四氢呋喃中(1ml),加入1%的盐酸甲醇溶液(5ml),置于70℃下反应30min,反应完毕,浓缩后柱层析纯化(CH2Cl2:CH3OH=100:1),得淡黄色油状物0.07g,收率82.3%。目标产物结构表征:1HNMR(400MHz,CDCl3):δ0.67(s,3H),0.86(d,6H,J=6.4Hz),0.91(d,3H,J=6.6Hz),0.99(s,3H),0.67-2.37(remainingcholesterolprotons),1.99(s,3H),2.69(t,2H),3.20(m,1H),3.42(m,2H),3.63-3.66(m,12H),3.87(s,2H),3.99(s,2H),4.09(s,2H),4.19(m,2H),4.36(m,1H),4.71(s,1H),5.33(m,1H),7.24-7.32(m,5H,Ar-H),7.96(s,1H)。
所述的脑靶向锁定功能脂质体的具体制备方法。
实施例15
薄膜分析法作为经典的脂质体制备方法,应用最为广泛,操作简单,制备出的脂质体结构典型。因此,本发明选择采用薄膜分析法来制备多烯紫杉醇脂质体。
根据对多烯紫杉醇脂质体的制备摸索,最终我们选取最优化处方:脂质摩尔比1:2(胆固醇:大豆磷脂),水化液为pH6.5的磷酸盐缓冲液(PBS)(0.02M),多烯紫杉醇:脂质材料比为1:40。我们用以下处方(表1)分别制备了空白、Vc-L修饰的以及TDS-Vc-L修饰的载多烯紫杉醇脂质体DTX-L、DTX-Vc-L和DTX-TDS-Vc-L。
表1载多烯紫杉醇脂质体脂质成分摩尔比
注:DTX:多烯紫杉醇;L:脂质;SPC:卵磷脂(磷脂酰胆碱);Chole:胆固醇。
准确称取处方量脂质材料(按大豆磷脂:胆固醇=2:1的摩尔比)、多烯紫杉醇(脂质材料比为1:40)于茄型烧瓶中,用适量氯仿溶解,加入相应比例的脂质体配体(空白脂质体不加),37±1℃恒温水浴旋转蒸发除去氯仿后得均匀薄膜,真空干燥过夜除去残余溶剂。加入pH6.5(0.02M)的PBS缓冲液5ml,37℃恒温空气浴摇床,125r/min条件下水化1h后,冰水浴探头超声(300w,15s,10s)10次,用微型挤压器依次挤压通过200nm和100nm聚碳酸酯膜10次,即得载多烯紫杉醇的各脂质体。
表2三种载多烯紫杉醇脂质体的包封率、粒径以及Zeta电位
由表2可知,三种载药脂质体的粒径大小适中,包封率均大于80%。随着配体的加入,Zeta电位绝对值也随之下降,表明配体的加入对脂质体稳定性有一定程度的影响。这可能是因为配体中的羟基与水溶液中氢离子结合,从而降低了Zeta电位的绝对值;特别的TDS-Vc-L的结构中含有二硫键,在水溶液中产生分子间氢键,其亲水性也随之增强,因此其Zeta电位绝对值表现为最低。同时,Zeta电位的改变,也印证了配体嵌入在脂质体表层的事实。三种脂质体Zeta电位适中,比较稳定,符合脂质体制剂相关质量要求。
初步靶向性研究
实施例16
为了评价此类具有“锁定”功能的脑靶向脂质体,选择实施例13中的3种脂质体进行了小鼠脑及血浆中药物浓度的测定。
实验动物选择昆明小鼠,雌雄过半,体重18-22g不等,随机分成4组。一组尾静脉注射DTX(多烯紫杉醇),一组尾静脉注射DTX-L(多烯紫杉醇脂质体),一组尾静脉注射DTX-Vc-L(多烯紫杉醇脑靶向脂质体),另外一组尾静脉注射DTX-TDS-Vc-L(多烯紫杉醇脑靶向锁住功能脂质体)。各组三只小鼠在给药0.5、1、2、4、8、16、24h后,眼眶取血处死,同时获得小鼠脑组织,将所取血液样品及脑组织样品处理过后,进入高效液相色谱(HPLC)分析。不同时间点小鼠血浆和脑匀浆中的多烯紫杉醇药时曲线如图1、图2所示。
由图1、图2所示,无论在血浆中还是脑匀浆中,DTX-L中多烯紫杉醇的浓度高于DTX组,DTX-Vc-L组中多烯紫杉醇的浓度明显高于DTX-L组,表示DTX-Vc-L组具有脑靶向作用,而脑中DTX-TDS-Vc-L组中多烯紫杉醇的浓度又高于DTX-Vc-L组,说明DTX-TDS-Vc-L组具有明显的锁住功能,经过计算还可以得到以下药代动力学参数:如表3、表4。
表3血浆中多烯紫杉醇的药代动力学参数(n=3)
表4脑中多烯紫杉醇的药代动力学参数(n=3)
由表3、表4可知血液中DTX-TDS-Vc-L组多烯紫杉醇的药时曲线下面积(AUC0-t)是DTX组的1.58倍,最大血药浓度(Cmax)是DTX组的2.36倍。与此同时,在脑组织中DTX-Vc-L组以及DTX-TDS-Vc-L组中多烯紫杉醇的AUC0-t及Cmax较多烯紫杉醇组均有大幅度提高,表明脂质体具有脑靶向功能,而DTX-TDS-Vc-L组中多烯紫杉醇的AUC0-t及Cmax较DTX-Vc-L组有明显提高,其相对摄取率比Re((AUC0-t)pro/(AUC0-t)ibu)分别为2.51、3.24,峰浓度比Ce((Cmax)pro/(Cmax)ibu)分别为4.38、5.62,表明DTX-TDS-Vc-L在脑内的分布有显著提高,说明了DTX-TDS-Vc-L组具有脑靶向锁定功能。
以上数据表明,本发明的两种新型脂质材料作为脑靶向脂质体载体制得的脂质体A提高了药物在脑内的分布,具有脑靶向功能,而脂质体B则显著提高了脑中的药物浓度,防止了维生素C修饰的脂质体存在的入脑后外排现象,具有明显的脑靶向锁定功能。
附图说明。
图1为血浆中DTX、以及DTX-L、DTX-Vc-L、DTX-TDS-Vc-L中多烯紫杉醇的药时曲线。
图2为脑匀浆中DTX、以及DTX-L、DTX-Vc-L、DTX-TDS-Vc-L中多烯紫杉醇的药时曲线。
Claims (7)
1.本发明的目的在于提供了一种具有延长体内循环和具有脑部靶向药物传递功能的新型脂质材料A:维生素C-聚乙二醇-胆固醇聚合物(Vc-PEG-L),和在第一种材料的基础上用TDS修饰的具有脑部靶向药物锁定功能的脂质材料(TDS-Vc-PEG-L),包括此两种材料的制备,及其作为药物载体在药物传递中的应用。
2.新型脂质材料A的结构通式如下或其药学上可接受的盐或水合物:
其中:m表示2~4;
新型脂质材料B的结构通式如下或其药学上可接受的盐或水合物:
其中:
X代表且并不仅限于-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2-C6H5等;n表示2~4,或者代表所用的PEG的分子量等于但并不仅限于200、400、600、800、1000、1500、2000、4000等。
3.根据权利要求1所述的以新型脂质材料A和B所制成的脑靶向脂质体,其特征在于,包括膜材与活性剂,所述的膜材为磷脂双分子层,由卵磷脂,胆固醇以及脂质体配体组成,其中,各组分配比关系如下:胆固醇和磷脂的摩尔比为1~2:1~10,脂质体配体的摩尔含量为胆固醇和磷脂的总摩尔数的1~25%;本发明所述的活性剂优选治疗剂或显影剂,如本领域所知的,活性剂的剂量可以依据包含在甾体中的活性剂来调整,其中按重量百分数计算,活性剂占总脂质的0.1%-50%。
4.根据权利要求1所述的以新型脂质材料A和B所制成的脑靶向脂质体,其特征在于,根据上述组分配比关系,可采用薄膜法制备脑靶向配体脂质体,可制备得到粒径及Zeta电位稳定的脑靶向脂质体,其脂质体粒度为110-140nm,包封率大于80%。
5.根据权利要求1所述的以新型脂质材料A和B所制成的脑靶向脂质体,其特征在于,所述磷脂包括所有类型的磷脂,包括但不限于大豆磷脂、卵磷脂、磷脂酰乙醇胺、磷酯酰丝氨酸、磷脂酰肌醇、磷脂酰甘油、二磷脂酰甘油;优选卵磷脂。
6.根据权利要求1所述的以新型脂质材料A和B所制成的脑靶向脂质体,其特征在于,所述的活性剂可以是抗肿瘤药物,包括但不限于烷化剂、抗代谢物、抗肿瘤抗生素、蒽环类抗生素、植物生物碱、紫杉醇衍生物、拓朴异构酶抑制剂、单克隆抗体、光敏剂、激酶抑制剂和含铂化合物;抗癫痫药物,包括但不限于巴比妥类、乙丙酰脲类、双链脂肪酸类、琥珀酰亚胺类、苯甲二氮卓类、亚氨基苷类、磺胺类、恶唑烷双酮类、胡椒碱类、皮质激素类、免疫球蛋白等;抗抑郁药物,包括但不限于去甲肾上腺素再摄取抑制剂、单胺氧化酶抑制剂、5-羟色胺再摄取抑制剂。
7.根据权利要求1-6所述的以新型脂质材料A和B所制成的脑靶向脂质体,在制备治疗抗肿瘤药物、抗癫痫药物以及抗抑郁药物中,可提高药物的脑靶向性,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。
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