CN113368256A - 分枝葡萄糖和生物素介导的脑胶质瘤靶向智能脂质体材料 - Google Patents
分枝葡萄糖和生物素介导的脑胶质瘤靶向智能脂质体材料 Download PDFInfo
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- CN113368256A CN113368256A CN202110607739.9A CN202110607739A CN113368256A CN 113368256 A CN113368256 A CN 113368256A CN 202110607739 A CN202110607739 A CN 202110607739A CN 113368256 A CN113368256 A CN 113368256A
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- liposome
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- Medicinal Preparation (AREA)
Abstract
本发明公开了一种分枝葡萄糖和生物素共同介导的脑胶质瘤靶向智能脂质体材料的制备及应用。所述的智能脂质体材料包括:1、分枝葡萄糖基修饰的胆甾化合物Ⅰ(配体材料a);2、两分子生物素修饰的胆甾化合物Ⅱ(配体材料b)。两个配体材料联合制备脂质体后,通过暴露在该脂质体表面的葡萄糖和生物素残基可特异性识别血脑屏障和脑胶质瘤细胞表面过表达的葡萄糖转运体GLUT1和多维生素转运体SMVT,实现特异性的血脑屏障和脑胶质瘤的主动靶向,并进一步靶向到脑胶质瘤细胞,实现强效治疗脑胶质瘤的作用。
Description
技术领域
本发明涉及一类分枝葡萄糖和生物素共同介导的脑胶质瘤靶向智能脂质材料及其在药物传递系统中的应用,具体涉及两种脂质分子,属于医药技术领域。
背景技术
神经胶质瘤是最常见的颅内原发性恶性肿瘤之一,约占所有颅内肿瘤的51%,由于其恶性程度高,复发率高,存活率低,致残率高,患者的整体5年生存率低于5%,中位生存期约为12-15个月,对人类健康构成严重威胁。目前,脑肿瘤的临床治疗主要包括最大程度的手术切除、放疗和替莫唑胺(TMZ)同步化疗。然而,由于胶质瘤的侵袭性和高浸润性,肿瘤细胞会侵袭到控制感觉、行为和言语的大脑关键功能区域,且神经胶质瘤缺乏清晰的切缘,完全手术切除肿瘤是无法实现的。此外,放射疗法通常不适用于中枢神经系统区域,辐射与认知障碍,DNA损伤和其他严重的全身性副作用有关,而大多数化疗失败是由于血脑屏障(BBB)穿透能力和化疗药物靶向性差所致,血脑屏障(BBB)的存在限制了几乎所有的大分子和98%以上的小分子药物进入中枢神经系统,因此,迫切需要开发一种具有高效BBB穿透能力和脑胶质瘤主动靶向能力的新方法。
迄今为止,纳米材料因其具有表面易修饰、颗粒大小和表面电荷可调控、孔隙率高、比表面积大等特点,在肿瘤治疗研究中受到广泛研究,纳米递送系统(NDS,Nano-delivery system)已显示出神经胶质瘤靶向的巨大潜力。未修饰的纳米载体通常缺乏BBB穿透能力和肿瘤靶向性,而基于BBB中受体和转运体的发现,使主动靶向成为脑靶向递药系统研究的热点。纳米递药系统的主动靶向主要是通过载体介导的转运(carrier-mediatedtransport,CMT)、受体介导的转运及吸附介导的转运这三种方式,而由于转运体与其底物之间的高转运亲和力,载体介导的转运(CMT)已成为了促进药物进入大脑的最有前途的方法之一,以转运体的配体作为功能基,采用共价键或非共价键连接方法对纳米载体进行修饰以构建脑靶向递药系统,可使得药物成功跨越BBB并且在脑内病灶部位释药。载体介导的策略利用了血脑屏障上高表达的各种营养物质和内源性化合物的生理转运系统,例如己糖转运系统,维生素C转运系统,氨基酸转运系统,一元羧酸转运系统,核苷转运系统,胺转运系统,多肽转运系统,肉碱转运系统等。
在众多的纳米递药系统中,脂质体是目前研究最为成熟的一种纳米载体,除了具备上述特点外,还具有良好的稳定性、生物可降解性,生物相容性和低毒性、制备方便等优点,脂质体的发展趋势之一是表面配体功能化,其表面易于修饰特定的靶向配体,使脂质体除了被动靶向外,还可以通过主动靶向跨越BBB并特异性的富集于脑胶质瘤部位直接提高其靶向能力。
葡萄糖作为维持脑部正常生理功能所必须的物质,是通过BBB上的己糖转运系统中的钠离子非依赖型的葡萄糖转运蛋白1(GLUT1)透过血脑屏障进入脑组织,而GLUT1在脑毛细血管内皮细胞管腔内膜面和近腔膜面的表达最为丰富,被认为是BBB上最高效的转运系统之一。脑内的GLUT1运载力极高,相比BBB上其他营养物质的转运载体,其转运能力甚至高于氨基酸或羧酸转运系统的50倍,且运转速率非常快,因此成为脑靶向药物修饰时常用的靶点。同时“瓦博格效应”(Warburg Effect)表明,肿瘤细胞即使在供氧充足的条件下也仍然以糖酵解作为产能的主要方式,致使肿瘤细胞表面过表达GLUT1以维持肿瘤细胞的能量代谢。此外,深入的构效关系研究发现,当对葡萄糖的C6位进行修饰时,能最大程度地保留与转运蛋白GLUT1的亲和力。本课题组之前的研究也表明,药物或脂质体经葡萄糖基化后,能够特异性识别GLUT1,具有一定的脑靶向性,从而能够增加药物在脑内的分布。
生物素,又称维生素B7/维生素H,是水溶性维生素B家族的成员。有研究表明脑内生物素浓度是血浆中浓度的50倍左右,而生物素不能在大脑中内源性合成,且通常只有不到10%的维生素通过简单扩散进入中枢神经系统,其余的则通过BBB上的特殊载体系统从血液转运到脑中,而脑内皮细胞表面的钠依赖型复合维生素转运体(SMVT)已被证实是生物素的关键转运体,在人脑毛细血管内皮中有丰富表达。Szilvia Veszelka等的研究也表明,生物素作为固体NPs的靶向配体显著增加了其脑内皮细胞内的摄取。因此,生物素化是增强脂质体脑靶向能力的一种有前途的策略。
采用一种靶向功能基修饰脂质体往往存在一定的问题,例如受体饱和、竞争性抑制、靶向效率低等。鉴于此,针对BBB和病灶部位,可以构建双重靶向递药系统,即在递药系统表面同时修饰两种靶向分子,一种靶向分子靶向于BBB,另一种靶向分子靶向于病灶部位,或者双重靶向的功能基也可能都靶向于BBB或都靶向于病变组织,双重靶向递送系统可以将药物递送至病灶部位,有望提高脑部疾病的治疗效果并降低药物在非病灶部位的蓄积,如有研究开发了一种转铁蛋白和RGD肽结合的双靶向脂质体,用于胶质瘤靶向的治疗。本课题组之前的研究中也开发了一种以葡萄糖和维生素C为配体的双重脑靶向脂质体给药系统,证明相对于单配体修饰的脂质体,其脑胶质瘤靶向能力大大提高。
近年来,载体介导的转运系统 (CMT)已经被广泛研究以提高靶向效果,一些研究探索了单独利用葡萄糖或生物素作为配体提高纳米载体通过BBB进入脑的可能性,但目前还没有使用二者共同修饰的双重脑靶向递药系统的报道,且迄今所使用的双重靶向纳米递药系统通常是通过单纯的物理混合的方式将两种配体共同修饰于纳米载体上。在本课题组以前的工作中,我们发现脂质体表面配体上的靶分子的密度和空间结构等因素会影响纳米载体的靶向性,增加靶分子密度可以增加转运体介导的识别和转运,而在靶分子密度相同时,将靶分子共价连接成分枝状配体再修饰于脂质体上相比简单物理混合方式修饰的脂质体具有更好的靶向能力。
发明内容
基于上述研究及假设,本发明的目的是利用葡萄糖和生物素能被BBB和脑胶质瘤细胞上高表达的GLUT1转运体和SMVT转运体特异性识别的能力,以及分枝配体的设计理念,设计将三个葡萄糖分子与胆固醇衍生物偶联形成配体材料a,将两个生物素分子与胆固醇衍生物偶联形成配体材料b,并将其双重修饰于脂质体表面,以提高脂质体的BBB透过率和脑胶质瘤靶向能力,使脂质体同时具有高效的跨血脑屏障和脑胶质瘤靶向性,提高脑胶质瘤瘤部位药物剂量,提高药物疗效,减少药物在外周器官的浓度,降低毒副作用。
将该材料制备成具体的脂质体,具有以下优点:1、靶向性:通过肿瘤组织特有的EPR效应,以及葡萄糖和生物素与BBB和脑胶质瘤细胞上高表达的GLUT1和SMVT转运体的特异性作用,充分利用脂质体的被动靶向和主动靶向能力,实现脂质体对脑胶质瘤的靶向治疗。2、细胞亲和性和组织相容性:脂质体是类似生物膜结构的囊泡,对正常细胞和组织无损害和抑制作用,使用生物相容性的载体材料包载药物,可以减少免疫反应;3、对所载药物有广泛的适应性:水溶性药物载入水相内,脂溶性药物溶于脂膜内,两亲性药物可插于脂膜上,可以同时包载亲水和疏水性药物;4、对于如紫杉醇这样的生物药剂学分类系统(BCS)IV类药物,可以显著改善其生物利用度;5、一些不稳定的药物被脂质体包封后受到脂质体双层膜保护,可提高其稳定性;6、脂质材料与所包载的药物整体进入肿瘤细胞后再释放药物,可以减少药物与外排蛋白的作用,从而降低耐药性等。该脂质材料可结合多种药物对脑胶质瘤实施联合给药。因此,我们设计了三分枝葡萄糖修饰的配体材料a、双分枝生物素修饰的配体材料b,联合配体材料a、b制成包封紫杉醇的脑胶质瘤靶向智能脂质体,脂质体材料的胆固醇部分嵌入到脂质体磷脂双分子层中,暴露在该脂质体表面的葡萄糖和生物素残基可以通过与GLUT1和SMVT转运体的特异性识别,介导其高效透过BBB,并进一步靶向至脑胶质瘤的病灶部位。这种脂质材料可用于脂质体、纳米粒、胶束等在内的不同剂型,具有很大的应用前景。
本发明提供化合物I所示结构的化合物或其药学上可接受的盐或水合物:
化合物I所示化合物的具体制备方法:
本发明提供化合物Ⅱ所示结构的化合物或其药学上可接受的盐或水合物:
化合物Ⅱ所示化合物的具体制备方法:
本发明所述的新型智能脂质材料可以作为配体用于制备脑胶质瘤靶向的脂质体。
所述脂质体其特征在于包含磷脂、胆固醇、配体材料a(化合物Ⅰ,Glucose3-Chol)、配体材料b(化合物Ⅱ,Biotin2-Chol)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,脂质体配体材料a、b的摩尔含量分别为胆固醇和磷脂的总摩尔数的4%、4%。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载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。
本发明所述的脑胶质瘤靶向性脂质体的制备方法,包括以下步骤:
(一) 称取磷脂、胆固醇、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35-40 ℃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20 ℃恒温空气浴摇床水化约0.5-2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110 nm左右。
优选的步骤(一)中的紫杉醇:脂质材料质量比为1:22。
优选的步骤(一)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pH 7.4的0.01 M磷酸盐缓冲液(PBS)。
附图说明
图1:PTX-Glu3+Bio2-Lip的透射电镜图;
图2:不同配体修饰的载紫杉醇脂质体在50%血清中孵育后透光率的变化(n=3,mean ± SD);
图3:CFPE标记的脂质体在Bend.3细胞(A) 和C6细胞(B)中的摄取情况(*P<0.05,**P<0.01, ***P<0.001, **** P<0.0001 versus CFPE-Lip; n=3,mean ± SD);
图4:CFPE标记的脂质体在Bend.3细胞(A)和C6细胞(B)中的摄取的共聚焦图片。
本发明通过以下技术方案实现上述目的。
具体实施方式
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具体由以下步骤制备:
实施例1 化合物Ⅰ的制备
采用已报道的合成路线(European Journal of Medicinal Chemistry, 2014,72, 110-118),以胆固醇、葡萄糖、季戊四醇等作为原料,总共经过13步反应,合成了目标化合物Glu3-Chol,总收率为5.50%,其1H-NMR、MS同文献报道一致。
实施例2 化合物17的制备
将二乙醇胺16(5.0 g,47.5 mmol)溶于100 mL乙腈,滴加二碳酸二叔丁酯Boc2O(11.4 g,52.25 mmol)的乙腈溶液(45 mL),1 h后滴毕,继续放置于室温条件下反应1.5 h,TLC监测至反应完毕,减压浓缩除去溶剂,得到9.45 g的透明油状化合物17,收率96.93%,产品无需纯化直接用于下一步反应。1H NMR (400 MHz, CDCl3) δ 3.91 (brs, 2H), 3.74(s, 4H), 3.39 (s, 4H), 1.43 (s, 9H)。
实施例3 化合物18的制备
将生物素(4.762 g,19.49 mmol)于100mL无水二氯甲烷及120mL无水N,N-二甲基甲酰胺的混合溶剂中溶清,在氩气保护下分别加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI,5.60 g,29.23 mmol)、4-二甲氨基吡啶(DMAP,3.57 g,29.23 mmol)和N,N-二异丙基乙胺(DIPEA,5.67 g,43.85 mmol),加毕后,于0℃活化30 min。将化合物17(1.0 g,4.87 mmol)用5 mL无水二氯甲烷溶解,缓慢滴加上述活化溶液中,滴加完毕移至室温搅拌反应24 h。TLC监测反应完全,减压浓缩除去反应溶剂,残留物用20 mL二氯甲烷溶解,分别用1N盐酸水溶液(200 mL×2)、饱和NaCl溶液(100 mL)洗涤,收集有机层并合毕,用无水Na2SO4干燥后,减压浓缩除去溶剂,残留物经硅胶快速柱层析纯化(二氯甲烷:甲醇=10:1),得到2.75 g白色固体化合物18,收率为85.84%。1H NMR (600 MHz, CDCl3) δ 6.56 (s,1H), 6.48 (s, 1H), 5.86 (brs, 1H), 5.77 (brs, 1H), 4.50 (t, J = 6.0 Hz, 2H),4.33-4.31 (m, 2H), 4.18-4.17 (m, 4H), 3.50 (s, 2H), 3.48-3.42 (m, 2H), 3.15-3.13 (m, 2H), 2.90 (dd, J = 12.6, 4.2 Hz, 2H), 2.73 (d, J = 12.6 Hz, 2H),2.36 (s, 4H), 1.74-1.63 (m, 8H), 1.45-1.39 (m, 13H)。
实施例4 化合物19的制备
化合物18(3.0 g,4.56 mmol)用30 mL二氯甲烷溶解,于0℃搅拌下加入CF3COOH(16.97 g,136.81 mmol),加毕,移至室温下继续反应20 min,TLC监测反应完全,减压浓缩除去溶剂,得到2.918 g淡棕色油状物化合物19,收率92.5%,产品无需纯化可直接用于下一步反应。
1H-NMR (400 MHz, DMSO-d 6 ) δ 8.81 (brs, 1H), 6.41 (s, 2H), 6.37 (s,2H), 4.33-4.30 (m, 2H), 4.27 (t, J = 4.8 Hz,4H), 4.15-4.12 (m, 2H), 3.28 (s,4H), 3.13-3.08 (m, 2H), 2.82 (dd, J = 12.4, 5.2 Hz, 2H), 2.58 (d, J = 12.4Hz, 2H), 2.36 (t, J = 7.2 Hz, 4H),1.67-1.43 (m, 8H), 1.41-1.32 (m, 4H)。
实施例5 化合物20的制备
将化合物19(2.918 g,4.22 mmol)置于反应瓶中,氩气置换3次,以25 mL无水二氯甲烷溶清,0℃搅拌下加入三乙胺(1.71 g,16.87 mmol),将丁二酸酐(844.59 mg,8.44mmol)以45 mL无水二氯甲烷溶清后转入滴液漏斗,滴加入上述溶液,0.5 h滴毕,移至室温继续反应18 h,反应液以布氏漏斗抽滤,固体以少量二氯甲烷洗涤,收集固体并干燥,得到2.27 g白色固体化合物20,收率81.8%,产品无需纯化可直接用于下一步反应。1H NMR (400MHz, DMSO-d 6 ) δ 6.47 (s, 1H), 6.45 (s,1H) ,6.41 (s, 1H), 6.38 (s, 1H), 4.31(s, 2H), 4.18-4.14 (m, 4H), 4.07 (s, 2H), 3.61 (s, 2H), 3.50 (s, 2H), 3.10(s, 2H), 2.83 (dd, J = 12.4, 4.8 Hz, 2H), 2.63-2.56 (m, 4H), 2.42 (s, 2H),2.35-2.26 (m, 4H), 1.60-1.42 (m, 8H), 1.33-1.31 (m, 4H)。
实施例6 化合物2的制备
将胆固醇1溶解于25 mL无水吡啶溶液中,并将15 mL吡啶溶解的对甲苯磺酰氯(TsCl,5.92 g,31.05 mmol)溶液于0℃下缓慢滴加至上述溶液中,然后于50℃下反应5 h,TLC监测反应完全,减压浓缩除去吡啶,残留物则用100 mL乙酸乙酯溶解,并依次用1N盐酸溶液(40 mL×2)、饱和NaCl溶液(40 mL×2)洗涤,无水Na2SO4干燥,将溶剂减压浓缩后得到白色固体10.25 g,收率91.58%,产品无需纯化可直接用于下一步反应。Mp: 129-132 ℃(文献Mp:130-132 ℃)。
实施例7 化合物21的制备
将化合物2(5.0 g,9.25 mmol)溶于30 mL二氧六环中,并加入四甘醇(17.97 g,92.5 mmol),然后将反应液在回流条件下继续反应6 h,TLC 监测原料反应完全,减压除去溶剂,残留物用100 mL乙酸乙酯溶解后,用饱和NaHCO3水溶液洗涤(100 mL×2),有机层用无水Na2SO4干燥,过滤,滤液经减压除去溶剂,残留物经硅胶柱层析纯化(石油醚:乙酸乙酯=5:1),得到3.11 g的无色油状化合物21,收率59.81%%。1H NMR (400 MHz, Chloroform-d)δ:5.33 (dd, J=5.0, 2.5 Hz,1H), 3.79-3.55 (m, 16H), 3.18 (tt, J=11.3, 4.4 Hz,1H), 0.8-2.50 (remain CHOLE protons), 0.67 (s, 3H)。
实施例8 化合物22的制备
将化合物21(400 mg,0.711 mmol),置于反应瓶中,氩气置换3次,用5 mL无水THF和5 mL无水1,4-二氧六环的混合溶剂溶清,室温搅拌下加入4-二甲氨基吡啶(DMAP,26.0mg,0.213 mmol),丁二酸酐(213.3 mg,2.130 mmol),然后将反应液移至120℃ 回流反应10h,TLC监测反应完全,反应液以布氏漏斗抽滤,除去未溶解的丁二酸酐,滤饼以少量上述混合溶剂洗涤,合并收集滤液减压浓缩除去反应溶剂,将残留物溶于10 mL二氯甲烷中,反应液依次用1N HCl溶液(10 mL×2)、饱和NaCl溶液(10 mL×1)洗涤,有机层用无水Na2SO4干燥后,减压浓缩除去溶剂,残留物经硅胶柱层析纯化(二氯甲烷: 甲醇=80: 1),得到435.0 mg透明无色油状产物22,收率92.29%。1H NMR (400 MHz, Chloroform-d) δ: 5.33 (dd, J=5.0, 2.6 Hz, 1H), 4.26 (t, J=4.4, 2H), 3.80-3.48 (m, 14H), 3.18 (ddt, J=11.3,8.9, 4.4 Hz, 1H), 2.65 (s, 4H), 0.8-2.50 (remain CHOLE protons), 0.67 (s,3H)。
实施例9 化合物23的制备
将化合物22(435.0 mg,0.656 mmol)置于反应瓶中,氩气置换3次,加入3 mL无水二氯甲烷溶解,氩气保护下依次加入二环己基碳二亚胺(DCC,270.3 mg,1.312 mmol)、4-二甲氨基吡啶(DMAP,24.07 mg,0.197 mmol),于0℃下活化30 min。将四甘醇(637.27 mg,3.281 mmol)溶于3 mL无水二氯甲烷中,氩气保护下缓慢滴加入上述反应液中,加毕,移至室温搅拌4 h。TLC监测反应完全,过滤除去不溶物,收集滤液减压浓缩除去反应溶剂,将残留物溶于10 mL二氯甲烷中,反应液依次用1N HCl溶液(10 mL×1)、水(10 mL×1)、饱和NaCl溶液(10 mL×1)洗涤,有机层用无水硫酸钠干燥后,减压浓缩除去溶剂,残留物经硅胶柱层析纯化(二氯甲烷: 甲醇=80: 1),得透明无色油状化合物302.2 mg,收率54.87%。1HNMR (400 MHz, Chloroform-d) δ: 5.33 (d, J=5.1 Hz, 1H), 4.24 (q, J=4.7 Hz,4H), 3.74-3.50 (m, 28H), 3.23-3.11 (m, 1H), 2.66 (s, 4H), 0.8-2.50 (remainCHOLE protons), 0.66 (s, 3H)。
实施例10 化合物24的制备
将N-叔丁氧基羰基甘氨基(177.8 mg,1.015 mmol)溶解于3 mL无水二氯甲烷中,氩气保护下依次加入EDCI(292.0 mg,1.523 mmol)、DMAP(186.1 mg,1.523 mmol)和DIPEA(328.0 mg,2.665 mmol),于-5℃下活化30 min。将化合物23(284.0 mg,0.338 mmol)溶于2.5 mL无水二氯甲烷后,缓慢加入上述反应液中,加毕,移至室温搅拌2.5 h。TLC监测反应完全,反应液依次用1N HCl溶液(10 mL×2)、饱和NaHCO3溶液(10 mL×1)、饱和NaCl溶液(10 mL×1)洗涤,有机层用无水Na2SO4干燥后,减压浓缩除去溶剂,残留物经硅胶柱层析纯化(二氯甲烷: 甲醇=60: 1),得295.0 mg透明无色油状化合物24,收率87.61%。
1H NMR (400 MHz, Chloroform-d) δ: 5.33 (d, J=4.9 Hz, 1H), 5.07 (s,1H), 4.27 (m, 6H), 3.93 (d, J= 5.6 Hz, 2H), 3.81-3.52 (m, 24H), 3.17 (tt, J=10.9, 5.8 Hz, 1H), 2.66 (d, J=4.5 Hz, 4H), 1.46 (s, 9H), 0.8-2.50 (remainCHOLE protons), 0.67 (d, J=4.4 Hz, 3H)。
实施例11 化合物25的制备
将化合物24(282.0 mg,0.283 mmol)用3.5 mL二氯甲烷溶解,于0℃搅拌下加入CF3COOH(968.2 mg,8.491 mmol),加完后移至室温,继续反应45 min,TLC监测反应完全,减压浓缩除去溶剂,得到淡棕色油状物242.0 mg,收率84.65%,产品不经纯化可直接用于下一步反应。
实施例12 化合物Ⅱ的制备
将化合物24(282.0 mg,0.283 mmol)用3.5 mL二氯甲烷溶解,于0℃搅拌下加入CF3COOH(968.2 mg,8.491 mmol),加完后移至室温,继续反应45 min,TLC监测反应完全,减压浓缩除去溶剂,得到淡棕色油状物242.0 mg,收率84.65%,产品不经纯化可直接用于下一步反应。
实施例13 脂质体的制备
薄膜-水化超声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,本文选择采用薄膜-水化超声法来制备载紫杉醇脂质体。
根据本课题组前期对载紫杉醇脂质体的处方摸索,我们选取最优化处方:①PTX-Lip:大豆磷脂:胆固醇=65:35,②PTX-Glu3-Lip/ PTX-Bio2-Lip:大豆磷脂:胆固醇:Glucose3-Chol/Biotin2-Chol配体=65:31:4,③PTX-Glu3+Bio2-Lip:大豆磷脂:胆固醇:Glucose3-Chol配体:Biotin2-Chol配体=65:27:4:4,④PTX-(Glu3+Bio2)1/2-Lip:大豆磷脂:胆固醇:Glucose3-Chol配体:Biotin2-Chol配体=65:31:2:2;药脂质量比为脂质:紫杉醇=22:1,水化液为pH 7.4的磷酸盐缓冲液(PBS,0.01 M)。我们用上述处方分别制备了5种载紫杉醇脂质体: PTX-Lip、PTX-Glu3-Lip、 PTX-Bio2-Lip、 PTX-Glu3+Bio2-Lip、PTX-(Glu3+Bio2)1/2-Lip。
具体操作如下:准确称取处方量脂质材料和紫杉醇于50 mL茄型烧瓶中,用适量氯仿-甲醇的混合溶液(v/v=2/1)溶解,于37 ℃恒温水浴旋转蒸发除去溶剂后得均匀完整的脂质薄膜,真空干燥过夜除去残余溶剂。加入pH 7.4的PBS缓冲液,于20 ℃恒温空气浴摇床,180 rpm条件下水化30 min后,冰水浴下探头超声(80W,5S,5S)3分钟,即得略带乳光的脂质体溶液。
实施例14 脂质体的包封率及粒径与电位的测定
根据文献报道,本申请采用冷冻离心的方法将未包载的游离紫杉醇与载紫杉醇脂质体分离。按实施例13所述方法分别制备PTX-Lip、PTX-Glu3-Lip、 PTX-Bio2-Lip、 PTX-Glu3+Bio2-Lip、PTX-(Glu3+Bio2)1/2-Lip。取部分上述载紫杉醇脂质体溶液在4 ℃条件下,10000 rpm离心20分钟,上清液即为不含游离紫杉醇的脂质体。分别取30 μL离心后的上清液和离心前的脂质体样品,加入270μL甲醇,涡旋震摇10分钟使之完全破乳后,再次10000rpm离心10分钟,取上清液注入高效液相色谱仪进行分析,并按公式计算载紫杉醇脂质体的包封率(encapsulation efficiency,EE%):EE% = A离心后/A离心前× 100%,其中,A离心后和A离心前分别指离心后和离心前的脂质体样品的峰面积。还对上述5种载紫杉醇脂质体进行了粒径和Zeta电位的测定。将所制得的脂质体用超纯水稀释到适宜浓度后,采用激光粒度及Zeta电位分析仪测定脂质体的粒径及电位,各组脂质体的粒径、电位及包封率见表1。此外,磷钨酸负染后于置于透射电子显微镜(TEM)下观察PTX-(Glu3+Bio2)-2-Lip的形态并拍照,结果如图1。
表1 不同配体修饰的载紫杉醇脂质体的粒径、电位及包封率(n=3,mean ± SD)
结果表明这5种载紫杉醇脂质体包封率(EE%)均大于85%,表明紫杉醇在脂质体中负载良好;粒径均在120 nm左右,聚合物分散性指数(polymer dispersity index,PDI)均在0.2左右,脂质体呈现均匀分布;Zeta电位为弱负电性(约−5mV),可降低网状内皮系统的吸收和免疫反应。上述所有的结果都有助于脂质体通过增强渗透性和保留效应(EPR效应)实现被动靶向。此外,图1显示脂质体在透射电子显微镜(TEM)下呈规则的圆形和合适的尺寸。
实施例15 血清稳定性评价
采用浊度法测定不同配体修饰的载紫杉醇脂质体在50%胎牛血清中的透光率,具体操作如下:取各组载紫杉醇脂质体分别与等体积的胎牛血清混合均匀,于37 ℃恒温摇床中缓慢震摇(45 rpm),于0 h、1 h、2 h、4 h、6 h、8 h、12 h、24 h、48 h分别取样,通过酶标仪测定样品在750 nm处的吸光度值,并换算成透光率。
结果(图2)表明,所有脂质体在和胎牛血清共孵育48小时后,其透光率仍大于90%,无明显的聚集现象,表明所制备的脂质体具有较好的血清稳定性,这对于获得较长的体内血液半衰期具有重要意义,这也为进一步的体内实验奠定了基础。
实施例16 细胞摄取实验
按实施例13中载紫杉醇脂质体的制备方法,将紫杉醇替换为荧光剂CFPE,制备CFPE标记的脂质体。首先从体外细胞水平验证各组脂质体的血脑屏障及脑胶质瘤靶向性,将鼠源脑毛细血管内皮细胞bEnd.3细胞、鼠源脑胶质瘤细胞C6细胞,以3 × 105个/孔的密度接种于12孔板内,培养24h后,将CFPE标记的各种脂质体分别加入细胞板内,用无血清培养基稀释后加入孔板中,使得CFPE在细胞孔板中的最终浓度为2μg/ml。在37°C条件下孵育2h 后,弃去含药培养基并用预冷PBS洗涤2次,消化收集细胞,于4 ℃下离心(2000 rpm×3min),弃去上清并用冰 PBS 清洗细胞三次,将细胞用PBS重悬,用流式细胞仪检测两种细胞的荧光强度,其结果如图3A、3B所示。
在定量检测脂质体入胞情况的同时,我们还将采用激光扫描共聚焦显微镜从定性的角度直接观察各组CFPE标记的脂质体在 bEnd.3细胞和C6细胞中的摄取情况。具体操作如下:将bEnd.3、C6细胞以5 × 105个/孔的密度接种于预铺盖玻片的 6 孔板内,于37 ℃、5% CO2条件下培养24 h。将CFPE标记的各种脂质体分别加入细胞板内,使得CFPE在细胞孔板中的最终浓度为2μg/ml。在37°C下孵育 2h 后弃去含药培养基并用冷 PBS 清洗三次,每次5 min,加入4% 多聚甲醛室温固定 30min,弃去多聚甲醛,PBS清洗3次,每次5 min。再用5μg/mL DAPI 染细胞核 5min 后,弃去染料,PBS清洗3次后,在载破片上滴加抗荧光淬灭剂,将盖玻片倒置于载玻片上,封片后置于激光扫描共聚焦显微镜下观察成像。结果如图4A、4B所示。
共聚焦拍摄的定性摄取结果与流式细胞仪的定量摄取结果一致,数据表明,本发明设计的智能配体材料a和配体材料b单独修饰的脂质体相比空白脂质体在bEnd.3细胞和C6细胞的摄取均提高了约一倍,同时,本发明联合使用智能配体材料a、b制成的双重配体修饰的脂质体相对空白脂质体在bEnd.3细胞上的摄取提高了约2.02倍,在C6细胞上的摄取提高了约2.53倍,说明本发明设计的分枝葡萄糖和生物素配体可提高脂质体的BBB透过率和脑胶质瘤靶向性,且在胆甾数目保持一致的情况下,两种配体双重修饰的脂质体(Glu3+Bio2)1/2-Lip相较于单配体修饰的脂质体Glu3-Lip/ Bio2-Lip摄取效果更强,说明双配体修饰的脂质体相较于单配体修饰的脂质体,能进一步提高脂质体的BBB和脑胶质瘤靶向能力,使更多的脂质体能够进入到脑胶质瘤细胞中,从而发挥更强的药效。
Claims (9)
2.根据权利要求1所述的葡萄糖修饰的脑胶质瘤靶向智能脂质体材料(配体材料a)的结构特征在于:以经1,3-丙二醇链延长的季戊四醇为分枝骨架,其中三端通过酯化反应连接葡萄糖基,另一端则与胆固醇-寡聚乙二醇通过酯缩合相连。
3.根据权利要求1所述的生物素修饰的脑胶质瘤靶向智能脂质体材料(配体材料b)的结构特征在于:胆固醇经过与四甘醇、丁二酸的多个缩合反应延长桥链,再通过甘氨酸分子引入氨基用以连接双分枝生物素中间体。
4.根据权利要求3所述的脑胶质瘤靶向智能脂质体材料(配体材料b)的结构,其合成路线特征在于:以胆固醇为原料,3位的羟基通过TsCl活化后与四甘醇成醚得到胆固醇-四甘醇衍生物,再依次与丁二酸酐反应、与四甘醇缩合,所得化合物再与Boc保护的甘氨酸(N-叔丁氧基羰基甘氨基)缩合,继而经CF3COOH脱保护暴露出游离氨基,从而与双分枝生物素靶向中间体部分缩合得到目标化合物。
5.根据权利要求1所述的脑胶质瘤靶向智能脂质体材料作为药物载体在制备脑胶质瘤靶向药物中的应用。
6.根据权利要求1所述的脑胶质瘤靶向智能脂质体材料所制成的脑胶质瘤靶向脂质体,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材料组成,其中,各组分配比关系如下:胆固醇和磷脂的摩尔比为1:2,脂质体配体材料的摩尔含量为胆固醇和磷脂的总摩尔数的0.8~10%;本发明所述的活性剂采用治疗剂或显影剂,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%;水化液为pH 7.4的0.01 M磷酸盐缓冲液(PBS)。
7. 根据权利要求1所述的脑胶质瘤靶向智能脂质体材料所制成的脑胶质瘤靶向脂质体,其特征在于,根据上述组分配比关系,采用薄膜水化法制备脑胶质瘤靶向脂质体,可制备得到粒径及Zeta电位稳定的脑胶质瘤靶向脂质体,其脂质体粒度为120 nm左右,包封率大于85%。
8.根据权利要求1所述的脑胶质瘤靶向智能脂质体材料所制成的脑胶质瘤靶向脂质体,其特征在于,所述磷脂本发明中采用卵磷脂。
9.根据权利要求1所述的脑胶质瘤靶向智能脂质体材料所制成的脑胶质瘤靶向脂质体,其特征在于,本发明所述的活性剂采用治疗剂紫杉醇,显影剂采用CFPE。
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