CN111440253A - 立方形环糊精骨架-rgd组合物及其制备方法 - Google Patents
立方形环糊精骨架-rgd组合物及其制备方法 Download PDFInfo
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- CN111440253A CN111440253A CN201910045633.7A CN201910045633A CN111440253A CN 111440253 A CN111440253 A CN 111440253A CN 201910045633 A CN201910045633 A CN 201910045633A CN 111440253 A CN111440253 A CN 111440253A
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Abstract
本发明提供了一种立方形环糊精骨架‑RGD组合物(RGD‑COF)及其制备方法。具体地,本发明的环糊精骨架‑RGD组合物含有具有立方形结构的环糊精骨架(COF)和RGD。本发明的立方形环糊精骨架‑RGD组合物能够逃避巨噬细胞的吞噬和清除,增强对受损血管的迁移性和粘附性,高效地靶向和聚集于受损血管部位的活化血小板,对失控性出血、动脉粥样硬化和脑卒中等血管相关疾病的靶向诊疗具有巨大的应用前景。本发明利用环糊精‑金属有机骨架(CD‑MOF)尺寸可控的优势提供了一种纳米级可静脉注射用或微米级可局部外用的立方形环糊精骨架‑RGD组合物。
Description
技术领域
本发明涉及生物材料领域,更具体地涉及一种立方形环糊精骨架-RGD组合物及其制备方法。
背景技术
血管相关疾病如心肌梗塞和脑卒中的发病率和死亡率在世界范围内均很高。非靶向制剂如尿激酶等溶栓药均存在出血副作用、***暴露面过宽等问题。由于血液循环***复杂的血流动力学和一般载体的快速清除,靶向递送治疗药物或显影剂至血管损伤部位仍面临巨大挑战。载体的理化性质如形状会影响纳米载体的体内命运和生物功能。近年来研究表明,非球形的药物载体可以逃避机体的清除机制,延长循环时间,并增加对血管表面的粘附性。研究形态可控、具有靶向性和非球形形态载体,为血管相关疾病的靶向诊断和高效治疗带来了新的希望。
失控性失血造成的死亡率在医院和战场都很高。在严重受伤的情况下,正常的生理止血过程是远远不够的,比如车祸意外或战争创伤,有效快速止血并降低出血时间成为降低患者死亡率的重要措施。目前临床常用的止血材料如止血纱布、止血纤维、止血绷带都存在局限性,这些止血材料只能用于外出血,且止血时间较长,易与伤口粘连而不易换药,对伤口的感染和化脓无能为力。内出血大部分是因脏器破裂造成,因无法使用外用止血药,使伤后“第一时间”止血几乎不可能。重组人凝血因子VII(rFVII)是全身用止血药的代表,但rFVII具有价格昂贵、易失活、不易保存等缺点,大大限制了其临床应用。血小板制品的免疫原性、不易储存、易失活等缺陷,也限制了其在紧急救治中的应用。因此,用于治疗内出血的可静脉注射的止血材料在临床上具有巨大的需求。综上所述,亟需开发出止血速度更快、效果更佳、且可用于内出血的止血材料。
RGD序列和活化血小板表面GPIIb/IIIa受体的特异性结合是形成止血块的最终通路,同时RGD序列只能与出血部位活化的血小板结合,而正常血液循环中的静息血小板表面没有GPIIb/IIIa受体,因此对循环血小板没有影响。近年来,研究者采用高分子材料负载RGD多肽构建人工血小板成为了止血材料新的研究方向。Lavik小组使用PLGA-PLL作为高分子载体,将GRGDS五肽接到PLGA-PLL-PEG上,构建了一种合成血小板。该人工血小板通过静脉给药,能够靶向激活血小板,促进血小板聚集并进一步触发凝血机制,在大鼠的股动脉损伤模型中能将出血时间降低45%。但是,该人工血小板存在合成方法复杂等缺点。AnirbanSen Gupta团队采用环形RGD修饰纳米脂质体,构建出的人工血小板经尾静脉注射后在小鼠断尾损伤模型中将出血时间降低约50%。Mitragotri团队采用GRGDS修饰PAH-BSA纳米粒模拟血小板的形态和流变性,合成的人工血小板能将小鼠断尾损伤的出血时间降低45%。张建祥团队采用胆酸和聚乙烯亚胺合成的正电荷纳米粒尾静脉注射后,在大鼠的股动脉损伤模型中能将出血时间降低40%左右。檀英霞等人发明了PLGA-PEG纳米颗粒负载RGD的人工血小板PLGA-PEG-RGD。PLGA-PEG-RGD为规则的球形,但粒径大小不均一,虽然可以用作静脉用纳米止血材料。但在大鼠肝损伤模型中的止血效果有限,只能将止血时间降低30%左右。
人工血小板的止血效率,很大程度上取决于纳米粒的表面生物学功能和物理力学性质,如尺寸和形状。纳米载体的形态不仅影响其向血管壁的动态迁移过程,而且还影响它们与活化血小板的粘附和聚集相互作用。与球形颗粒相比,具有各向异性形状的载体(如椭圆体和棒状)具有较高的向血管壁迁移的能力,在生理相关的流动环境中具有较强的粘附性。此外,载体的几何形状也会影响其在体内的循环和清除等过程。因此,调控载体的形状为克服生理屏障,提高止血效率带来了新的希望。
然而,以往大多数研究主要集中在球形载体上,目前还无人尝试将立方形态的载体用于出血的靶向治疗。
发明内容
本发明的目的在于提供一种环糊精骨架-RGD组合物(RGD-COF)及其制备方法和用途。
在本发明的第一方面,提供了一种环糊精骨架-RGD组合物,所述组合物中,环糊精骨架与RGD的质量比为1:0.001-1:1,较佳地为1:0.005-1:0.5;
所述的环糊精骨架-RGD组合物粒径为10nm-50μm,优选为50nm-50μm,更优选为100-500nm或1-5μm。
在另一优选例中,所述组合物为立方形环糊精骨架-RGD组合物。
在另一优选例中,所述立方形环糊精骨架-RGD组合物中,环糊精骨架与RGD的质量比为1:0.001-1:1,较佳地为1:0.005-1:0.5,更佳地为1:0.04-1:0.5。
在另一优选例中,所述立方形环糊精骨架-RGD组合物中,环糊精骨架与RGD的质量比为1:0.005-1:0.1,较佳地为1:0.05。
在另一优选例中,所述立方形环糊精骨架-RGD组合物中环糊精骨架与RGD的质量比为1:0.05。
在另一优选例中,所述立方形环糊精骨架-RGD组合物中,环糊精骨架与RGD的质量比为1:0.049、1:0.08、1:0.005、1:0.015、1:0.05、1:0.016、1:0.065、或1:0.046。
在另一优选例中,所述立方形环糊精骨架-RGD组合物的粒径为50nm-50μm。
在另一优选例中,所述立方形环糊精骨架-RGD组合物的粒径为100-500nm。
在另一优选例中,所述立方形环糊精骨架-RGD组合物的粒径为100-300nm,较佳地为150-200nm。
在另一优选例中,所述立方形环糊精骨架-RGD组合物的粒径为1-50μm、优选30-50μm,更优选为10-30μm。
在另一优选例中,所述立方形环糊精骨架-RGD组合物的粒径为1-5μm。
在另一优选例中,所述立方形环糊精骨架-RGD组合物粒径为200-500nm、100-300nm、200-400nm、200-500nm、1-10μm、1-5μm、30-50μm、或10-30μm。
在另一优选例中,所述RGD包括线性的RGD和环形的RGD。
在另一优选例中,所述RGD为线性的RGD。
在另一优选例中,所述RGD选自下组:RGD、GRGD、RGDS、RGDV、RGDF、GRGDV、GRGDF、GRGDS、RGDDSP、RGDDAP、其他含RGD序列的多肽、或其组合。
在另一优选例中,所述线性的RGD选自下组:线性的RGD、线性的GRGD、线性的RGDS、线性的GRGDS、或其组合。
在另一优选例中,所述环形的RGD选自下组:环形的RGD、环形的GRGD、环形的RGDS、环形的RGDV、环形的RGDF、环形的GRGDV、环形的GRGDF、环形的GRGDS、环形的RGDDSP、环形的RGDDAP、其他含环形RGD序列的多肽、或其组合。
在另一优选例中,所述的环糊精选自下组:α-环糊精(阿尔法环糊精)、β-环糊精(贝塔环糊精)、γ-环糊精(伽马环糊精)、羟丙基-β-环糊精、磺丁基-β-环糊精、甲基-β-环糊精、羧甲基-β-环糊精、或其组合。
在另一优选例中,环糊精选自下组:α-环糊精、β-环糊精、γ-环糊精,进一步优选为γ-环糊精。
在另一优选例中,所述的环糊精为γ-环糊精。
在另一优选例中,所述的环糊精骨架-RGD组合物能将凝血块形成时间降低30%、40%、50%、60%、70%、80%或90%以上。
在另一优选例中,所述的环糊精骨架-RGD组合物能将出血时间缩短50%、60%、70%、80%、85%、90%或95%以上。
在另一优选例中,所述的环糊精骨架-RGD组合物能将失血量降低50%、60%、70%、80%、85%、90%或95%以上。
在本发明的第二方面,提供了一种立方形环糊精骨架-RGD组合物的制备方法,包括步骤:
(1)提供一立方形环糊精-金属有机骨架(CD-MOF);
(2)交联步骤,通过交联剂对(1)中的立方形环糊精-金属有机骨架进行交联,得到环糊精骨架(COF);
(3)RGD修饰步骤,在(2)中所述的环糊精骨架上修饰RGD,得到立方形环糊精骨架-RGD组合物(RGD-COF)。
在另一优选例中,所述步骤(2)中,所述交联为通过交联剂将所述的立方形环糊精-金属有机骨架上的羟基(-OH)交联。
在另一优选例中,所述步骤(2)中,所述环糊精骨架为在水相体系中稳定的环糊精骨架。
在另一优选例中,所述步骤(3)中,在(2)中所述的环糊精骨架表面修饰RGD,得到立方形环糊精骨架-RGD组合物。
在另一优选例中,所述步骤(2)中,还包括:
(2a)任选地,保留COF立方形态的步骤;
(2b)任选地,去除金属离子的步骤。
在另一优选例中,所述交联步骤包括下列子步骤:
(2a)分散步骤,将立方形的环糊精-金属有机骨架分散于有机溶剂A中,得到分散液2a;
(2b)交联剂和催化剂加入步骤,在交联反应温度T条件下向分散液2a中加入交联剂和催化剂A,反应时间t1之后,得到分散液2b;
(2c)任选地,冷却步骤,对分散液2b进行冷却,得到经冷却的分散液2b;
(2d)任选地,终止反应步骤,向经冷却的分散液2b中,加入反应终止剂,得到分散液2d;
(2e)任选地,离心步骤,对分散液2d进行离心,得到晶体2e;
(2f)任选地,洗涤步骤,洗涤晶体2e,得到经洗涤的晶体2f;
(2g)任选地,干燥步骤,对经洗涤的晶体2f进行干燥处理;
(2h)获得立方形的环糊精骨架(COF)。
在另一优选例中,所述分散液2a为混悬液、乳浊液、悬浮液、或胶体。
在另一优选例中,所述分散液2b为混悬液、乳浊液、悬浮液、或胶体。
在另一优选例中,所述分散液2d为混悬液、乳浊液、悬浮液、或胶体。
在另一优选例中,所述交联反应温度T为30-110℃,优选40-100℃,更优选60-90℃,最优选70-80℃。
在另一优选例中,所述交联反应温度T为80℃、40℃、100℃、50℃、70℃、或60℃。
在另一优选例中,所述步骤(2a)中环糊精-金属有机骨架与步骤(2b)中交联剂的摩尔比为1:1-1:20,优选为1:2-1:10,更优选为1:4-1:8。
在另一优选例中,所述步骤(2a)中环糊精-金属有机骨架与步骤(2b)中交联剂的摩尔比为1:6,1:2,1:5,1:10,1:20,1:8,1:15,或1:4。
在另一优选例中,所述步骤(2b)中,交联剂和催化剂在搅拌条件下加入,搅拌速度为200-1000rpm、优选300-800rpm,更优选400-600rpm。
在另一优选例中,所述步骤(2b)中,交联剂和催化剂在搅拌条件下加入,搅拌速度为600rpm、200rpm、1000rpm、900rpm、700rpm、400rpm、500rpm、或700rpm。
在另一优选例中,所述步骤(2b)中,环糊精-金属有机骨架内的羟基通过共价键交联起来。
在另一优选例中,所述步骤(2b)中,反应时间t1为4-48h,优选8-24h,更优选12-16h。
在另一优选例中,所述步骤(2b)中,反应时间t1为24h、48h、4h、12h、8h、或16h。
在另一优选例中,所述步骤(2c)中,冷却为冷却至室温。
在另一优选例中,所述步骤(2d)中,反应终止剂为乙醇。
在另一优选例中,所述步骤(2d)中,反应终止剂为95-100%乙醇或70-90%乙醇。
在另一优选例中,所述步骤(2e)中,离心为在3000-4500rpm下离心3-15min,优选为在4000rpm离心5min。
在另一优选例中,所述步骤(2f)中,所述洗涤为使用乙醇、纯水和/或丙酮洗涤。
在另一优选例中,所述COF为立方体形态。
在另一优选例中,所述COF的粒径为50nm-50μm,优选50-500nm或1-50μm。
在另一优选例中,所述COF的粒径为100-500nm。
在另一优选例中,所述COF的粒径为100-300nm,较佳地为150-200nm。
在另一优选例中,所述COF的粒径为1-50μm、优选30-50μm,更优选为10-30μm。
在另一优选例中,所述COF的粒径为1-5μm。
在另一优选例中,所述COF的粒径为200-500nm、100-300nm、200-400nm、200-500nm、1-10μm、1-5μm、30-50μm、或10-30μm。
在另一优选例中,所述RGD修饰步骤包括下列子步骤:
(3a)分散步骤,将立方形的环糊精骨架(COF)和RGD分散于有机溶剂B中,得到分散液3a;
(3b)偶联步骤,向分散液3a中加入催化剂B,使立方形的环糊精骨架与RGD偶联,反应时间为t2;
(3c)任选地,离心步骤;
(3d)任选地,洗涤步骤;
(3f)任选地,干燥步骤;
(3g)获得立方形环糊精骨架-RGD组合物(RGD-COF)。
在另一优选例中,所述步骤(3b)中,偶联为立方形的环糊精骨架表面的羟基与RGD的羧基偶联。
在另一优选例中,所述分散液3a为混合均匀的分散液。
在另一优选例中,所述分散液3a为混悬液、乳浊液、悬浮液、或胶体
在另一优选例中,所述偶联步骤在加热搅拌条件下进行。
在另一优选例中,所述搅拌过程中,磁力搅拌器转速为200-1000rpm。
在另一优选例中,所述搅拌过程中,磁力搅拌器转速为200rpm、400rpm、500rpm、600rpm、700rpm、900rpm、1000rpm。
在另一优选例中,所述加热温度为20-40℃,优选37-38℃。
在另一优选例中,所述加热温度为20℃、25℃、30℃、35℃、37℃、40℃。
在另一优选例中,所述反应时间t2为4-48h,较佳地为8-24h,更佳地为12-20h。
在另一优选例中,所述反应时间t2为4h、6h、8h、12h、18h、24h、48h。
在另一优选例中,步骤(3a)中,其中COF和RGD的摩尔比为1:0.1-1:10,优选1:0.2-1:5,优选1:1。
在另一优选例中,步骤(3a)中,COF和RGD的摩尔比为1:1、1:2、5:1、4:1、2:1、1:3或1:5。
在另一优选例中,步骤(3g)中,所述立方形环糊精骨架-RGD组合物(RGD-COF)粒径为200-500nm、100-300nm、200-400nm、200-500nm、1-10μm、1-5μm、30-50μm、或10-30μm。
在另一优选例中,所述的交联剂选自下组:过氧化物、多异氰酸酯、缩水甘油醚、二元或多元酸类、二元或多元醛类、含羰基的化合物、环氧化物类、丙烯酸酯类、酰氯类、或其组合。
在另一优选例中,所述过氧化物选自下组:过氧化苯甲酰、过氧化二异丙苯、叔丁基过氧化物、或其组合。
在另一优选例中,所述多异氰酸酯选自下组:异氰酸酯、甲苯二异氰酸酯、二苯基甲烷二异氰酸酯、二环己基甲烷二异氰酸酯、六亚甲基二异氰酸酯、赖氨酸二异氰酸酯、或其组合。
在另一优选例中,所述缩水甘油醚选自下组:乙二醇二缩水甘油醚、聚丙二醇缩水甘油醚、三羟甲基丙烷三缩水甘油醚、正丁基缩水甘油醚、或其组合。
在另一优选例中,所述二元或多元酸类选自下组:柠檬酸、丙二酸、丁二酸、邻苯二甲酸、间苯二甲酸、或其组合。
在另一优选例中,所述二元或多元醛类选自下组:乙二醛、戊二醛、丁二醛、或其组合。
在另一优选例中,所述含羰基的化合物选自下组:碳酸二苯酯、N,N’-羰基二咪唑、N,N’-二甲基咪唑啉、二环己基碳二亚胺、或其组合。
在另一优选例中,所述环氧化物选自下组:环氧氯丙烷、环氧丙烷、1,4-二氧六环、或其组合。
在另一优选例中,所述丙烯酸酯类选自下组:二甲基丙烯酸乙二醇酯、丙烯酸羟乙酯、丙烯酸羟丙酯、甲基丙烯酸、甲基丙烯酸羟乙酯、甲基丙烯酸羟丙酯、或其组合。
在另一优选例中,所述酰氯类选自下组:丁二酰氯、四异氰酸酯、或其组合。
在另一优选例中,所述的交联剂为碳酸二苯酯。
在另一优选例中,所述的交联剂为环氧氯丙烷。
在另一优选例中,所述的催化剂A选自下组:4-二甲氨基吡啶、三乙胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺或其盐、N,N'-琥珀酰亚胺基碳酸酯、N-羟基丁二酰亚胺、吡啶、或其组合;较佳地为三乙胺;
所述的有机溶剂A选自下组:二甲基甲酰胺、四氢呋喃、甲醇、乙腈、丙酮、异丙醇、乙酸乙酯、氯仿、正己烷、乙醇、二氯甲烷。
在另一优选例中,所述的有机溶剂A选自下组:二甲基甲酰胺、四氢呋喃、甲醇、乙腈、丙酮、异丙醇、乙酸乙酯、氯仿、正己烷、乙醇、二氯甲烷、或其组合。
在另一优选例中,所述的有机溶剂A为二甲基甲酰胺。
在另一优选例中,所述的催化剂A选自下组:4-二甲氨基吡啶、三乙胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺或其盐、N,N'-琥珀酰亚胺基碳酸酯、N-羟基丁二酰亚胺、吡啶、或其组合。
在另一优选例中,所述的催化剂A为三乙胺。
在另一优选例中,所述的有机溶剂B选自下组:二甲基甲酰胺、四氢呋喃、甲醇、乙腈、丙酮、异丙醇、乙酸乙酯、氯仿、正己烷、乙醇、二氯甲烷、或其组合。
在另一优选例中,所述的有机溶剂B为二甲基甲酰胺。
在另一优选例中,所述的催化剂B选自下组:4-二甲氨基吡啶、三乙胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺或其盐、N-羟基丁二酰亚胺、N,N'-琥珀酰亚胺基碳酸酯、吡啶、或其组合。
在另一优选例中,所述的催化剂B为4-二甲氨基吡啶。
在另一优选例中,所述的催化剂A选自下组:4-二甲氨基吡啶、三乙胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺或其盐、N,N'-琥珀酰亚胺基碳酸酯、N-羟基丁二酰亚胺、吡啶、或其组合;所述的催化剂B选自下组:4-二甲氨基吡啶、三乙胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺或其盐、N-羟基丁二酰亚胺、N,N'-琥珀酰亚胺基碳酸酯、吡啶、或其组合。
在另一优选例中,所述的有机溶剂A选自下组:二甲基甲酰胺、四氢呋喃、甲醇、乙腈、丙酮、异丙醇、乙酸乙酯、氯仿、正己烷、或其组合;
所述的有机溶剂B选自下组:二甲基甲酰胺、四氢呋喃、甲醇、乙腈、丙酮、异丙醇、乙酸乙酯、氯仿、正己烷、乙醇、二氯甲烷、或其组合。
在另一优选例中,所述的催化剂B选自下组:4-二甲氨基吡啶、三乙胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺或其盐、N-羟基丁二酰亚胺、N,N'-琥珀酰亚胺基碳酸酯、吡啶、或其组合;
所述的有机溶剂B选自下组:二甲基甲酰胺、四氢呋喃、甲醇、乙腈、丙酮、异丙醇、乙酸乙酯、氯仿、正己烷、乙醇、二氯甲烷、或其组合。
在另一优选例中,所述的有机溶剂B为二甲基甲酰胺。
在另一优选例中,所述的催化剂B为4-二甲氨基吡啶。
在另一优选例中,所述RGD序列包括线性的RGD,GRGD、RGDS、GRGDS、环形的RGD,GRGD、RGDS、GRGDS,优选线性的RGD序列,包括GRGD、RGDS、GRGDS。
在本发明的第三方面,提供了一种负载药物的立方形环糊精骨架-RGD组合物,所述立方形环糊精骨架-RGD组合物为本发明的第一方面所述的组合物,或通过本发明的第二方面所述的方法制备,所述的药物选自下组:抗菌药物、止血药物、抗血栓药物、抗感染药物、或其组合。
在另一优选例中,所述抗菌药物选自下组:纳米银、青霉素、头孢霉素、米诺环素、多西环素、四环素、氯霉素、林可霉素、万古霉素、或其组合。
在另一优选例中,所述止血药物选自下组:氨甲环酸、氨基己酸、维生素K1、或其组合。
在另一优选例中,所述抗血栓药物选自下组:阿司匹林、氯吡格雷、噻氯匹定、西洛他唑、替罗非班、奥扎格雷、利伐沙班、或其组合。
在另一优选例中,所述抗感染药物选自下组:磺胺嘧啶、头孢曲松、阿莫西林、左氧氟沙星、或其组合。
在另一优选例中,所述的负载药物的立方形环糊精骨架-RGD组合物可用于静脉注射(纳米级)和局部用药(微米级)。
在另一优选例中,所述组合物还具有以下一个或多个特征:
(1)所述的环糊精骨架-RGD组合物粒径为50nm-50μm,优选为100-500nm或1-5μm;
(2)所述组合物的载药量为1%-20%,优选为5%-10%。
在另一优选例中,所述的环糊精骨架-RGD组合物粒径为100-500nm;或者所述的环糊精骨架-RGD组合物粒径为1-5μm。
在另一优选例中,所述组合物的载药量为2.1%-13.5%。
在另一优选例中,所述组合物的载药量进一步优选为2.7%-8.6%。
在另一优选例中,所述的环糊精骨架-RGD组合物为粉体形式。
在另一优选例中,所述的环糊精骨架-RGD组合物为颗粒形式。
在另一优选例中,所述的负载药物的立方形环糊精骨架-RGD组合物能将凝血块形成时间降低30%、40%、50%、60%、70%、80%或90%以上。
在另一优选例中,所述的负载药物的立方形环糊精骨架-RGD组合物能将出血时间缩短50%、60%、70%、80%、85%、90%或95%以上。
在另一优选例中,所述的负载药物的立方形环糊精骨架-RGD组合物能将失血量降低50%、60%、70%、80%、85%、90%或95%以上。
在本发明的第四方面,提供了一种活性成分的用途,所述活性成分选自下组:
(i)本发明的第一方面所述环糊精骨架-RGD组合物;
(ii)本发明的第三方面所述的负载药物的立方形环糊精骨架-RGD组合物;
(iii)环糊精骨架(COF);
(iv)上述(i)、(ii)或(iii)的组合;
所述活性成分被用于:
(a)制备载药材料;
(b)制备治疗和/或诊断试剂或试剂盒;
(c)制备止血药物和/或材料;
(d)制备抗感染药物和/或材料;
(e)制备抗菌药物和/或材料;
(f)制备促进伤口愈合药物和/或材料;
(g)制备预防和/或治疗血栓的药物和/或材料。
在另一优选例中,所述治疗和/或诊断试剂或试剂盒用于疾病治疗和/或诊断。
在另一优选例中,所述疾病选自下组:血栓、动脉粥样硬化、脑卒中、肿瘤、出血、炎症、感染。
在另一优选例中,所述诊断试剂或试剂盒用于医学CT显影。
在另一优选例中,所述治疗和/或诊断试剂或试剂盒用于抗肿瘤、止血、抗炎、抗感染。
在另一优选例中,所述的止血药物和/或材料能将凝血块形成时间降低30%、40%、50%、60%、70%、80%或90%以上。
在另一优选例中,所述的止血药物和/或材料能将出血时间缩短50%、60%、70%、80%、85%、90%或95%以上。
在另一优选例中,所述的止血药物和/或材料能将失血量降低50%、60%、70%、80%、85%、90%或95%以上。
在本发明的第五方面,提供了一种药物组合物,所述药物组合物包含:
(1)活性成分,所述活性成分为如本发明的第一方面所述的环糊精骨架-RGD组合物或如本发明的第三方面所述的负载药物的立方形环糊精骨架-RGD组合物;和
(2)药学上可接受的载体。
在另一优选例中,所述药物组合物为胶囊剂、片剂、颗粒剂。
在另一优选例中,所述的载体选自下组:稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂、或其组合。
在另一优选例中,所述的药物组合物配制为固体剂型或液体剂型,较佳地适用于口服给药,更佳地适用于注射给药。
在另一优选例中,固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
在另一优选例中,液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。
在另一优选例中,所述药物组合物为胶囊剂、片剂、颗粒剂、注射剂。
在另一优选例中,所述药物组合物还包含表面活性剂,选自下组:聚山梨坦-80、聚山梨坦-60、聚乙二醇甘油脂肪酸酯、脱水山梨糖醇脂肪酸酯及两种以上的混合物。
在另一优选例中,所述的药物组合物能将凝血块形成时间降低30%、40%、50%、60%、70%、80%或90%以上。
在另一优选例中,所述的药物组合物能将出血时间缩短50%、60%、70%、80%、85%、90%或95%以上。
在另一优选例中,所述的药物组合物能将失血量降低50%、60%、70%、80%、85%、90%或95%以上。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1为实施例1中纳米CD-MOF的扫描电镜图。
图2为实施例1中纳米COF的扫描电镜图。
图3为实施例1中纳米RGD-COF的扫描电镜图。
图4为实施例1中纳米RGD-COF动态光散射粒径分布图。
图5为实施例1中纳米RGD-COF的物理稳定性(■:纯水;●:生理盐水;▲:PBS pH7.4;◆:大鼠血浆)。
图6为实施例1中纳米RGD-COF的细胞毒性结果。
图7为实施例6中微米CD-MOF的扫描电镜图。
图8为实施例6中微米COF的扫描电镜图。
图9为实施例6中微米RGD-COF的扫描电镜图。
图10为实施例9中球形RGD-NS的扫描电镜图。
图11为实施例10中的RGD-COF的体外凝血块形成时间结果。
图12显示实施例11中RGD-COF可以显著降低小鼠断尾模型的体内出血时间。
图13显示实施例11中RGD-COF可以显著降低小鼠断尾模型的体内失血量。
图14显示实施例12中载银RGD-COF等的时间-抗菌曲线。
图15显示实施例12中载银RGD-COF等对大鼠创口的愈合效果。
图16显示实施例16中RGD-COF可以靶向体内肠系膜血栓,与血栓部位的活化血小板有高度共定位。
具体实施方式
本发明人经过广泛而深入地研究,首次开发了一种立方形环糊精骨架-RGD组合物(RGD-COF)及其制备方法。本发明的立方形环糊精骨架-RGD组合物含有具有立方形结构的环糊精骨架和RGD,能够逃避巨噬细胞的吞噬和清除,增强对受损血管的迁移性和粘附性,高效地靶向和聚集于血管损伤部位的活化血小板,实现血管相关疾病(例如出血、血栓)的靶向治疗。利用CD-MOF尺寸可控的优势,以纳米级和微米级CD-MOF为基础材料,经交联步骤和RGD修饰步骤,获得了静脉注射用(纳米级)或外用(微米级)的新型高效的载体材料。具体而言,本发明所述的纳米级立方形环糊精骨架-RGD组合物通过静脉注射可以在小鼠断尾损伤模型中将出血时间和失血量均降低90%;微米级环糊精骨架-RGD组合物通过局部外用,可以在大鼠股动脉损伤模型中将出血时间降低60%,止血效率大大提高。在此基础上,完成本发明。
术语
金属有机骨架材料
金属有机骨架(metal organic frameworks,MOF)是一种由金属(金属离子、金属离子簇或金属链)和有机桥连配体在较温和的条件下以配位键方式通过自组装形成的无机-有机杂化材料。由于MOF超高的孔隙率和巨大的比表面积,且无机和有机等多种不同成分的组合使得其结构及组成多样,为MOF在气体储存、吸附和分离、催化、药物输送等领域的应用提供了新的研究方向。
环糊精
环糊精(CD)是由直链淀粉经葡萄糖基转移酶作用下生成的一系列环状低聚糖的总称,通常含有6~12个D-吡喃葡萄糖单元。其中研究得较多并且具有重要实际意义的是含有6、7、8个葡萄糖单元的分子,分别称为α、β-和γ-环糊精。环糊精是迄今所发现的类似于酶的理想宿主分子,并且其本身就有酶模型的特性。
环糊精-金属有机骨架
如本文所用,术语“环糊精-金属有机骨架”、“CD-MOF”可互换使用,是将环糊精作为有机配体,金属离子作为无机金属中心形成的新型、安全性较高、可药用的立方形环糊精-金属有机骨架,即CD-MOF。
典型地,所述环糊精-金属有机骨架为环糊精与碱金属盐形成的骨架材料;碱金属包括但不限于Li+、K+、Rb+、Cs+、Na+、Mg2+、Cd2+、Sn2+、Ag+、Yb+、Ba2+、Sr2+、Ca2+、Pb2+、La3+,优选K+。
典型地,所述环糊精-金属有机骨架材料的平均粒径为50纳米-50微米,较佳地为100-500纳米(纳米级)或1-5微米(微米级)。
典型地,制备环糊精-金属有机骨架(CD-MOF)(参考专利201610125456.X):所述制备方法包括将金属盐溶液与环糊***溶液混合后,预加一部分有机溶剂,一定温度下,通过溶剂蒸汽扩散方法,反应一定时间,再加入尺寸调节剂,从而得到所述基于环糊精的金属有机骨架材料;或将金属盐溶液与环糊***溶液混合,预加一部分有机溶剂,用溶剂热/微波/超声波振动反应介质,使得反应物快速反应,反应一定时间后加入尺寸调节剂,从而得到所述基于环糊精的金属有机骨架材料。
典型地,所述金属盐溶液中金属盐的浓度为0.05-0.4M,优选0.2M。
典型地,所述环糊***溶液中环糊精的浓度为0.013-0.05M,优选0.025M。
典型地,所述的环糊精选自下组:α-环糊精、β-环糊精、γ-环糊精、羟丙基-β-环糊精、磺丁基-β-环糊精、甲基-β-环糊精、羧甲基-β-环糊精、或其组合。
在本发明的一个优选的实施方式中,所述的环糊精为γ-环糊精。
在本发明的一个优选的实施方式中,所述环糊精-金属有机骨架为立方形。
在本发明的一个优选的实施方式中,所述的环糊精-金属有机骨架的制备包括步骤:
(1a)提供第一混合溶液,所述第一混合溶液为含有金属离子和环糊精的溶液;
(2a)向所述的第一混合溶液中加入第一有机溶剂,获得第二混合溶液,
其中,所述第一有机溶剂与所述第一混合溶液的体积比为(0.01-0.5):1,较佳地为(0.03-0.3):1,最佳地为(0.05-0.2):1;
(3a)对所述第二混合溶液进行预处理,获得经预处理的第一混合物,其中所述的预处理选自下组:
(3a1)溶剂热挥发处理;
(3b1)溶剂热挥发处理与选自A组的任一处理方式的组合,其中A组包括溶剂热处理、微波处理、超声波处理、或其组合;
(4a)当第一混合物中含有析出的环糊精-金属有机骨架材料时,从所述第一混合物中分离获得析出的环糊精-金属有机骨架材料;
或者从所述第一混合物中分离出部分或全部的溶液,作为第三混合溶液;并向所述第三混合溶液中加入第二有机溶剂和/或尺寸调节剂,从而析出环糊精-金属有机骨架材料;和
(5a)任选地对步骤(4a)中析出的环糊精-金属有机骨架材料进行分离和/或干燥。
在另一优选例中,在步骤(3a)中,所述的溶剂热挥发处理包括步骤:
(i)将混合溶液置于一开口容器I中;
(ii)提供一装有有机溶剂的开口容器II,将所述开口容器I和开口容器II共同置于一封闭体系内;和
(iii)对所述开口容器II中的有机溶剂进行加热/保温处理,使得所述有机溶剂蒸发扩散至混合溶液中。
在另一优选例中,在步骤(iii)中,对所述封闭体系进行整体加热处理,从而加热所述开口容器II中的有机溶剂
在另一优选例中,在步骤(iii)中,所述加热处理包括水浴加热、和油浴加热。
在另一优选例中,在步骤(iii)中,所述加热处理的温度为25-100℃,较佳地为30-80℃,更佳地为40-60℃。
在另一优选例中,在步骤(iii)中,所述加热处理的时间为4-48h,较佳地为6-24h。
环糊精骨架材料
术语“环糊精骨架材料”、“环糊精骨架”、“立方形的环糊精骨架”、“立方形环糊精骨架”、“COF”可互换使用。
CD-MOF中含有K+,不能直接静脉注射,且在水性环境中会迅速崩解,在到达靶部位之前无法确保多孔晶体结构的稳定。为了增加CD-MOF在水中的稳定性,迄今为止只报道了三种策略。Furukawa等人使用乙二醇二缩水甘油醚交联γ-CD-MOF以产生γ-CD-MOF水凝胶。然而,此种交联反应极其耗时,在65℃下需要三天以上时间,且需要诸多步骤来除去未反应的杂质。Li等人为了提高γ-CD-MOF的水稳定性,将富勒烯(C60)掺入到γ-CD的疏水空腔中。然而,由于配体-环糊精较弱的相互作用,超分子组装体系只能在较短时间内保持结构的完整性,在水中24h后便降解。此外,C60对γ-CD空腔的占用也可能降低γ-CD-MOF负载药物的能力。综上所述,合成稳定的多孔性CD-MOF材料仍然是一个巨大的挑战。
为此,本发明采用碳酸二苯酯、环氧氯丙烷等作为交联剂将CD-MOF中有序组织的CD交联起来,成功制备了在水中稳定的环糊精骨架(COF),仍然保留了CD-MOF的立方体形态,并且能将配位的K+除去,基于纳米级CD-MOF交联得到的COF可作为静脉注射用的新型纳米载体。
在本发明的一个优选的实施方式中,发明人采用碳酸二苯酯、环氧氯丙烷等作为交联剂成功地交联CD-MOF中的CD。使用三乙胺、吡啶等作为催化剂发明了一种简便的合成途径,能够在4h内合成水中稳定性好的COF。
在本发明的一个优选的实施方式中,所述环糊精骨架(COF)制备方法如下:称取适量制备的CD-MOF粉末于圆底烧瓶中,固定于磁力搅拌器上,加入一定体积的有机溶剂,加热搅拌条件下,再加入一定量的交联剂和催化剂,反应一段时间,使CD-MOF内的羟基(-OH)通过共价键交联起来,然后冷却至室温,采用95%乙醇终止反应后,离心得沉淀,用50%乙醇、纯水和丙酮各洗涤两次后,真空干燥后即得水中稳定的环糊精骨架(COF)。
RGD
RGD序列即精氨酸-甘氨酸-天冬氨酸(Arg-Gly-Asp)序列。内源性RGD序列存在于多种粘附蛋白中(如纤维蛋白原、玻连蛋白、纤维粘连蛋白、血管性血友病因子),发挥着多种生物学功能。纤维蛋白原中Aα链上的RGD序列和活化血小板表面的膜糖蛋白GPIIb/IIIa受体的特异性结合,是血小板聚集和血栓块形成的共同通路。RGD序列作为纤维蛋白原中的特定序列,是纤维蛋白原和活化的GPIIb/IIIa受体结合的活性位点。
本发明所述RGD序列包括线性的RGD、线性的GRGD、线性的RGDS、线性的RGDV、线性的RGDF、线性的GRGDV、线性的GRGDF、线性的GRGDS、线性的RGDDSP、线性的RGDDAP;环形的RGD,环形的GRGD、环形的RGDS、环形的RGDV、环形的RGDF、环形的GRGDV、环形的GRGDF、环形的GRGDS,环形的RGDDSP、环形的RGDDAP。
典型地,本发明所述RGD序列优选线性的RGD序列,包括线性的GRGD、线性的RGDS、线性的RGDF、线性的GRGDS。
立方形环糊精骨架-RGD组合物
如本文所用,术语“立方形环糊精骨架-RGD组合物”、“RGD修饰的COF”、“RGD-COF”、“立方形环糊精骨架-RGD多肽组合物”可互换使用,是指本发明第一方面所述的立方形环糊精骨架-RGD组合物。
典型地,本发明提供的一种立方形环糊精骨架-RGD组合物,其结构特征在于具有立方晶体结构的环糊精-金属有机骨架材料内的羟基(-OH)被合适的交联剂共价连接起来,形成在水中稳定的立方结构的环糊精骨架,外部采用活化剂将表面的羟基(-OH)与RGD的羧基(-COOH)共价连接,对环糊精骨架进行生物学修饰。立方形环糊精骨架作为人工血小板载体,RGD作为靶头,和活化血小板表面GPIIb/IIIa受体的特异性结合,靶向血管损伤部位活化的血小板。RGD修饰后的环糊精骨架材料作为新型高效的人工血小板,该特征能提高人工血小板向受损血管的迁移能力,提高对出血部位的靶向性,并促进与活化血小板的结合。
具体地,本发明提供了一种由COF和RGD组成的立方形环糊精骨架-RGD组合物,其内部为具有立方晶体结构的环糊精骨架,表面采用RGD进行生物学修饰。立方形环糊精骨架作为载体,RGD作为靶头,靶向血管损伤部位活化的血小板表面的GPIIb/IIIa受体。RGD修饰的COF作为新型高效的功能材料,该特征能提高向受损血管的迁移能力,提高对受损部位的靶向性,并促进与活化血小板的结合和聚集。
本发明所述的立方形环糊精骨架-RGD组合物不同于已有的人工血小板报道,Anirban Sen Gupta团队采用RGD和胶原蛋白结合肽修饰球形的脂质体,构建出的人工血小板经尾静脉注射后在小鼠断尾模型中具有一定的止血效果,但靶向性和止血效果仍待提高。檀英霞等人发明了PLGA-PEG纳米颗粒负载RGD的人工血小板PLGA-PEG-RGD。PLGA-PEG-RGD为规则的球形,但粒径大小不均一,虽然可以用作静脉用全身性纳米止血材料,但在大鼠肝损伤模型中的止血效果有限,只能将出血时间降低30%左右。
本发明所述的纳米级立方形环糊精骨架-RGD组合物通过静脉注射可以在小鼠断尾损伤模型中将出血时间和失血量均降低90%,微米级环糊精骨架-RGD组合物通过局部外用,可以在大鼠股动脉损伤模型中将出血时间降低60%,止血效率大大提高。
在本发明的一个优选的实施方式中,所述立方形环糊精骨架-RGD组合物(RGD-COF)制备方法如下:称取适量COF和RGD于圆底烧瓶中,加入一定体积的有机溶剂B,混合均匀后再加入适量的催化剂B和活化剂,置于磁力搅拌器上加热搅拌适当时间,使COF表面的羟基(-OH)与RGD的羧基(-COOH)充分偶联。反应完成后,分别使用等体积的无水DMF和纯水各洗涤2遍,冷冻干燥过夜即得立方形环糊精骨架-RGD组合物(产物简写为RGD-COF),置于-20℃冷冻保存备用。
本发明提供的立方形环糊精骨架-RGD组合物(RGD-COF)具有高效的靶向性能,可静脉注射用于全身性失血和血栓,也可局部用药治疗外伤,为复杂战争创伤、意外创伤、外科手术出血、脑卒中和肿瘤相关疾病的救治提供了更多选择,应用前景广阔。
立方形环糊精骨架-RGD组合物的制备方法
本发明提供了立方形环糊精骨架-RGD组合物的制备方法。
在本发明的一个优选的实施方式中,采用可药用的环糊精作为有机连接体,K+作为无机金属中心,制备立方体形态、粒径均一的CD-MOF,采用交联剂将CD-MOF的CD通过交联,制备水相中稳定的COF,将RGD序列的羧基(-COOH)通过酯键的方式键合在COF表面,形成立方形环糊精骨架-RGD组合物(RGD-COF)。本发明所涉及的CD-MOF,是基于一种制备环糊精-金属有机骨架材料的方法(201610125456.X),该方法快速、简便,尺寸可调节、产率高。
在本发明的又一个优选的实施方式中,所述立方形环糊精骨架-RGD组合物(RGD-COF)的制备方法包括步骤:
(1)制备立方形环糊精-金属有机骨架(CD-MOF);
(2)通过交联剂对所述的立方形环糊精-金属有机骨架(CD-MOF)进行交联,去除金属离子,保留立方形态,得到环糊精骨架(COF);
较佳地,具体交联反应过程为:将立方形的环糊精-金属有机骨架分散于有机溶剂A中,一定温度下搅拌条件下加入交联剂和催化剂A进行反应,使环糊精-金属有机骨架内的羟基通过共价键交联起来,经冷却、乙醇终止反应、离心、洗涤和干燥,得到立方形的环糊精骨架(COF);
(3)在所述的立方形环糊精骨架表面修饰RGD,得到所述的立方形环糊精骨架-RGD组合物(RGD-COF);较佳地,具体的RGD修饰过程为:将立方形环糊精骨架和RGD按照一定比例加入有机溶剂B中,混合均匀后加入催化剂B加热搅拌,使立方形环糊精骨架表面的羟基与RGD的羧基充分偶联,反应完成后洗涤干燥得立方形环糊精骨架-RGD组合物(RGD-COF)。
药学上可接受的载体
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的主要优点在于:
本发明提供了一种可静脉注射用(纳米级)或局部用药(微米级)的立方形环糊精骨架-RGD组合物(RGD-COF)及其制备方法,其安全性高、生物相容性好。可用于血管相关疾病的靶向治疗,包括创伤失血、深部出血、动脉粥样硬化、脑卒中、血栓和肿瘤等疾病,具有以下技术优点:
(1)本发明RGD-COF具有规则的立方体形态,突破以往载体球形形态的限制,有效逃避巨噬细胞的吞噬和清除,增强对受损血管的迁移性和粘附性,提高靶向性和治疗效率。
(2)本发明采用RGD序列修饰后,立方形的RGD-COF可以高效地靶向和聚集于血管损伤部位的活化血小板,实现血管相关疾病的靶向治疗,减少对正常血液循环***的影响和副作用。
(3)本发明充分发挥CD-MOF尺寸可控的优势,以纳米级和微米级CD-MOF为基础材料,经交联步骤和RGD修饰步骤,获得了可静脉注射用和/或可外用的新型高效的载体材料。静脉注射给药适于复杂条件下的创伤救治,适用于全身性失血的控制和血栓类疾病;微米级RGD-COF可用于车祸、手术等外部创伤的止血、抗炎和抗感染治疗。
(4)本发明中的RGD-COF具有良好的稳定性,可制成冻干粉使用,利于保存,适合在野外条件下使用,比如装备部队,提高复杂战创伤救治能力。
(5)本发明制备方法简单可控、无需昂贵的设备、可大规模生产、不具有免疫原性,不会传播传染性疾病。
(6)本发明其制备方法简单,安全性高、生物相容性好,可用于创伤失血、脏器内出血、深部出血等失控性出血和血栓类疾病的靶向诊断和治疗。
下面的具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,例如(Sambrook和Russell等人,分子克隆:实验室手册(Molecular Cloning-A LaboratoryManual)(第三版)(2001)CSHL出版社)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例1
制备纳米级CD-MOF:使用溶剂热的方式,直接对γ-CD与KOH水溶液与一部分有机溶剂混合体系进行加热。称取163.0mgγ-CD和56.0mg KOH混合物(γ-CD和KOH摩尔比为1:8)溶解于5m L水中,预加3mL甲醇至混合溶液内,50℃水浴加热20min后,取出溶液,加入等体积的甲醇,再加入64mg PEG20000,静置1h后,4000rpm离心5min,分别用乙醇(10mL×2)、二氯甲烷(10mL×2)洗涤,将所得晶体50℃真空干燥12h,即得纳米级CD-MOF晶体(CD-MOF-Nano),得到的CD-MOF为规则的立方体形态,粒径为200-500nm(图1)。
制备纳米级COF:称取778.3mg纳米级CD-MOF粉末于圆底烧瓶中,固定于磁力搅拌器上,加入10mL二甲基甲酰胺,80℃加热,600rpm搅拌条件下,加入771mg交联剂碳酸二苯酯(CD-MOF与交联剂的摩尔比为1:6)和450μL催化剂三乙胺,反应24h后,冷却至室温,采用20mL 95%乙醇终止反应后,4000rpm离心5min,分别用50%乙醇(10mL×2)、纯水(10mL×2)和丙酮(10mL×2)洗涤,将所得晶体50℃真空干燥12h即得水中稳定的纳米COF,产率为61%,得到的COF为规则的立方体形态,粒径为200-500nm(图2)。
制备纳米级环糊精骨架-RGD组合物(RGD-COF):称取230mg纳米级COF和10mg线性GRGDS五肽(COF和GRGDS的摩尔比为1:1)置于圆底烧瓶中,加入5mL二甲基甲酰胺,搅拌均匀后再加入5mg 4-二甲氨基吡啶和6mg 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,置于磁力搅拌器上37℃,600rpm搅拌12h,使COF与GRGDS多肽充分偶联。反应完成后,4000rpm离心5min,分别用二甲基甲酰胺(10mL×2)和纯水(10mL×2)洗涤,-50℃冷冻干燥12h即得GRGDS修饰的COF,SEM(图3)和DLS(图4)结果显示得到的RGD-COF为规则的立方体形态,粒径为200-500nm,高效液相色谱法(HPLC)测得环糊精骨架材料与RGD的质量比为1:0.049。
制备的RGD-COF在纯水、磷酸盐缓冲溶液(PBS,pH=7.4)、生理盐水和大鼠血浆中均具有良好的物理稳定性(图5)。MTT结果显示RGD-COF无细胞毒性,具有良好的生物相容性和安全性(图6)。
实施例2
同实施例1制备纳米级CD-MOF。
制备纳米级COF:称取778.3mg纳米级CD-MOF粉末于圆底烧瓶中,固定于磁力搅拌器上,加入10mL乙腈,40℃加热,200rpm搅拌条件下,加入194.6mg交联剂N,N'-羰基二咪唑(CD-MOF与交联剂的摩尔比为1:2)和450μL催化剂吡啶,反应48h,其余同实施例1,得到的COF为规则的立方体形态,粒径为100-300nm。
制备纳米级RGD-COF:称取230mg纳米级COF和14mg线性RGD(COF和RGD的摩尔比为1:2)置于圆底烧瓶中,加入5mL乙腈,搅拌均匀后再加入5mg N,N'-琥珀酰亚胺基碳酸酯和6mg 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,置于磁力搅拌器上20℃,200rpm搅拌48h,其余同实施例1,得到的RGD-COF为规则的立方体形态,粒径为100-300nm,HPLC法测得环糊精骨架与RGD的质量为1:0.08。
实施例3
同实施例1制备纳米级CD-MOF。
制备纳米级COF:称取778.3mg纳米级CD-MOF粉末于圆底烧瓶中,固定于磁力搅拌器上,加入10mL四氢呋喃,100℃加热,1000rpm搅拌条件下,加入0.5mL交联剂乙二醇二缩水甘油醚(CD-MOF与交联剂的摩尔比为1:5)和5mg催化剂N-羟基丁二酰亚胺,反应4h后,其余同实施例1,SEM和DLS结果显示得到的COF为规则的立方体形态,粒径为200-400nm。
制备纳米级RGD-COF:称取230mg纳米级COF和3mg环形GRGD多肽(COF和环形GRGD的摩尔比为5:1)置于圆底烧瓶中,加入5mL甲醇,搅拌均匀后再加入5mg N-羟基丁二酰亚胺和6mg 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,置于磁力搅拌器上40℃,1000rpm搅拌4h,其余同实施例1,SEM和DLS结果显示得到的RGD-COF为规则的立方体形态,粒径为200-400nm,HPLC法测得环糊精骨架材料与RGD的质量比为1:0.005。
实施例4
同实施例1制备纳米级CD-MOF。
制备纳米级COF:称取778.3mg纳米级CD-MOF粉末于圆底烧瓶中,固定于磁力搅拌器上,加入10mL丙酮,50℃加热,900rpm搅拌条件下,加入0.6mL交联剂戊二醛(CD-MOF与交联剂的摩尔比为1:10)和5mg催化剂吡啶,反应12h后,其余同实施例1,SEM和DLS结果显示得到的COF为规则的立方体形态,粒径为200-500nm。
制备纳米级RGD-COF:称取200mg纳米级COF和3mg环形RGDS(COF和环形RGDS的摩尔比为4:1)置于圆底烧瓶中,加入5mL丙酮,搅拌均匀后再加入5mg N-羟基丁二酰亚胺和6mg1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,置于磁力搅拌器上40℃,900rpm搅拌6h,其余同实施例1,得到的RGD-COF为规则的立方体形态,尺寸为200-500nm,HPLC法测得环糊精骨架材料与RGD的质量比为1:0.015。
实施例5
制备微米级CD-MOF:使用溶剂热的方式,直接对γ-CD与KOH水溶液与一部分有机溶剂混合体系进行加热。称取163.0mgγ-CD和56.0mg KOH混合物(γ-CD和KOH摩尔比为1:8)溶解于5mL水中,预加3mL甲醇至混合溶液内,50℃水浴加热20min后,取出溶液,再加入64mg PEG 2000,静置半小时后,4000rpm离心5min,分别用乙醇(10mL×2)、二氯甲烷(10mL×2)洗涤,将所得晶体50℃真空干燥12h,即得微米级CD-MOF晶体,SEM和DLS结果显示得到的CD-MOF为规则的立方体形态,尺寸为1-10μm。
制备微米级COF:称取778.3mg微米级CD-MOF粉末于圆底烧瓶中,固定于磁力搅拌器上,加入10mL乙酸乙酯,70℃加热,700rpm搅拌条件下,加入0.9mL交联剂环氧氯丙烷(CD-MOF与交联剂的摩尔比为1:20)和5mg催化剂4-二甲氨基吡啶,反应16h后,其余同实施例1,得到的COF为规则的立方体形态,粒径为1-10μm。
制备微米级RGD-COF:称取230mg微米级COF和4mg RGDS(COF和RGDS的摩尔比为2:1)置于圆底烧瓶中,加入6mL正己烷,搅拌均匀后再加入5mg 4-二甲氨基吡啶和0.2mL三乙胺,置于磁力搅拌器上25℃,700rpm搅拌24h,其余同实施例1,得到的微米级立方形环糊精骨架-RGD组合物RGD-COF,SEM和DLS结果显示得到的RGD-COF为规则的立方体形态,尺寸为1-10μm,HPLC法测得环糊精骨架材料与RGD的质量比为1:0.05。
实施例6
同实施例5制备微米级CD-MOF,粒径为1-5μm(图7)。
制备微米级COF:称取778.3mg微米级CD-MOF粉末于圆底烧瓶中,固定于磁力搅拌器上,加入10mL丙酮,50℃加热,400rpm搅拌条件下,加入0.7mL交联剂甲苯二异氰酸酯(CD-MOF与交联剂的摩尔比为1:8)和450μL催化剂1-(3-二甲氨基丙基)-3-乙基碳二亚胺,反应8h后,其余同实施例1,得到的COF为规则的立方体形态,粒径为1-5μm(图8)。
制备微米级RGD-COF:称取230mg微米级COF和18.5mg环形RGD多肽(COF和环形RGDS的摩尔比为1:2)置于圆底烧瓶中,加入6mL异丙醇,搅拌均匀后再加入5mg 4-二甲氨基吡啶和6mg N-羟基丁二酰亚胺,置于磁力搅拌器上35℃,400rpm搅拌8h,其余同实施例1,得到的RGD-COF为规则的立方体形态,尺寸为1-5μm(图9),HPLC法测得环糊精骨架材料与RGD的质量比为1:0.016。
实施例7
同实施例5制备微米级CD-MOF。
制备微米级COF:称取778.3mg微米级CD-MOF粉末于圆底烧瓶中,固定于磁力搅拌器上,加入10mL异丙醇,60℃加热,500rpm搅拌条件下,加入1729mg交联剂柠檬酸(CD-MOF与交联剂的摩尔比为1:15)和450μL催化剂吡啶,反应16h后,其余同实施例1,得到的COF为规则的立方体形态,粒径为30-50μm。
制备微米级RGD-COF:称取230mg微米级COF和30mg GRGDS五肽(COF和环形GRGDS摩尔比为1:3)置于圆底烧瓶中,加入6mL正己烷,搅拌均匀后再加入5mg 4-二甲氨基吡啶和6mg N,N'-琥珀酰亚胺基碳酸酯,置于磁力搅拌器上30℃,500rpm搅拌24h,其余同实施例1,得到的RGD-COF为规则的立方体形态,粒径为30-50μm,HPLC法测得环糊精骨架材料与RGD的质量比为1:0.065。
实施例8
同实施例5制备微米级CD-MOF。
制备微米级COF:称取778.3mg微米级CD-MOF粉末于圆底烧瓶中,固定于磁力搅拌器上,加入10mL氯仿,70℃加热,700rpm搅拌条件下,加入403mg交联剂丁二酰氯(CD-MOF与交联剂的摩尔比为1:4)和450μL催化剂吡啶,反应16h后,其余同实施例1,得到的COF为规则的立方体形态,粒径为10-30μm。
制备微米级RGD-COF:称取230mg微米级COF和25mg环形GRGD(COF和环形GRGD摩尔比为1:5)置于圆底烧瓶中,加入6mL氯仿,搅拌均匀后再加入5mg 4-二甲氨基吡啶和6mg N-羟基丁二酰亚胺,置于磁力搅拌器上37℃,700rpm搅拌18h,其余同实施例1,SEM和DLS结果显示得到的RGD-COF为规则的立方体形态,粒径为10-30μm,HPLC法测得环糊精骨架材料与RGD的质量比为1:0.46。
实施例9
GRGDS修饰的球形的环糊精纳米海绵(RGD-NS)的制备(对比实施例)
(1)制备球形的环糊精纳米海绵:称取3.891gγ-CD(3.000mmol)超声溶于20mL0.1M氢氧化钾水溶液,0.8μm滤膜过滤,得到水相备用。称取1.297g(8.00mmol)N,N'-羰基二咪唑溶于20mL二氯甲烷中,得到有机相。在连续磁力搅拌(600rpm)下,将γ-CD氢氧化钾水溶液滴加到有机相中。反应30min后,分别用去离子水和无水乙醇洗涤沉淀物各两次,每次4000rpm离心5min,收集沉淀。冷冻干燥,即得球形的环糊精纳米海绵(CD-NS),得到的CD-NS为球形,粒径为200-500nm。
(2)GRGDS修饰环糊精纳米海绵:称取230mg球形的CD-NS和10mg GRGDS五肽(CD-NS和GRGDS的摩尔比为1:1)置于圆底烧瓶中,加入5mL二甲基甲酰胺,搅拌均匀后再加入5mg4-二甲氨基吡啶和6mg 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,置于磁力搅拌器上37℃,600rpm搅拌24h,使CD-NS与GRGDS多肽充分偶联。反应完成后,4000rpm离心5min,分别用二甲基甲酰胺(10mL×2)和纯水(10mL×2)洗涤,-50℃冷冻干燥12h即得GRGDS修饰的CD-NS(产物简写为RGD-NS),SEM和DLS结果显示得到的GS5-NS为球形,粒径为200-500nm(图10),HPLC法测得环糊精骨架材料与RGD的质量比为1:0.052。
实施例10
RGD-COF的体外凝血性能检测
通过测定体外凝血块形成时间,可以评价止血材料的体外凝血性能。取健康大鼠3.2%柠檬酸钠抗凝的新鲜全血适量于干净的试管中,加入80μL CaCl2(0.1M)使Ca2+的终浓度为10mM,随后加入样品溶液或生理盐水,使反应体系终体积为800μL,500rpm/min涡旋10s。分别设生理盐水对照组(是空白对照)、RGD-COF组(20、50、100μg/mL)、COF组(100μg/mL)和RGD-NS组(100μg/mL)。立即移取60μL上述处理过的全血于96孔板中,每个样品种12个孔。每隔30s,采用生理盐水洗涤一个样品孔,除去可溶性的血液成分,阻止该孔的凝血反应,直到洗涤液为无色,说明已经彻底清除可溶性的血液成分。当血凝块覆盖整个孔的底部,且在后续时间点冲洗时凝血块的大小保持不变时,认为已经形成稳定的凝血块,该时间记为体外凝血块形成时间。
体外凝血块形成时间结果如图11所示,RGD-COF能显著缩短大鼠全血在体外的凝血时间,并且具有剂量依赖性。健康大鼠全血在体外的凝血块形成时间平均为5.5min,实施例1中制备的COF空白载体组的平均凝血块形成时间为5.4min,说明COF载体自身对凝血过程无影响。实施例1中制备的立方形RGD-COF低(20μg/mL)、中(50μg/mL)、高剂量组(100μg/mL)分别将凝血块形成时间降低了39%、52%和68%,而实施例9中制备的球形RGD-NS仅将凝血块形成时间降低了29%,体外止血作用远不如立方形的RGD-COF。
实施例2中制备的RGD-COF低、中、高剂量组分别将凝血块形成时间降低了32%、49%和61%。
实施例3中制备的RGD-COF低、中、高剂量组分别将凝血块形成时间降低了36%、55%和69%。
实施例6中制备的RGD-COF低、中、高剂量组分别将凝血块形成时间降低了37%、48%和65%。
实施例11
RGD-COF的体内止血效果评价:纳米级静脉注射用RGD-COF止血药,需用生理盐水分散后才可以进行静脉注射,供静脉注射用纳米级RGD-COF止血药的制备方法,包括以下步骤:
(1)按实施例1、实施例2、实施例3和实施例4的方法制备立方形RGD-COF纳米颗粒;按实施例9球形的RGD-NS纳米颗粒。
(2)纳米颗粒的分散:用生理盐水悬浮纳米颗粒(1-10mg/mL,优选为2mg/mL),得到纳米颗粒分散液。
采用小鼠断尾模型评价RGD-COF纳米颗粒的体内止血能力。取健康昆明小鼠50只,随机分为5组,每组10只。分别设空白对照组(只断尾损伤处理,对应于图12和图13中的“损伤处理”)、生理盐水组、COF组、RGD-NS组、RGD-COF低剂量组(20mg/kg,即图12和图13中的20mg/kg)和RGD-COF高剂量组(40mg/kg,即图12和图13中40mg/kg)。给药方式为尾静脉注射,单次给药,给药剂量为20-40mg/kg体重,给药体积:10mL/kg。给药后5min,用锋利的剪刀在距小鼠尾尖0.5cm处快速剪断,当血液自行流出后立即计时,每隔20s,用吸水纸轻触尾部断处,直到断尾处不再有血液流出(无血丝出现),这段时间记为出血时间。采用Image ProPlus软件计算吸水纸上的血滴面积,进而估算小鼠的失血量。
体内止血实验结果表明,RGD-COF能显著缩短小鼠的出血时间,并能大大降低小鼠的出血量,具有良好的体内止血效果。如图12和图13所示,与生理盐水组或COF载体组相比,实施例1中制备的RGD-COF低剂量组(20mg/kg)能将出血时间从400s缩短到150s,出血时间缩短了62.5%;将失血量从2mL/kg降低到0.6mL/kg,失血量减少了70%。实施例1中制备的RGD-COF高剂量组(40mg/kg)能将出血时间从400s缩短到40s,缩短了90%;将失血量降低到0.2mL/kg,降低了90%。
实施例2中制备的RGD-COF低剂量组能将出血时间从400s缩短到155s,出血时间缩短了61%;将失血量从2mL/kg降低到0.8mL/kg,失血量减少了60%。实施例2中制备的RGD-COF高剂量组能将出血时间从400s缩短到50s,缩短了87.5%;将失血量降低到0.12mL/kg,降低了94%。然而,实施例9中制备的球形RGD-NS仅仅将出血时间缩短了23%,且不能降低失血量。因此,立方形的RGD-COF比球形的RGD-NS具有更高效的体内止血效果。
实施例3中制备的RGD-COF高剂量组能将出血时间从400s缩短到52s,缩短了87%;将失血量降低到0.15mL/kg,降低了92.5%。
实施例4中制备的RGD-COF高剂量组能将出血时间从400s缩短到47s,缩短了88.2%;将失血量降低到0.17mL/kg,降低了91.5%。
实施例12
同实施例6制备微米级CD-MOF。
CD-MOF载银:称取169mg硝酸银,用乙腈定容在100mL容量瓶内,配制成10mmol/L的硝酸银溶液。称取微米级CD-MOF 600mg于EP管内,加入1.5mL乙腈混合后超声10min,然后加入5mL 10mmol/L的硝酸银溶液,放置于暗处72h后,用乙腈(10mL)洗涤3次,4000rpm离心5min,放入真空干燥箱40℃干燥12h。
微米级载银COF:称取80℃真空干燥过的微米级载银CD-MOF粉末1g于圆底烧瓶中,固定于磁力搅拌器上,加入12.85mL N,N-二甲基甲酰胺,80℃加热,500rpm搅拌,当反应液温度达到60℃时,加入0.99g交联剂碳酸二苯酯(CD-MOF与交联剂的摩尔比为1:6)和0.5mL催化剂三乙胺,反应24h后,4000rpm离心5min,分别用乙醇(10mL)、纯水(10mL)、丙酮(10mL)洗涤2次,真空箱60℃干燥6h。得到的微米级载银COF为规则的立方体形态,粒径为1-5μm。
载银RGD-COF:称取1g微米级载银COF和21.7mg 4-二甲氨基吡啶置于圆底烧瓶中,加入21.7mL N,N-二甲基甲酰胺,搅拌均匀后再加入21.7mg线形GRGDS,13.36mg碳酰二亚胺和86.95uL三乙胺,置于磁力搅拌器上37℃,500rpm避光搅拌24h,4000rpm离心5min,分别用N,N-二甲基甲酰胺(10mL)、乙醇(10mL)、纯水(10mL)、丙酮(10mL)各洗涤1遍,将所得晶体60℃真空干燥6h即得。得到的载银RGD-COF为规则的立方体形态,粒径为1-5μm,HPLC法测得环糊精骨架材料与RGD的质量比为1:0.015。
抗菌效果:载银CD-MOF、载银COF、载银RGD-COF对大肠杆菌CMCC(B)44102的MIC值均为16μg/mL,与市售制剂相比,抗菌效果均优于市售制剂(128μg/mL)。时间-杀菌曲线上(图14)可见,当Ag的浓度在4μg/mL~16μg/mL时,纳米银对大肠杆菌CMCC(B)44102的杀菌作用微弱,当Ag浓度大于16μg/mL并逐渐升高时杀菌作用明显增强,1.0MBC(32μg/mL)的纳米银在6-8h内能很好地抑制菌的生长。载银CD-MOF、载银COF、载银RGD-COF对金黄色葡萄球菌CMCC(B)26112的MIC值均为128μg/mL,抗菌效果类似于市售制剂(128μg/mL)。
创口愈合效果(图15):与市售纳米银试剂(对照组)相比,载银RGD-COF显著加速大鼠表皮创口愈合的速度;同时相比于载银CD-MOF与载银COF组相比,载银RGD-COF对大鼠表皮创口愈合效果更佳。
实施例13
RGD-COF载抗血栓药:分别称取适量阿司匹林、盐酸噻氯匹定、西洛他唑、硫酸氢氯吡格雷II型、利伐沙班、盐酸奥扎格雷、盐酸替罗非班等7种抗血栓药物,加入30mL无水乙醇超声10min使其溶解,然后分别加入500mg实施例1中制备的RGD-COF,药物与RGD-COF的摩尔比为2:1,室温下300rpm搅拌24h,孵育载药。载药完成后,4000rpm离心5min,得到下层载药RGD-COF,采用HPLC法测定载药量如表1。
表1纳米级RGD-COF负载抗血栓药物的载药量
实施例14
RGD-COF载止血药:分别称取适量氨甲环酸、氨基己酸、维生素K1等3种止血药物,加入30mL无水乙醇超声10min使其溶解,然后分别加入500mg实施例1中制备的RGD-COF,药物与RGD-COF的摩尔比为2:1,37℃温度下400rpm搅拌12h,孵育载药。载药完成后,4000rpm离心5min,得到下层载药RGD-COF,采用HPLC法测定载药量分别为13.5%、4.3%和2.1%。
实施例15
RGD-COF载抗感染药:分别称取适量磺胺嘧啶、头孢曲松、阿莫西林、左氧氟沙星4种抗感染药物,加入30mL无水乙醇超声10min使其溶解,然后分别加入500mg实施例1中制备的RGD-COF,药物与RGD-COF的摩尔比为1:1,室温下200rpm搅拌48h,孵育载药。载药完成后,4000rpm离心5min,得到下层载药RGD-COF,采用HPLC法测定载药量分别为3.8%、3.3%、4.6%和6.7%。
实施例16
RGD-COF靶向体内血栓:采用FeCl3诱导形成小鼠肠系膜血栓,并采用预先注射的罗丹明B标记血栓部位的活化血小板,血栓形成后,尾静脉注射红色Cy5荧光标记的实施例3中制备的RGD-COF(40mg/kg),荧光显微镜下观察到,红色Cy5荧光标记的RGD-COF可以靶向富集肠系膜血栓,RGD-COF纳米粒与血栓处活化血小板的共定位系数高达0.65,远远高于未修饰的COF和球形的RGD-NS组(图16),说明立方形的RGD-COF可以高度靶向体内血栓。
实施例17
RGD-COF靶向体内出血部位:采用小鼠断尾模型评价实施例2中制备的RGD-COF对体内出血部位的靶向性。昆明小鼠经尾静脉注射Cy5荧光标记的COF、RGD-NS和RGD-COF纳米粒(40mg/kg)5min后,用锋利的剪刀在距小鼠尾尖0.5cm处快速剪断,建立小鼠断尾模型。断尾损伤10min后,当断尾处的出血已停止,在距第一次切口1cm处剪断小鼠尾巴,得到1cm长的小鼠尾巴样品,采用小动物活体成像仪测定断尾处聚集的RGD-COF的荧光信号。因为RGD-COF可以靶向出血部位聚集的活化血小板,RGD-COF组断尾处的荧光信号是COF组的4倍,是RGD-NS组的3倍,说明立方形RGD-COF可以高度靶向并聚集到断尾出血部位,比球形RGD-NS具有更好的体内靶向性。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (11)
1.一种环糊精骨架-RGD组合物,其特征在于,所述组合物中,环糊精骨架与RGD的质量比为1:0.001-1:1,较佳地为1:0.005-1:0.5;
所述的环糊精骨架-RGD组合物粒径为10nm-50μm,优选为50nm-50μm,更优选为100-500nm或1-5μm。
2.如权利要求1所述的组合物,其特征在于,所述组合物为立方形环糊精骨架-RGD组合物。
3.一种立方形环糊精骨架-RGD组合物的制备方法,其特征在于,包括步骤:
(1)提供一立方形环糊精-金属有机骨架(CD-MOF);
(2)交联步骤,通过交联剂对(1)中的立方形环糊精-金属有机骨架进行交联,得到环糊精骨架(COF);
(3)RGD修饰步骤,在(2)中所述的环糊精骨架上修饰RGD,得到立方形环糊精骨架-RGD组合物(RGD-COF)。
4.如权利要求3所述的制备方法,其特征在于,所述交联步骤包括下列子步骤:
(2a)分散步骤,将立方形的环糊精-金属有机骨架分散于有机溶剂A中,得到分散液2a;
(2b)交联剂和催化剂加入步骤,在交联反应温度T条件下向分散液2a中加入交联剂和催化剂A,反应时间t1之后,得到分散液2b;
(2c)任选地,冷却步骤,对分散液2b进行冷却,得到经冷却的分散液2b;
(2d)任选地,终止反应步骤,向经冷却的分散液2b中,加入反应终止剂,得到分散液2d;
(2e)任选地,离心步骤,对分散液2d进行离心,得到晶体2e;
(2f)任选地,洗涤步骤,洗涤晶体2e,得到经洗涤的晶体2f;
(2g)任选地,干燥步骤,对经洗涤的晶体2f进行干燥处理;
(2h)获得立方形的环糊精骨架(COF)。
5.如权利要求3所述的制备方法,其特征在于,所述RGD修饰步骤包括下列子步骤:
(3a)分散步骤,将立方形的环糊精骨架(COF)和RGD分散于有机溶剂B中,得到分散液3a;
(3b)偶联步骤,向分散液3a中加入催化剂B,使立方形的环糊精骨架与RGD偶联,反应时间为t2;
(3c)任选地,离心步骤;
(3d)任选地,洗涤步骤;
(3f)任选地,干燥步骤;
(3g)获得立方形环糊精骨架-RGD组合物(RGD-COF)。
6.如权利要求3所述的方法,其特征在于,所述的交联剂选自下组:过氧化物、多异氰酸酯、缩水甘油醚、二元或多元酸类、二元或多元醛类、含羰基的化合物、环氧化物类、丙烯酸酯类、酰氯类、或其组合。
7.如权利要求3所述的方法,其特征在于,
所述的催化剂A选自下组:4-二甲氨基吡啶、三乙胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺或其盐、N,N'-琥珀酰亚胺基碳酸酯、N-羟基丁二酰亚胺、吡啶、或其组合;较佳地为三乙胺;
所述的有机溶剂A选自下组:二甲基甲酰胺、四氢呋喃、甲醇、乙腈、丙酮、异丙醇、乙酸乙酯、氯仿、正己烷、乙醇、二氯甲烷。
8.如权利要求3所述的方法,其特征在于,
所述的催化剂B选自下组:4-二甲氨基吡啶、三乙胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺或其盐、N-羟基丁二酰亚胺、N,N'-琥珀酰亚胺基碳酸酯、吡啶、或其组合;
所述的有机溶剂B选自下组:二甲基甲酰胺、四氢呋喃、甲醇、乙腈、丙酮、异丙醇、乙酸乙酯、氯仿、正己烷、乙醇、二氯甲烷、或其组合。
9.一种负载药物的立方形环糊精骨架-RGD组合物,其特征在于,所述立方形环糊精骨架-RGD组合物为权利要求1或2所述的组合物,或通过权利要求3所述的方法制备,所述的药物选自下组:抗菌药物、止血药物、抗血栓药物、抗感染药物、或其组合。
10.一种活性成分的用途,其特征在于,所述活性成分选自下组:
(i)权利要求1或2所述环糊精骨架-RGD组合物;
(ii)权利要求9所述的负载药物的立方形环糊精骨架-RGD组合物;
(iii)环糊精骨架(COF);
(iv)上述(i)、(ii)或(iii)的组合;
所述活性成分被用于:
(a)制备载药材料;
(b)制备治疗和/或诊断试剂或试剂盒;
(c)制备止血药物和/或材料;
(d)制备抗感染药物和/或材料;
(e)制备抗菌药物和/或材料;
(f)制备促进伤口愈合药物和/或材料;
(g)制备预防和/或治疗血栓的药物和/或材料。
11.一种药物组合物,其特征在于,所述药物组合物包含:
(1)活性成分,所述活性成分为如权利要求1或2所述的环糊精骨架-RGD组合物或如权利要求9所述的负载药物的立方形环糊精骨架-RGD组合物;和
(2)药学上可接受的载体。
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EP3913003A1 (en) | 2021-11-24 |
EP3913003A4 (en) | 2022-11-02 |
US20220073653A1 (en) | 2022-03-10 |
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