CN100542612C - 类脂化糖胺聚糖颗粒及其在诊断和治疗用药物和基因传递中的应用 - Google Patents
类脂化糖胺聚糖颗粒及其在诊断和治疗用药物和基因传递中的应用 Download PDFInfo
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- CN100542612C CN100542612C CNB028196600A CN02819660A CN100542612C CN 100542612 C CN100542612 C CN 100542612C CN B028196600 A CNB028196600 A CN B028196600A CN 02819660 A CN02819660 A CN 02819660A CN 100542612 C CN100542612 C CN 100542612C
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Abstract
公开了一种类脂化糖胺聚糖颗粒,它是通过糖胺聚糖与至少一种类脂反应,使糖胺聚糖的羧酸基团与类脂的伯氨基交联而形成的。所述颗粒可用于包封活性成分,例如用于治疗动物病理学状态的药物。
Description
技术领域
本发明涉及基于类脂化(lipidated)糖胺聚糖颗粒的药物传递系统,所述颗粒中包封有随后传递以供治疗和诊断的药物。
背景技术
糖胺聚糖类或粘多糖类以及胶原是所有结缔组织的主要构成成分。糖胺聚糖类(Gags)是多糖链与少量蛋白质的大复合物。这些化合物能与大量水结合,由此而产生能形成身体结缔组织的凝胶状基质。糖胺聚糖类是由重复的二糖单元(氨基糖-酸性糖重复单元)构成的长链。氨基糖典型地为葡糖胺或半乳糖胺。氨基糖也可硫酸化。酸性糖可以是D-葡糖醛酸或L-艾杜糖醛酸。在体内,糖胺聚糖类(除了透明质酸外)与蛋白质共价结合,形成蛋白聚糖单体。酸性糖与氨基糖的加成使多糖链展长。
最常见的糖胺聚糖是透明质酸、硫酸角质素、硫酸软骨素、硫酸肝素和硫酸皮肤素(dermatin sulfate)。经化学修饰,可使糖胺聚糖较其最初提取形式含有更多的硫基团。另外,可部分或全合成糖胺聚糖,也可以是植物或动物来源。
透明质酸是糖胺聚糖家族中的天然成分,它尤其以高浓度存在于关节的软骨和滑液中,以及玻璃体、血管壁中和脐带和其他结缔组织中。透明质酸可以是游离形式(例如在滑液中);也可以是结合(attached)形式(例如作为胞外基质的组成)。这种多糖由与交替(alternating)β-1,3-葡萄糖苷(glucuronidic)和β-1,4-氨基葡糖苷(glucosaminidic)键结合的交替乙酰-D-葡糖胺和D-葡糖醛酸残基所组成。在水中,透明质酸溶解而形成高粘性流体。由天然来源分离的透明质酸的分子量一般在5×104-107道尔顿之间。透明质酸对胞外基质和各种肿瘤(包括乳房、脑、肺、皮肤和其他器官和组织肿瘤)具有高度的亲和力。
药物传递系统通过将药物施用到体内而持久保持恒定的血药浓度,或者或经全身或局部施用而在特定的靶器官持久保持最适的药物浓度。
经化学修饰的透明质酸可用于控释给药。Balazs等在US4582865中披露了“透明质酸的交联凝胶能降低低分子量物质的释放,所述低分子量物质分散于凝胶中但未与凝胶大分子骨架共价结合”。
多种形式的药物制剂可用作药物传递系统,这包括利用聚合物薄膜或脂质体作为药物载体。
药物载体大体分二类:微粒体系,例如细胞、微球、病毒包膜和脂质体;和非微粒体系(通常为可溶性系统),由大分子例如蛋白质或合成聚合物构成。
通常,显微-和亚显微-微粒载体具有几个明显的优点。它们可用作持续释药或控释型药物贮库(贮库),因此可改善药物效力并能降低给药频率。通过为被包封药物和生物环境提供保护,这些载体降低了药物失活和降解的风险。从颗粒中释放出的游离药物的药物动力学不同于直接施用的游离药物,这些载体可用于降低毒性以及不想要的副作用。
尽管药物包封生物聚合物有一定的优点,仍存在着一些相关的问题。例如,呈微米颗粒或纳米颗粒结构的生物聚合物的靶向能力有限、在循环中的保留和稳定性有限、长期施用有潜在毒性以及不能外渗等。为了赋于微粒体系(例如脂质体、微球等)以靶向作用,曾采用许多措施使其与不同的识别物质(包括抗体、糖蛋白和凝集素)结合。尽管这些识别物与微粒体系的结合取得了一定的成功,但是这些经修饰的微粒体系的表现并不尽人意(尤其是在体内)。
当采用这种识别物质时,也会产生其他问题。例如,由于抗体可能是患者特异性的,这样就增加了药物疗法的费用。另外,识别底物与载体之间的结合并非均是共价的。共价结合是必须的,因为非共价的结合可能使识别物质在施用部位与微粒体系解离(这是由于微粒体系与识别对应体(counterpart)对识别物质靶点的竞争所致)。当出现解离时,所施用的经修饰微粒体系会重新变成常规微粒体系,这样就达不到施用改良微粒体系的目的。
发明概述
本发明的一个目的是克服现有技术的缺陷。
本发明另一目的是制备包封了药物的含糖胺聚糖颗粒。
本发明另一目的是传递包封在含糖胺聚糖基颗粒中的药物。
本发明另一目的是提供采用类脂化糖胺聚糖颗粒为给药载体的传递药物的方法。
在一个优选的实施方案中,所述传递是口服施用颗粒剂型。在另一个优选的实施方案中,所述传递是经鼻内施用颗粒剂型,特别是用于治疗需要通过血脑屏障(BBB)的脑部和相关器官(例如,脑膜和脊髓)。在这些方案中,也可经眼内给药。在另一优选的实施方案中,所述传递是经静脉内(iv)施用颗粒剂型,这对于施用长效静脉内制剂特别有益。
本发明的另一目的是提供采用类脂化糖胺聚糖颗粒为基因传递材料进行基因传递的方法。
本发明提供新颖的多产品基因和药物传递技术及其制备和应用方法。传递系统包括类脂化糖胺聚糖(亦称gagomer),它是由具有伯氨基的类脂与含羧酸的糖胺聚糖交联而制得的生物粘附性生物聚合物。以可控方式制得的微米-或纳米粒,其中大多数颗粒的直径约为2-5微米(微粒)和约50-200纳米(纳米粒)。小的或大的药物、生物活性物质或活性成分,例如抗生素、化疗药物、蛋白质和核酸,均可以较高包封率包封于这些颗粒中(即使较大大分子的包封率也一般大于50%)。例如,对于质粒DNA,纳米粒可提供约66%的包封率,而微粒可提供约75%的包封率。
在本发明中,“药物”是指能治疗性地作用于身体或用于体内诊断的任何物质。示例性治疗药物包括治疗癌症的化疗药物、治疗感染的抗生素和治疗真菌感染的抗真菌剂。示例性诊断药物包括放射性同位素例如99Tc、127I和67Gd,以及用于体内部位显影的荧光分子。
本发明生物聚合物的制备和药物包封是简单且低成本的方法。这些新颖的载体可用作持续释放药物贮库,其中抗生素和化疗药物的外流(efflux)半衰期为19-35小时。这些特性以及生物粘附性特性,提供了新颖的载药能力,可用作供全身(包括口服、局部)和部位(包括鼻内)给药的位点附着、位点存留、持续释放的药物贮库。
另外,本发明类脂化糖胺聚糖是无毒的。当将被包封的化学治疗药物在细胞培养物模型中进行实验时,系统在肿瘤治疗方面表现出高活性,甚至能克服已知的耐药问题。因此,类脂化糖胺聚糖可用作具有广泛治疗活性的显微和亚微药物传递系统,例如癌症、感染性疾病、创伤愈合、酶疗法、基因疗法等。
令人惊奇的是,空白颗粒(仅含类脂化糖胺聚糖而不含药物或其他治疗剂型)也呈现出重要的肿瘤-抑制作用。因此,这种颗粒作为主要或辅助化疗药物,可用于癌症疗法特别是用于转移癌。
附图简述
附图1A和1B为同批颗粒的视野扫描电子显微镜图片(两种不同放大率)。附图1A为5000×倍。附图1B为3000×倍。
附图2A-2C表示个体细胞与与3种不同剂型温育的共聚焦显微照片。附图2A表示与游离溴乙啡锭(ethidium bromide,EtBr)温育的细胞C6(鼠神经胶质瘤)系。附图2B表示与混悬于游离EtBr溶液的“空白”(即仅包封缓冲剂)类脂化糖胺聚糖温育的C6细胞。附图2C表示与包封EtBr的gagomer温育的C6细胞。
附图3A表示用包封EtBr的类脂化糖胺聚糖处理的PANC-1细胞系(人胰腺癌)细胞。
附图3B表示细胞用游离EtBr处理的PANC-1细胞系细胞。
附图4A为似于附图3B系统的共聚焦显微照片,但放大率更大。
附图4B为似于附图3A系统的共聚焦显微照片,但放大率更大。
附图5表示游离透明质酸和基于透明质酸的gagomer的浊度研究结果(游离透明质酸和基于透明质酸的gagomer的浓度在600nm处的吸收度变化对大分子的浓度作图)。
附图6A和6B表示微米类脂化糖胺聚糖和纳米类脂化糖胺聚糖的显微镜照片。附图6A表示包封模型蛋白质(BSA-FITC)的微米类脂化糖胺聚糖的荧光显微镜照片,放大因子为2000。附图6B表示包封质粒DNA的纳米类脂化糖胺聚糖的光学显微镜照片,放大因子为2000。
附图7为单向流出状况下阿霉素从微米类脂化糖胺聚糖(圆形)和纳米类脂化糖胺聚糖(正方形)中外流的曲线。独立变量为时间。因变量(f)是时间=t时释放的药物相对于t=0时系统总药物的百分率。符号表示实验数据,和实线表示按多室(multipool)外流机制所作的理论期望值。
附图8为C6细胞经不含药物微米类脂化糖胺聚糖(即仅包封缓冲剂,即附图2B定义的“空白”)、给定剂量的游离化学治疗药物、包封相等剂量的相同药物的微米类脂化糖胺聚糖处理48小时后的存活示意图。实验药物为丝裂霉素C(MMC)、阿霉素(DOX)和长春碱(VIN),结果分成3个数据组(每种药物为一组)。每条是3个独立实验的均值,每一实验包括20个独立的测量数据。误差棒表示各自的标准偏差。
附图9表示Zeta电势(有效的表面电荷)对纳米粒和微粒浓度作图。Zeta电势反映了混悬液中胶体大小颗粒之间的总相互作用力。
附图10表示不含药物传递系统(DDS)纳米粒的毒性实验结果(DDS剂量为1mg/ml和温育时间为24小时)。每条是32-64个独立测量的均值,和误差棒表示标准偏差。
附图11A和11B表示与游离药物和不含药物传递系统(DDS)相比,包封于DDS(纳米颗粒)中MMC(附图11A)和DOX(附图11B)对C26的细胞毒性作用,其中细胞与处理介质接触4小时。***表示p<0.001,每一物种和剂量下载体与不含药物剂型的比较。
附图12表示血液中MMC浓度对剂型类型和注射时间作图。每一符号为5只动物的均值,和误差棒表示标准差均值(SEM)。曲线是非理论性的,旨在表明数据趋势。
附图13表示肿瘤体积随时间的增加。点值为实验数据,每个代表5只动物的均值;误差棒为SEM,曲线为非理论性的,仅表明数据趋势。箭头及其上面的数字表示处理天数。符号边的数字为肿瘤出现的天数。
附图14表示第1轮中的动物存活。每种剂型给每一动物注射3次。盐水和游离MMC组的数据来自10动物/组;DDS和MMS/DDS的数据来自5只动物/组。
附图15表示第2轮中的动物存活。每种剂型给每一动物注射4次。DDS的数据来自3只动物和MMC/DDS的数据来自5只动物。
附图16为标记物MMC的脑部蓄积条形图(鼻内(IN)施用游离MMC和包封于DDS纳米粒中的MMC,数据来自第1轮,实验动物为鼠)。
附图17为标记物MMC的脑部蓄积条形图(鼻内(IN)施用游离MMC和包封于DDS纳米粒中的MMC,数据来自第2轮,实验动物为小鼠)。
附图18表示在C57BL/6小鼠(静脉注射B16F10细胞)肺中发现的转移灶数量,对照组是没有注射肿瘤细胞的健康动物。每条是5只动物/组的均值,和误差棒为标准偏差。
附图19表示荷瘤鼠的肺部增重(由肺重量的原始数据计算,见实验部分公式)。每条为5只动物/组的均值,和误差棒为标准偏差。
附图20表示附图18和19数据(均值)的重绘图。点值表示实验数据,和实线为非理论性的,旨在表明数据趋势。
附图21表示被摄取到MCF7细胞中的类脂化糖胺聚糖包封的BSA-FITC(光学和荧光显微镜)。上面两格表示蛋白质的摄取和非特异性结合。下面两格表示进入胞液和细胞核的蛋白质。
发明详述
本发明涉及显微和亚微传递系统的制备和应用,以及可用于组织工程学和组织支架的材料。本发明药物传递系统是微粒载体形式(也被称作gagomer)的新颖粘附性生物聚合物,所述载体由含有至少一种伯胺的类脂与糖胺聚糖制得,即类脂化糖胺聚糖。
如表1所示,与其他微粒载体相比,本发明颗粒是特别低成本的。
本申请中所用的术语透明质酸或HA,是指透明质酸以及任何透明质酸盐类,包括例如透明质酸钠、透明质酸钾、透明质酸镁和透明质酸钙。类似地,术语糖胺聚糖包括任何糖胺聚糖/盐类以及游离酸。
本发明类脂化糖胺聚糖是微米颗粒(MDDS)和纳米微粒药物传递系统(NDDS),是可用于包封药物的粘附性生物聚合物。与以游离形式施用的相同药物相比,这些负载了药物的载体改善了临床效果。所述类脂化糖胺聚糖是由生物相容和生物可降解的天然材料制得的。
表1.本发明优点:低成本生产方面
本发明类脂化糖胺聚糖还具有许多优于其他微粒载体的优点,包括体内过程方面,这可参见表2。
表2.本发明在体内过程方面的优点
本发明类脂化糖胺聚糖还提供优于其他微粒载体的生物和治疗活性,其中的一些优点如表3所示。
表3.本发明在生物/治疗活性方面的优点
可以合成两种基本类型的类脂化糖胺聚糖:低类脂-糖胺聚糖比例(1:1,w/w)记为LLG,和高类脂-糖胺聚糖比例(5:1-20:1,w/w)记为HLG。通过变化制备中的特定步骤,可按需形成微米或纳米粒。
本发明类脂化糖胺聚糖(类脂化糖胺聚糖),可在治疗有此需要动物病理学病症的药物疗法中用作传递系统。在此所用的术语“动物”是指包括人和其他哺乳动物例如牛、犬、猫、鼠、小鼠,以及鸟类,爬行类动物和鱼类。
在本发明中,适于经类脂化糖胺聚糖治疗的病理学病症包括但不限于癌症,真菌或细菌感染(包括创伤例如烧伤的继发感染),寄生虫或病毒引起的感染,朊病毒(prion)感染等。
本发明类脂化糖胺聚糖也可用于疫苗制剂和基因疗法。含免疫原多肽为活性成分的疫苗制剂是本领域技术人员熟知的。同样地,制备用于基因插入的载体也是本领域技术人员熟知的。
可在制剂的不同阶段,对本发明方法制得的类脂化糖胺聚糖进行冻干或脱水。例如,可在以除去溶剂后和加入药物之前,冻干类脂膜。也可在水合类脂化糖胺聚糖之前冻干类脂-药物膜。可以在减压下进行类脂或类脂化糖胺聚糖的脱水,以除去所有悬浮的溶剂。
另外或选择性地,也可将水合的类脂化糖胺聚糖制剂置于在液氮中的周围介质中进行脱水,并在脱水步骤之前进行冷冻。可在一种或更多保护剂(例如糖类)存在下,进行脱水(预先冷冻)。这种技术能提高制剂长期贮存性和稳定性。
再水化后,可加热制剂。也可采用其他适宜方法对类脂化糖胺聚糖制剂进行脱水。类脂化糖胺聚糖也可不经预先冷冻而脱水。一旦类脂化糖胺聚糖脱水后,可在用前长期贮藏。适当的贮存温度取决于类脂化糖胺聚糖的类脂剂型和包封材料的温敏性。
当欲施用脱水的类脂化糖胺聚糖时,简单地向类脂化糖胺聚糖中加入水溶液(例如蒸馏水或适当的缓冲液),即可使其再水合。可在室温或类脂化糖胺聚糖组合物及其内容物适宜的其他温度下进行再水化。
优选地,按照以下方法,经具有至少一种伯氨基的类脂与含羧酸的糖胺聚糖共价结合制备本发明的gagomer,即类脂化糖胺聚糖:
(a)提供反应容器,其中类脂薄层铺展于容器底部和壁上。将类脂溶于有机溶剂中,并于旋转蒸发仪中低压蒸发类脂至干燥即可。
(b)在酸性pH下与交联剂预温育,使糖胺聚糖活化。
(c)将活化的糖胺聚糖加至反应容器中。
(d)类脂和活化糖胺聚糖的反应混合物缓冲至碱性(pH8.6)。
(e)在连续搅拌下,将缓冲后的反应混合物温育一定时间(例如37℃过夜),使类脂化糖胺聚糖形成。由于类脂化糖胺聚糖预期在体内使用,因此其应在约37℃时稳定。当温度高于类脂化反应温度时,类脂会随温度的升高而发生物理变化,通常约62℃。因此,优选在约30-40℃的温度进行类脂化反应。
(f)将类脂化糖胺聚糖缓冲至中性pH,并加入其他离子和水溶性添加剂,以提高离子强度,使其相当于生物流体中离子或盐类(例如NaCl、KC1、Ca2+和Mg2+)的生理水平。
(g)经连续离心(4℃,40分钟,1.3×105g)分级颗粒:3次操作后的小球(pellet)是富含微粒的级分,富含微粒的上层再离心3次操作即获得富含纳米粒的级分。
(h)冻干所得的类脂化糖胺聚糖。
为了将药物或其他活性成分包封于类脂化糖胺聚糖中,将所需材料溶于无离子的纯水中。然后,在含有待包封材料的水溶液中,对上述得到的冻干干粉状类脂化糖胺聚糖进行重建。
通过在分光光度计中光散射,对相同浓度的可溶性透明质酸和由透明质酸、磷脂酰乙醇胺制备的类脂化糖胺聚糖进行浊度研究,以确定是否合成了微粒物质。该研究的代表性结果如附图5所示。同预期一致,整个浓度范围内的待试游离透明质酸均是是可溶性的,并且其溶液没有散射光。相反,含类脂化糖胺聚糖的试样是混浊的,并且光散射随着类脂化糖胺聚糖浓度的提高而增加,表明生物聚合物为不溶性材料。
包封了大分子的类脂化糖胺聚糖试样在光学和荧光显微镜均可见。如附图6所示,表示微粒(由HLG和包封的模型蛋白质BSA-FITC制得,直径2-5微米)在荧光显微镜下可见的典型视野(上格)。这些微粒的制备如上。在显微镜照片下观察之前,应除去制剂中未被包封蛋白质(4℃,30分钟和1.2×105g超速离心)。将含颗粒(包封有蛋白质)的小球再混悬于磷酸盐缓冲盐水(PBS)中。
如附图6所示,表示纳米粒(50-200nm直径,由HLG和包封的质粒DNA制得)在光学显微镜下可见的典型视野(下格)。FTTC-BSA纳米粒的制备如上。
糖胺聚糖制得的颗粒具有广泛的应用,例如相同的颗粒可单独使用,或者与包封其中的任何类型材料一起使用。优选地,糖胺聚糖颗粒制备中不包封任何材料,然后冻干形成粉末。然后,将粉状糖胺聚糖颗粒与待包封的粉末材料混合。备选地,粉状糖胺聚糖颗粒可与包含待包封材料的水溶液重建。一旦混合物被重建,颗粒将包封混合在溶液中的待包封材料。这样,采用这种技术可包封小分子(例如抗生素和化学治疗药物)和大分子(例如蛋白质)。颗粒可用于包封DNA,并且大的颗粒甚至可以包封全细胞和细胞系。因此,这种颗粒也可用作组织工程学支架。
由至少一种长型糖胺聚糖(即gag未裂成较小尺寸)反应制备本发明颗粒。所有糖胺聚糖(除透明质酸以外),均是蛋白质部分天然地与多糖部分共价结合的形式。水解蛋白质-糖键的方法是本领域技术人员已知的,例如化学和酶促法。另外,也可采用一些市售产品(已经除去其蛋白质部分)。
糖胺聚糖聚合物与含有至少一种伯氨基的类脂反应,使糖胺聚糖的羧酸残基与类脂中的伯胺交联。一旦发生反应,热力学稳定性会引起类脂间的相互作用,形成外层为糖胺聚糖和内层类脂的球状产物。这些颗粒可随后用于包封其他材料,包括药物、DNA、细胞、蛋白质等。
在本发明的一个实施方案中,除去了糖胺聚糖中的蛋白质部分,仅仅是糖主链与类脂反应。
本领域已知,将透明质酸结合到脂质体外层,使脂质体具有靶向或使其更具生物粘附性。在本发明中,是将类脂分子(而非脂质体)与透明质酸共价结合。
在本发明的另一实施方案中,其他分子可先与糖胺聚糖结合,然后糖胺聚糖再与类脂反应。其中其他分子处于这些颗粒的外层。这些其他分子可以是例如抗体、叶酸盐、卟啉或凝集素,并可用于靶向。
尽管本发明为了避免与免疫原性和毒性相关的问题而优选使用天然糖胺聚糖,但是也可以采用合成糖胺聚糖以及天然、合成或半合成分子,包括但不限于:软骨素、透明质酸、葡糖醛酸、艾杜糖醛酸、硫酸角质素、硫酸角质蛋白、硫酸乙酰肝素、硫酸皮肤素,和其片段、盐类、及混合物。在此所用的术语“糖胺聚糖”进一步包括经化学改变(并非部分水解)但仍保持功能的糖胺聚糖。这些修饰包括但不限于酯化、硫酸化、多硫酸盐化和甲基化。
糖胺聚糖的天然来源包括植物和动物来源,包括但不限于山毛榉树和动物软骨形式,包括鲨鱼软骨、牛气管、鲸隔膜、猪鼻,和软体动物例如Perna canaliculus和海参。
业已发现,与游离药物相比,包封于本发明糖胺聚糖颗粒中的药物更有效(尤其是对那些业已耐药的癌细胞)。很明显,类脂化糖胺聚糖通过与癌细胞附着而成为药物贮库,该贮库能更快地进入细胞(快于其排泄速度)。尽管大多数癌细胞已形成耐药机制,但是这些包封的药物对细胞仍具有毒性作用。
本发明类脂化糖胺聚糖几乎可以包封任何未经修饰的分子。与之形成对照的是,为了与DNA络合,脂质体必须首先荷正电,然而许多其他材料却不是荷正电的。本发明的一个优点在于所述类脂化糖胺聚糖实质上能包封任何类型的分子。
至于所用糖胺聚糖的大小,可采用其由生物来源提纯时的尺寸,并且不易于被化学和/或生物降解。例如,对于透明质酸,其相应大小约1×105-1×107道尔顿。
本发明采用类脂化糖胺聚糖的药物组合物可经任何常规途径施用,包括非肠道,例如皮下、静脉内、局部、肌内、腹膜内、经皮、直肠、阴道、鼻内、眼内。选择性或同时地,可以口服途径施用。
可采用浓注或随着时间梯度灌注进行非肠道给药。非肠道给药通常是注射施用,最典型地是经皮下、肌内或静脉内。
局部剂型由类脂化糖胺聚糖、透皮促进剂,和其他生物活性药物或药剂所构成,可以多种方式施用。例如,可用适宜给药装置将溶液滴至适当的皮肤或患病皮肤或粘膜区域,并用手擦涂或任其在空气中干燥。可将适宜胶凝剂加至溶液中,将制剂施于适当区域并擦涂。为了施用到伤口或烧伤上,可将类脂化糖胺聚糖掺入例如油、乳剂等剂型中。这种制剂可以以洗剂、膏剂、糊剂、软膏等形式直接施于患部表面。
备选地,也可将局部溶液剂型填入喷雾器装置中,并经喷雾器施用。这种类型的药物传递装置尤其适于向大的患皮肤病的皮肤区域、高度敏感性皮肤或鼻腔或口给药。任选地,以软膏或经皮贴剂形式施用类脂化糖胺聚糖。
口服途径施用包括经颊和舌下途径施用。
也可经适于粘膜吸收的其他途径施用本发明类脂化糖胺聚糖。例如,优选经阴道(特别是治疗阴道疾病时)、直肠和鼻内途径施用。另外,类脂化糖胺聚糖尤其适于经粘膜组织或上皮施用。当鼻内施用时,可典型地以气雾剂或滴剂形式施用类脂化糖胺聚糖。这在治疗肺部疾病方面特别有益。适宜剂型可参见Remington’Pharmaceutical Sciences,第16和18版,MackPublishing公司,Easton,Pa.(1980和1990),和Introduction to Pharmaceutical Dosage Forms,第4版,Lea & Febiger公司,Philadelphia(1985),其公开内容在此引入作为参考。
根据施用方式的不同,所用组合物可呈固体、半固体或液体剂型形式,例如片剂、栓剂、丸剂、胶囊剂、散剂、液体、混悬液等。优选采用适宜以精确剂量单独施用的单位剂型。药物组合物包括类脂化糖胺聚糖和可药用赋形剂,和任选地包括其他药剂、药物、载体、辅剂等。药用载体优选是对所述活性化合物呈化学惰性的物质,并且在施用中没有有害的副作用或毒性。可以部分地根据特定活性成分以及施用组合物的具体方法,来确定所需载体。因此,广泛的剂型均适宜本发明药物组合物。
具体地说,适宜赋形剂包括填充剂例如糖类(例如乳糖或蔗糖、甘露醇或山梨醇、纤维素制剂和/或磷酸钙(例如磷酸三钙或磷酸氢钙),以及粘合剂例如淀粉糊(例如玉米淀粉、小麦淀粉、大米淀粉、土豆淀粉)、明胶、西黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、和/或聚乙烯吡咯烷酮。
供非肠道施用的注射用剂型可为液体溶液或混悬液、适于注射前用液体配制成溶液或混悬液的固体制剂、或乳剂。适宜赋形剂例如水、盐水、葡萄糖、甘油、乙醇等。另外,如有需要,药物组合物中也可含有少量非毒性的辅剂,例如润湿剂或乳化剂、pH缓冲剂等,例如醋酸钠、脱水山梨醇单月桂酸酯、三乙醇胺油酸酯等。
水性注射用混悬液也可含有能增加混悬液粘度的物质,包括例如羧甲基纤维素钠、山梨醇和/或葡聚糖。任选地,混悬液中也可含有稳定剂。
非肠道剂型可以是单位剂量或多剂量的密封容器形式,例如安瓿和小玻璃瓶,并可在冷冻干燥(冻干)状况下贮存,用前仅需加入无菌液体载体(例如水)而配成注射剂。可采用前述的各种无菌散剂、颗粒剂和片剂,配制临时调配型注射溶液和混悬液。
可向口服施用的药用非毒性组合物中掺入任何常规赋形剂,例如甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、交联纤维素钠、葡萄糖、明胶、蔗糖、碳酸镁等。这种组合物包括溶液剂、混悬液、片剂、分散片、丸剂、胶囊剂、散剂、缓释剂型等。适宜口服施用制剂包括:液体溶液(例如有效量化合物溶于稀释剂例如水、盐水或橙汁中);囊剂、锭剂和含片,其中含有预定量的固体或颗粒状活性成分;散剂;适当液体中的混悬液;和适宜乳剂。液体剂型包括稀释剂(例如,水和醇,例如乙醇、苯甲醇、和聚乙烯醇),也可以加入药用表面活性剂、助悬剂或乳化剂。
当组合物为丸剂或片剂时,可含有活性成分、稀释剂(例如乳糖、蔗糖、磷酸二钙等)、润滑剂(例如硬脂酸镁等)和粘合剂(例如淀粉、树胶、阿拉伯胶、明胶、聚乙烯吡咯烷、纤维素及其衍生物等)。
片剂可包括一种或更多乳糖、蔗糖甘露醇、玉米淀粉、土豆淀粉、藻酸、微晶纤维素、阿拉伯胶、明胶、瓜尔胶、胶体二氧化硅、交联纤维素钠、滑石、硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸、其他防腐剂、矫味剂、药用崩解剂、湿润剂、防腐剂、矫味剂和药物相容性载体。
胶囊剂可以是常规的硬或软壳的明胶类型,其中含有例如表面活性剂、润滑剂和惰性填充剂(例如乳糖、蔗糖、磷酸钙和玉米淀粉)。
锭剂包括负载于载体(一般为蔗糖和阿拉伯胶或西黄蓍胶)中的活性成分,以及锭剂包括负载于惰性基质(例如明胶或甘油或蔗糖和阿拉伯胶)中的活性成分。
在确定类脂化糖胺聚糖颗粒的施用剂量,应根据特定活性成分的药理学特性确定施用剂量和频率。一般至少采用3种剂量水平。通常,在毒性研究中,最高剂量应达到毒性水平但是对组中的大多数动物是亚致死量的。如有可能,最低剂量应产生可生物学证明的效力。应对选定的每种化合物平行进行这些研究。
另外,活性成分的ED50(50%待试群体有效的剂量)水平应是上述剂量水平的一种,和其他两种选定剂量水平为毒性水平。最低剂量是指未出现可生物学证明效力的剂量。应采用根据所得结果计算出的适当的新剂量,重复毒理学试验。
首选物种为种系明确的年轻、健康小鼠或大鼠,并通常最先对优选施用途径进行研究。试验中的对照组给予安慰剂或不经处理。通常,应对另一种非啮鼠动物(例如兔子或犬),重复进行上面概述的常规毒性试验。也可采用交替的施用途径重复实验。
应在出现急性毒性迹象和确定的死亡方式下,进行单剂量毒性实验。根据上述毒性实验结果计算出施用剂量。也可无需对所有最初选定的化合物进行连续研究。
可采用重量或体积/kg体重的单位形式,表示单剂量毒性数据(例如LD50,即50%实验动物死亡的剂量),并且通常应来自不同施用方式的至少两种物种的实验。至于啮鼠动物的LD50值,应测定其他物种(即犬和兔子)的最高耐受剂量和/或最低致死剂量。
当如上确定了适宜和大概的安全剂量水平后,也应对药物的长期毒性、对生殖的作用和潜在的致突变性进行研究,以确保计算出的大致剂量范围是安全的。
然后,对药动学参数(例如活性成分和代谢物的吸收、分布、生物转化和排泄)进行药理学动物研究。然后,根据所得结果,设计对人的药理学研究。
应采用健康受试者、期望的临床施用途径(可在患者身上重复的),就化合物对人的药效学和药动学进行研究。当采用不同的剂量、或者几种类型的络合物或络合物与游离化合物联用时,应研究剂量反应关系,以阐明量效关系(剂量—血浆浓度—效力)、治疗范围和最适剂量间隔。也应对时效关系(尤其是其他重要器官系统)进行研究,例如研究效力的时程和研究不同器官,以阐明药物之所需或不需要的药理作用。
接着,本发明化合物准备进行临床试验,与已知疗法进行比较。期间应更为细致地研究治疗效力和副作用的量效关系。
应根据经验确定本发明化合物对任一选定患者的施用量,并应根据患者状况而变化。首先施用相对少量的活性成分,如果未观察到不良反应则平稳地提高剂量,不应超过常规动物毒性实验测定的最大安全毒性剂量。
本发明组合物包括所有组合物,其中活性成分的有效量足以达到其预期目的。本领域技术人员可根据个体差异,确定每种化合物有效量的最佳范围。施用剂量取决于个体接受者的年龄、健康和体重状况,以及共存治疗的性质和所需效力。典型的剂量包括0.01-100mg/kg体重。优选剂量包括0.1-100mg/kg体重。最优选剂量包括1-50mg/kg体重。
类脂化糖胺聚糖可配制成包封有药物或基因疗法的治疗组合物,或者也可以是空白,用于治疗癌症特别是转移癌。
实施例1:微米-类脂化糖胺聚糖的结构研究
通过扫描电子显微镜(SEM)获得的结构数据见附图1A和1B。附图1的两部分是两种不同的放大率的同一批产品的视野(参见每一附图底部的装置标注的信息)。以下结果证明了3种特征:
(1)这些数据证明了这些聚合物的微粒性质;
(2)这些数据也证实了粒径范围(参见附图1A中的1μM条);和
(3)一些细节提供了颗粒的形状。
可观察到颗粒的粒径是不均匀的(如附图1A,附图1B更明显)。这是可以预料的,因为显微镜观察是在分级成纳米-和微粒之前进行的。可根据微粒选择SEM中显微镜的放大率范围。
实施例2:化学键合
由于类脂的氨基基团与透明质酸的羧酸残基交联,使游离透明质酸贡献给类脂化糖胺聚糖的游离羧酸的数量下降。与类脂的结合越多,游离羧酸基团数量的降低就越多。另外,由游离羧酸的降低程度,可以测量出类脂相对于透明质酸的化学计量。可采用羧酸分析法测定预期的下降程度。也可以估算出,微粒中约有33%的葡糖醛酸残基被类脂分子俘获,而在纳米粒仅有约20%的葡糖醛酸残基被类脂分子俘获。
实施例3:EtBr类脂化糖胺聚糖剂型的物理化学和特性
测定了药物或其他生物活性物质在类脂化糖胺聚糖中的包封率,以及小分子量药物外流的药动学。采用ELISA板式读数器,在适当波长处测定每一选定被包封实体的吸光度。
微粒和纳米粒的典型包封率结果分别如表4和5所示。
表4.微米类脂化糖胺聚糖:药物包封率和药物外流半衰期
表5.纳米-类脂化糖胺聚糖:药物包封率和药物外流半衰期
类脂化糖胺聚糖包封的EtBr的浓度为25μM。包封率为49.8(±3.1)(%)。EtBr从类脂化糖胺聚糖中外流的半衰期为27.7小时。
实施例4:体外毒性研究
在细胞培养物中,对微米和纳米尺寸的不含药物类脂化糖胺聚糖(低类脂和高类脂的类脂化糖胺聚糖)进行毒实验。试验中采用两种细胞系(鼠神经胶质瘤细胞系C6和鼠成纤维细胞系NIH3T3)。在所有情况下,在100倍于0.02-2mg/ml聚合物的浓度范围内,未发现类脂化糖胺聚糖有毒性。
实施例5:示例性的对耐药(MDR)神经胶质瘤细胞系的治疗活性
由于其部位以及对化学治疗药物的反应较差,脑肿瘤(尤其是神经胶质瘤)是难于治疗的(Wolff等,1999,Nutt等,2000.The poor drug response is duein part to lack of access and in part to inherent multidrug resistance(MDR)of thesetumors(Larsen,2000;Gottesman等,1995)。
在脑肿瘤中,即使在药物已进入肿瘤(例如局部施用或通过外科操作放置局部贮库)的情况下,多药耐药也是一种障碍。在这种普遍的耐药机制(以获得或固有性模式)中,药物没有失去其固有的毒性活性,耐药细胞也不能使药物代谢成非毒性实体。而且,跨细胞膜被动扩散进入细胞的药物自动流出,使胞内水平降至低于其致死阈。表现出固有MDR的神经胶质瘤C6系用作实验模型体系,研究类脂化糖胺聚糖包封的化学治疗药物的治疗效力是否优于游离药物的治疗效力。
方法学
细胞接种于96孔平皿中,并一般在接种后24小时,于半融合时开始实验。细胞接受选定剂量的药物(包封于类脂化糖胺聚糖剂型中,用前洗去过量的非被包封药物)。对照系统接受相同剂量的游离药物,和似于待试系统剂量的不含药物类脂化糖胺聚糖。采用MTT分析法(Nutt等,2000;Larsen等2000),于处理后48小时测定细胞存活。
结果
3种化学治疗药物的结果如附图8所示(3种数据组)。游离类脂化糖胺聚糖的数据(每一3种数据组中的最左条)是附加的证实数据,表明类脂化糖胺聚糖没有毒性。根据特定药物的不同,每种药物在其各自的剂量范围内发挥作用,相对高剂量的游离药物允许20-60%的细胞存活。如每一种数据组中的中间条所示,这种结果对多药耐药细胞的固有模式而言是典型的。当用相同剂量的类脂化糖胺聚糖包封的药物代替游离药物时,产生了显著差异(如每一种数据组的右最条所示)。对每一3种药物而言,新剂型可使细胞死亡增加3-4-倍(与相应的游离药物相比)。两种发现的紧密结合提高了本发明新颖给药剂型在治疗中的响应:游离类脂化糖胺聚糖的无毒性,和各自具有独特细胞毒性机制的3种不同药物所致的细胞死亡增加。
为了克服多药耐药,必须发现能使化学治疗药物的胞内剂量高于致死阈的机制。传统方法是采用逆转剂(即化学致敏剂)降低流出。虽然已确认了一些这类物质(其中最主要的是维拉帕米),然而目前可获得化学致敏剂均不能临床应用。另外,治疗中需要细致的协作,因为两种活性实体(化学治疗药物和化学致敏剂)必须一起到达靶点才能有效。然而,这在临床实践中并非易事。
提高胞内药物剂量的另一方法是在强度和持续时间方面增加内流。很显然,通过增加内流,显著地增加了本发明包封药物的类脂化糖胺聚糖的药物响应。类脂化糖胺聚糖的生物粘附特性使其成为能与与细胞膜结合的药物贮库。这增加了药物跨细胞膜的电化学梯度(与游离药物相比),并增加了药物进入的时间间隔。这样,治疗就仅需要一种实体,即含药的类脂化糖胺聚糖组合物。通过采用显著降低的药物剂量进行连续处理,这些新剂型也会使非耐药肿瘤的治疗受益。
实施例6:微米类脂化糖胺聚糖与细胞的相互作用
已知细胞不可透过核酸敏感性荧光标记物EtBr(溴乙啡锭)。与DNA和RNA结合,可显著增强标记物的荧光发射,用于测定某种载体是否使细胞透过EtBr,具体地说是否抵达细胞核。
为了探察这些新颖聚合物与细胞的相互作用,制备了包封EtBr的类脂化糖胺聚糖,测定了这些类脂化糖胺聚糖的物理化学特性,然后类脂化糖胺聚糖与细胞温育。结果采用共聚焦显微镜扫描。
测试了两种细胞系,即C6--鼠恶性神经胶质瘤细胞系,和PANC-1--人胰腺癌细胞系。对于每一种细胞系,将单层细胞与3种不同剂型温育:(1)游离EtBr,(2)混悬于游离EtBr溶液中的“空白”(仅包封缓冲剂)类脂化糖胺聚糖,和(3)包封EtBr的类脂化糖胺聚糖。
EtBr在所有3种剂型中的浓度相同(25μM)。类脂化糖胺聚糖在剂型(2)和(3)中的浓度相同(0.25mg/ml)。在共聚焦显微照相前,每一种剂型与细胞温育60分钟(室温)。结果如附图2(细胞系C6)、附图3和4(细胞系PANC-1)所示。
C6细胞系结果如附图2A所示。左上部分表示细胞与游离EtBr温育的结果。可将细胞内部有微量荧光,与含该游离标记物的溶液相似。附图2A的右上部分是细胞与含游离EtBr的溶液温育,其中溶液中混悬有空白类脂化糖胺聚糖。在此也可见与游离EtBr相似的微量荧光,这表明颗粒本身并不能促进游离(非被包封的)EtBr进入细胞。
与这两种对照品形成对照的是,当EtBr被包封颗粒内部时,它可进入细胞和细胞核中。这可从附图2A底部的高荧光强度清晰地看出,从其在细胞核内部(与DNA相互作用)以及在胞液(与RNA相互作用)中的定位也可清晰地看出。这些发现不限于特定细胞系,由PANC-1系获得的结果也类似。
在附图3中,描述了剂型(2)和(3)的结果。游离EtBr与类脂化糖胺聚糖包封的EtBr之间的较大差异如附图4所示。附图4A表示单细胞与游离EtBr温育。仅有微量的标记物进入细胞并抵达细胞核。同样地,进入胞液的EtBr也是微量的。与此形成对照的是,如附图4B所示,当与类脂化糖胺聚糖包封的EtBr温育时,大量标记物进入细胞,并在细胞核(DNA-结合)和胞液(RNA-结合)中发现标记物。
由于所有数据均来源于采用相同浓度的EtBr,很明显所述差异是由聚合物的包封所引起的。载体促进其所负载核酸-敏感性标记物进入细胞并使游离胞内标记物与RNA相互作用以及进入细胞核并与DNA相互作用的主要机制有以下3种:
(1)吸附和扩散。负载标记物的颗粒于细胞膜附着,形成局部贮库。标记物从颗粒中扩散出来,并且一些自由标记物跨细胞膜扩散进入细胞。
(2)融合。负载标记物的载体首先与细胞膜结合,然后与其融合,并在融合过程中将被包封材料释放到胞液中。
(3)胞吞和释放。负载标记物的载体经胞途径进入细胞。胞吞进入的载体成功地将标记物释放道胞液中。在所有3种机制中,一旦标记物在胞液呈自由态,胞内标记物部分会发现其进入细胞核的方式。
根据物化数据(表示被包封标记物的外流相当缓慢),可以排除第一种机制。根据恒定的外流速率(以半衰期形式表示),可以计算出在显微照相之前的50分钟温育过程中,被包封标记物的外流最多为2%,相应地有0.5μM的EtBr变为自由的。即使所有这些EtBr跨细胞膜进入细胞,其结果与50倍高浓度的游离EtBr结果相比也是极微量的(25μM相对于0.5μM)(附图2A)。与此形成对照的是,载体包封的标记物的结果表明,例如不能通过“吸附和扩散”机制进入的标记物表现出了相当高进入率。
不管被包封标记物对癌细胞的治疗是否通过融合或胞吞机制进入细胞,很明显载体可使不可透过的分子进入细胞和细胞核。这种能力暗示了类脂化糖胺聚糖在传递中的作用。
实施例7:制剂研究
颗粒特性
颗粒粒径:采用ALV-NIBS粒径仪,测量了低类脂—糖胺聚糖比例(LLG)和高类脂—糖胺聚糖比例(HLG)纳米-和微粒的粒径。结果见表6,提供了所有定量数据,与先前获得的显微镜数据(EM,荧光)一致。两种粒径彼此不同,每种系统中相对低的散射表示各自方法的优良包封。数据也表明,通过控制类脂/HA比例,可使每种颗粒类型中的颗粒粒径具有一定的灵活性。
表6.纳米和微米TauDDS系统的粒径分布
Zeta电势:测定了微米和纳米粒Zeta电势随颗粒浓度的变化。Zeta电势或动电势表示荷离子胶体颗粒周围的离子跨扩散层的电势,它对胶体稳定性有影响。典型的结果如附图9所示,表明:(a)如同根据颗粒化学组成和颗粒结构特征所推测的结果一致,Zeta电势为负值;和(b)zeta电势对浓度的依赖模式与荷负电颗粒视野中观察到的模式一致。
包封率
研究了两种剂型;胰岛素和α-干扰素各自包封于独立的微粒制剂中。所得包封率如表7所示。很明显,所有蛋白质的包封率较高,与其他大分子的结果(表4和5)一致。胰岛素浓度为10mg/ml。在该范围内,蛋白质为聚集成二聚体和六聚体,表明被包封实体大于6000da。该胰岛素剂量水平下的包封率如此高,还未见其他微粒载体报道。
表7.治疗性蛋白质在新DDS(微粒)中的包封率
包封物 | MW范围(Da) | 包封率(%) |
胰岛素(人重组体) | 6,000 | 86.9±4.7 |
α-干扰素(人重组体) | 19,000 | 72.5±3.7 |
实施例8:体外研究
细胞培养物中的毒性实验
如下进行DDS毒性实验:选定细胞系的细胞与递增浓度的DDS(0.01-5mg/ml)温育24或48小时。对照组细胞未与DDS接触。对来源于人、大鼠和小鼠的8种不同细胞系进行了实验。所有8种细胞系的共同特征在于均具有透明质酸受体。如附图10所示,所有待试DDS浓度范围(即0.01-5mg/ml)的结果似于1mg/ml剂量的DDS。附图10的数据表明,所有剂量下的DDS与细胞系温育后,DDS未表现出细胞毒性。
基因转染
如表4和5所示,DDS以令人意料的高亲和力包封了质粒。对该剂型转染所需质粒(导致表达编码蛋白质)细胞的潜力,进行了体外实验。
待试细胞系为PANC-1和C6(均含有透明质酸受体)。报道基因为绿色荧光蛋白质(GFP)编码。DDS与两种市售载体“基准”(Polyplex阳离子聚合物和lipofectarmine-阳离子脂质体)进行了比较。市售载体的使用方案由制造商提供。
质粒包封于DDS(微粒)中,用前平衡24小时。所有3种载体中DNA浓度相同(1.5μg/孔)。细胞与选定载体-DNA制剂在DMEM中温育5小时;对照组在DMEM中温育5小时。5小时后,将加有血清的细胞生长介质加至所有孔中。
于起始点的12和24小时,在倒置荧光显微镜下观察细胞。对观测试样的总细胞数量和荧光细胞数量进行计数。由这些数据计算出转染率,定义为%荧光细胞/试样总细胞。观测试样中的总细胞数量为200-400细胞。于实验终点时(自起始点24小时),测定细胞存活力。
所得结果见表8。基准的剂量为2mg/ml(制造商所提供方案中推荐)和DDS的剂量为0.2mg/ml(剂量降低10倍)。所有3种的DNA浓度相同。于12小时,用已建立的载体检测基因制品GFP。尽管这一发现是所期望的,但仍令人鼓舞,因为试验细胞系是那些具有特定治疗价值的细胞系,而非转染中所用的经典细胞系(例如COS7)。采用DDS,蛋白质表达需要24小时。3种载体各自在所有细胞系中的转染率表明,1/10基准剂量(0.2mg/ml相对于2mg/ml)的DDS载体的性能与基准相同。
表8.体外基因转染
基因转染载体的缺点之一是阳离子聚合物或阳离子类脂具有毒性。在每种细胞系中,已观察到上述两种已建立的载体的毒性,与未处理的对照组相比,活细胞在24小时时的水平低于50%。与此形成对照的是,DDS载体没有毒性。细胞存活力保持与对照细胞相同的高水平。先前部分报道的毒性数据表明,即使DDS的剂量提高至已建立的载体的水平(2mg/ml)也没有毒性。
数据明确支持新的DDS在基因疗法中的潜在应用。这明显是优于竞争性非病毒载体两个优点:(1)在两种不同的细胞系中,10倍低的浓度即可达到与已建立的载体相同的蛋白质表达水平,表明相同载体浓度的DDS系统显著优于其竞争者;和(2)在两种不同的细胞系,DDS载体系统未表现出毒性,而其他两种载体具有相当大的毒性。
治疗MDR肿瘤
在供评价包封药物的靶向载体的细胞毒性(与相同剂量游离药物相比)的细胞培养物研究设计中,实验设计与其结果通常是与游离药物有偏差。这是由于在体外是静态的,而在体内是动态的。在体外实验期间(一般为24小时或更长),游离药物与细胞连续接触。以游离形式施用的药物在肿瘤部位的体内持续时更短,这是由于其有限的施用间隔和天然清除进程。与游离药物相比,药物/载体制剂(即使靶向载体)的体外表现(温育24小时或更长)没有明显差异。与此形成对照的是,与游离药物相比,如果载体在体内与靶体附着并驻留而成为持续释放贮库,则向肿瘤部位供应的药物非常高(剂量和持续时间),由此增强了细胞毒性。
为了减少与游离药物的体外偏差,细胞与下述治疗剂型接触4小时:游离药物、包封于DDS中的药物和不含药物的DDS(free DDS)。然后,用加有血清细胞生长介质(不含药物或载体)替换处理介质,并于20小时后(自开始后24小时)测定活细胞数量。如果一些载体剂型与细胞附着,即使改变介质它也会驻留成为贮库,并连续向细胞供给药物,而一旦介质改变,给予游离药物的细胞则不能再与任何药物接触。
细胞死亡增加(与未处理的对照组比较)随治疗剂型变化的典型结果如附图11所示(细胞系C26)。这来源于鼠结肠癌的为固有多药耐药(MDR)系。附图11A为药物丝裂霉素C(MMC)的结果。如在先体外毒性研究一致(附图2),不含药物的DDS(测试剂量为1mg/ml)没有毒性。两种剂量(30和50μg/ml)游离MMC几乎没有作用,其细胞死亡百分率低于15%。这种相当高剂量下的低响应是由这些细胞.之MDR特性的表现。与此形成对照的是,当用包封于DDS中的相同剂量的药物处理时,80-100%细胞被杀死。载体介导的药物与游离药物之间的差异非常显著(p<0.001)。相似结果如附图11B的另一药物阿霉素(DOX)所示。游离药物(每种药物具有不同的剂量范围)是无效的,而包封于载体中相同剂量的药物非常有效,导致80-100%细胞杀死。两种其他细胞系-C6和PANC-1获得的结果相似。所有待试的3种细胞系均含有HA受体。
实施例9:体内研究
体内研究I:肿瘤化学疗法
对8周龄雌性BALB/c小鼠进行了实验。所用肿瘤模型为C-26细胞(来源于鼠结肠癌),皮下注射到右后足垫中。化学治疗药物为游离或包封于LLG纳米微粒DDS中的丝裂霉素C(MMC)。MMC剂量为2mg/kg体重,游离和DDS制剂和DDS剂量均为1mg/ml。
第1轮实验设计
对20只动物进行了实验,分成4组,每组5小鼠,接受如下表9的特定处置。
表9.动物组
组# | 处理 |
1 | 盐水 |
2 | Free DDS |
3 | 游离MMC |
4 | MMC/DDS |
C-26细胞于细胞培养烧瓶中生长以提供肿瘤。于0天,收集细胞并洗涤几次,计数并立即注射。注射剂量为8×105细胞30μl。
于5、12和19天进行处理。经尾静脉注射施用。所有注射体积为0.1ml。
第2轮实验设计
实验设计基本上同第1轮实验,不同之处在于:
a.药物剂量提高至5mg/ml;
b.肿瘤接种量为8×105细胞30μl;
c.实验采用2组动物。一组接受不含药物的DDS(free DDS)和另一组接受MMC/DDS,每组分别为3和5小鼠;
d.于14、17、20和23天进行处理;
e.开始处理时肿瘤大小为75mum3。
第1轮测量的参数是循环中保留、肿瘤发生、肿瘤体积、存活。第2轮测量的参数是存活。
第1轮结果:循环中保留
网状内皮系统(RES)的一项正常生理作用即是相当迅速地从循环中除去外源性微粒物质。除非经静脉内(iv)施用的微粒载体的靶点在RES内,否则这种清除是所有经静脉内施用的微粒载体所要面临的主要问题,这降低了足量药物以有效方式抵达其目的靶点的可能性。这种问题并不是肿瘤治疗特异性的,任何需要静脉内给药的病理学病症通常要遇到这一问题。
通过广泛的研究,对阻滞这一清除进程从而使微粒物质长循环的手段总结如下:颗粒应很小,并应具有亲水性包衣(一般富含羟基残基)。纳米级的球形微粒载体(毫微球)--一般包被有聚合物例如泊洛沙姆(poloxomar)或poloxamine。小脂质体的表面通常负载聚乙二醇(PEG),称为例如“隐形(stealth)脂质体”、“PEG化脂质体”和“立体稳定化的脂质体”。
在着手进行本发明和研发本发明DDS的过程中,推测是由于颗粒表面的主要组分--透明质酸富含羟基残基而提供了固有的循环中的长保留能力和靶向能力。同时具有的靶向和“隐形”特性使DDS明显优于其他竞争性载体。
在注射一段时间后,取接受含药物制剂的动物放血,并按照已建立的方案处理试样。HPLC分析法测定MMC浓度。对游离MMC和包封于载体中的MMC(MMC/DDS)作了比较,其在循环中保留的典型结果如附图12所示。数据表明,游离MMC从循环快速消失,而经载体施用中的MMC具有更长的循环时间。这一发现在另一实验中得以重现,即经载体注射施用长达72小时后,仍在循环发现了药物。游离药物的快速消失表明,在接受MMC/DDS制剂动物的循环中发现的MMC是载体中的MMC。这些结果证实了上述假说,即这些DDS具有内在的“隐形”能力。当然,上述有关载体的积极蕴义不限于在此试验的特定病理学。
第1轮结果:肿瘤发生和肿瘤体积
如附图13所示,为所有4组的肿瘤体积增加结果和首次探测到肿瘤的平均天数。在单独接受盐水的所有动物中,于第7天检测到肿瘤,肿瘤呈指数形式快速增加。在接受游离药物的所有动物中,也于第7天检测到肿瘤。与盐水组相比,尽管接受了3种剂量化学治疗药物的肿瘤的体积增加也没有明显差异。这表示体外所见的细胞系MDR性质(附图3)在体内也存在。令人惊奇的是,用不含药物的DDS(free DDS)处理的效力强于盐水以及游离药物。其肿瘤出现的平均天数为第9天(相对于7天),并且肿瘤生长速度明显减慢。与相比盐水和游离药物组相比,肿瘤也显著小。
不含药物的DDS(free DDS)的体内性能完全不同于体外。透明质酸是胞外基质(ECM)的关键组分,并且已知具有HA受体肿瘤细胞能利用这一特性。通过其HA受体与ECM中的HA相互作用,肿瘤细胞会在肿瘤演进过程中将ECM作为一个平台。阻断受体可以延迟肿瘤演进。这可能是不含药物的DDS(free DDS)发挥作用的主要机制,载体在此与HA受体结合并将其阻断。其他不互斥的可能机制是不含药物的DDS(free DDS)可作为抗血管生成因子或促发宿主防御机制。将对DDS本身的这一积极作用机制进一步研究,以理解这些现象,并获知如何开发而取得更好的治疗成果。无论其起源如何,这均是该DDS积极的附加优点,并且是无法由体外数据所预知的。
包封于载体中的药物表现出最佳结果。由附图13可见,最先约在第17天才检测到肿瘤,这明显迟于用不含药物的DDS(free DDS)、游离药物或盐水处理组。在所有实验组中,该组肿瘤的生长速度最慢且肿瘤最小。这可能是由于DDS之内在的靶向性所致,其抵达肿瘤的部分在此成为药物贮库,并且药物的细胞毒性可能与载体作用(如同不含药物的DDS(free DDS)表现的)相结合。与游离药物不同,体外结果表明这种剂型能杀死MDR细胞,这在体内也得以重现和证实。
第1轮结果:存活
在整个90天内,监视动物的存活存活,直至最后一只动物死亡。结果如附图14所示。
接受盐水组的所有动物在第29-31天之间死亡,和接受游离药物的动物在第31-33天之间死亡。与盐水和游离药物相比,接受不含药物的DDS(free DDS)的动物的存活期要长2倍,在第59-66天之间死亡。
这种较长的存活期蕴涵着两种临床含义。首先,DDS在体内没有出现体外观察到的毒性。对于这种技术的所有应用而言,其体内迹象的重要性更为显著。其次,不含药物的载体本身即对荷瘤动物的肿瘤发展和大小同时具有有益的治疗效力(附图13)。
在接受DDS包封的药物完全处理的动物组中,观察到了最长的存活,即3倍于盐水和游离药物组的存活期。最后的动物于第94天死亡。这对于荷瘤小鼠(尤其是具有MDR)来说是格外长的存活期,同时表示该药物传递技术优于其竞争者。
第2轮结果:存活
在实验的91天,仍监视动物的存活存活,结果如附图15所示。用不含药物的DDS(free DDS)处理的3只荷瘤动物具有最长存活期(长至69天)。用MMC/DDS制剂处理的5只荷瘤动物在接种肿瘤91天后仍能较好地进食,所有动物均存活。
这些数据的趋势与第1轮相似,表明对新的DDS的出人意料的反应具有重现性的。两实验间存在两个主要差异。首先,在第2轮中,在肿瘤发生后开始治疗的(参见上述实验设计),这使得其治疗与第1轮相比更具挑战性。其次,在第2轮中,动物接受了较高的累积药量。共注射4次(而第1轮中为3次),并且其剂量高出2.5倍(5mg/ml:2mg/ml).
这些差异所致的积极趋势表示新的DDS具有产生更佳响应的效力。对于已长至100-150mm3的肿瘤,新颖DDS技术是更具挑战性、同时也更现实的治疗方式。
实施例10:体内研究II:经鼻内传递至脑部
治疗神经变性疾病需要将药物通过完整的BBB或绕过(bypass)BBB而传递至脑部。进行了两项实验(一项采用大鼠和另一项采用小鼠),用来评价本发明新颖DDS将药物传递至脑部的能力(经鼻内施用绕过BBB)。
第1轮包括大鼠实验(健康着色(pigmented)鼠)。DDS是纳米微粒形式的LLG,和标记物为MMC。待试系统为包封于新的DDS中的标记物。不含药和含药的DDS制剂的施用剂量为5mg/kg体重,300μl/动物。DDS剂量为1mg/ml。
实验中采用4只动物(分成2对)。一对经鼻内(IN)接受游离标记物至右鼻孔中。另一对经鼻内接受标记物/DDS制剂至右鼻孔中。采用适宜的无针注射器,缓慢给药(用时若干分钟)。
给药6小时后,处死动物并取出脑部。每个脑均浸于10ml的PBS中1小时,释放出松散结合的标记物,然后对脑部均质处理。采用HPLC分析法,分析洗液和脑匀浆中的标记物。
所得结果如附图16所示,其中以“%施用剂量”表示标记物蓄积。虽然每个治疗组仅有2只动物,每组间的符合程度足以计算均值。每对的平均和标准偏差,分列于相关条(洗液和脑匀浆)的上部。
对脑匀浆的研究表明,当以游离形式施用时,标记物在脑部的蓄积非常少(与游离小分子处于同一数量级)。与此形成对照的是,当以DDS形式施用时,标记物在脑部有相当高的蓄积(接近10%施用剂量)。这是较高的数值(高于游离药物80倍),尤其是当相关药物也能达到这一数值时。这些结果表示新颖DDS对那些需要药物传递至脑部的病理学病症有较高的应用潜力。
第2轮包括小鼠实验(健康C57BL/6小鼠)。DDS是纳米微粒形式的LLG。标记物为MMC,待试系统为包封于新的DDS中的标记物。不含药和含药的DDS制剂的施用剂量为5mg/kg体重,150μl/动物。DDS剂量为1mg/ml。
实验中采用4只动物(分成2对)。一对经鼻内(IN)接受游离标记物至右鼻孔中。另一对经鼻内接受标记物/DDS制剂至右鼻孔中。采用适宜的注射器,缓慢给药(用时若干分钟)。
给药6小时后,动物经心脏灌注,然后处死.,取出脑部并进行均质处理,按第1轮方法测定标记物浓度。
灌注后,脑部是清洁的。所得结果以“%施用剂量”,如所示附图17。由于动物之间变异性,报告每只动物的数据。虽然存在个体变异性,其结果还是相当清楚的。当以游离形式施用时,标记物的蓄积非常少,而当以DDS形式施用时其蓄积显著。在大鼠实验中也有积极的发现,与以游离形式施用的标记物相比,经载体施用的标记物的蓄积要高600-2,500倍。这些结果表明,这种药物传递技术经非侵入性施用途径将药物传递至脑部的潜力并不限于单一物种。
实施例11:新的DDS治疗荷耐药肿瘤小鼠:肿瘤转移灶模型动物研究
本研究目的是评价肿瘤转移灶模型中的新的DDS。与采用小鼠和固有MDR的C-26细胞系的在先研究相似,本研究也采用固有MDR的细胞系(B16F10,来源于鼠黑素瘤)。采用本领域已建立的特定方案,用于诱发肺转移。
实验开始时采用12周龄的C57BL/6雌性小鼠。肿瘤模型为B16F10,静脉内注射细胞。所用化学治疗药物为丝裂霉素C(MMC)。DDS系统为纳米颗粒形式的LLG。待试系统为包封于本发明新的DDS中的MMC(MMC/DDS)。MMC的注射剂量为5mg/Kg体重和DDS剂量为1mg/ml。
取25只动物实验,分成5组,每组5只小鼠,接受见表10的特定处置。组1为是未接种肿瘤细胞的健康小鼠对照组。
表10.动物组
组# | 1 | 2 | 3 | 4 | 5 |
处理 | 无 | 盐水 | 游离MMC | 不含药物的DDS(free DDS) | MMC/DDS |
B16F10细胞于细胞培养烧瓶中生长。于0天,收集细胞并洗涤几次,计数并立即注射给2-5组。注射剂量为在50μl PBS中的5×105细胞。
于1、5和19天进行治疗。经尾静脉注射施用。所有注射体积为0.1ml。于肿瘤接种21天后中止实验。处死动物,取出肺,称重并固定于Bouin氏溶液中。按下述公式计算肺增重:
肺重增加(%)=100×(肿瘤肺重-正常肺重)/正常肺重
由专家采用解剖显微镜对表面转移灶进行计数。样品采用盲法编号,因此专家不知每一动物接受的处置。
采用两种独立测量的数据定量评价在肺中的转移:离体并适当固定的肺中转移灶的实际计数;和/或注射肿瘤细胞的动物中因转移所致肺增重的测量数据。本研究采用上述两种技术。
1-5组中发现的转移灶数量如附图18所示。
如所预料的一致,对照动物(没有接受任何肿瘤细胞)肺中没有出现转移灶。所以接受静脉内注射B16F10细胞的其他组出现了肺转移。在接受盐水或游离药物的动物中出现了最侵略性的转移。这些组间没有统计学差异,表明这些细胞在体内也表达其固有MDR特性。
与盐水相比,用不含药物的DDS(free DDS)处理使转移灶数量降低6倍,而用实验剂型处理使转移灶数量降低得更多(达17倍)。
所有注射肿瘤的4组,均与正常动物(对照组)比较肺增重。所得结果如附图19所示。
在未接受任何处置的动物(盐水组)中,出现了最高肺增重(接近400%),接受游离药物处理的动物的状况也类似。与未接受处置和和接受游离药物的相比,接受DDS的动物的肺增重较小,但是与对照组的健康动物肺重相比仍增加2倍。在接受包封于DDS的MMC实验制剂的动物中,观察到相对(与其他组比较)和绝对(与健康动物比较)最佳的反应。与健康动物相比,其%增加属于10%数量级,不具有统计学显著意义,表明该剂型具有破坏(abolish)肺转移的潜力
由于肺转移可致肺增重,因此两种独立测量的参数之间有适当的相关性。可从附图20中明确地看出这种相关性,该附图附图18和19数据(均值)的重绘图。附图20也证明了实验剂型在最具挑战性的肿瘤治疗中的优越性,它能消除MDR肿瘤转移。
至此,已对新的DDS作为化学治疗药物的载体在两种独立动物模型中的性能进行了研究。一种为实体瘤和另一种为肺转移。在两种模型中,将来源于C-26和B16F10细胞系的肿瘤细胞注入动物体内,证实了它们在体内也表达先前体外所见的MDR特性。
在两种模型中,与游离药物相比,用不含药物的DDS(free DDS)自身处理表现出良好的临床反应。然而,在两种模型中具有最佳临床反应的是包封化学治疗药物的新的DDS实验剂型。这表示此种新颖系统具有较高的临床应用潜力。
实施例12:BSA-FITC进入MCF-7细胞
用游离形式和包封于DDS中的荧光标记物FITC(BSA-FITC)标记牛血清白蛋白,用于测定DDS是否也能促使大的大分子进入细胞。于25℃,不含药的和DDS-被包封的BSA-FITC与MCF7细胞(来源于人乳癌)的融合单层温育60分钟。据报道,MCF-7细胞具有两种已知的透明质酸受体(ICAM-1和CD44)。除去蛋白质/DDS系统中的游离蛋白质。游离形式和被包封蛋白质的浓度相同(均3.3mg/ml)。温育后,用共聚焦显微镜观察细胞。
游离蛋白质的结果如附图21的上面两格所示。一些蛋白质进入细胞,并看见与核被膜结合,但没有进入细胞核内部。已知BSA可与细胞非特异性结合,并且可以通过非特异性受体或通过胞饮作用而进入细胞。
DDS包封BSA-FITC的结果如附图21下面两格所示。进入细胞的蛋白质明显多于游离蛋白质,并且蛋白质也进入了细胞核中。至于被包封的EtBr(附图2-4),其确切的相关机制仍无法完全获知。然而,对于大的蛋白质而言,蛋白质-DDS通过受体介导的胞吞作用而被摄取的可能性,要高于小的EtBr。
前述对特定实施方案的描述旨在充分地说明本发明的一般性质,本领域技术人员可采用当前的知识,根据该特定实施方案的不同应用而容易地进行并不偏离其一般概念的改进和变化,因此,这种借用和改进应当均在此公开实施方案之同等物的精神和范畴之内。在此所用的的措词或术语应理解为旨在描述而没有限制作用。
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Claims (63)
1.类脂化糖胺聚糖微米颗粒或纳米颗粒,包括至少一种糖胺聚糖与至少一种含有伯氨基的类脂的反应产物,其中所述类脂与糖胺聚糖的比例是1:1或5:1-20:1重量/重量,其中所述颗粒是通过包含下述的步骤制备:
(a)提供反应容器,其中类脂薄层铺展于容器底部和壁上;
(b)在酸性pH下与交联剂预温育,使糖胺聚糖活化;
(c)将活化的糖胺聚糖加至反应容器中;
(d)类脂和活化的糖胺聚糖的反应混合物缓冲至pH8.6的碱性;
(e)在连续搅拌下,将缓冲后的反应混合物温育足以形成类脂化糖胺聚糖的时间;
(f)将类脂化糖胺聚糖缓冲至中性pH,并根据需要加入其他离子和水溶性添加剂,以提高离子强度,使其相当于生物流体中离子或盐类的生理水平;
(g)经连续离心,每操作在4℃,1.3×105g离心40分钟,分级颗粒:3次操作后的小球是富含微粒的级分,富含微粒的上层再离心3次操作即获得富含纳米粒的级分。
2.根据权利要求1的类脂化糖胺聚糖微米颗粒或纳米颗粒,其中糖胺聚糖选自透明质酸,硫酸角质素,硫酸软骨素,硫酸肝素,硫酸乙酰肝素,硫酸皮肤素,和透明质酸、硫酸角质素、硫酸软骨素、硫酸肝素、硫酸乙酰肝素、硫酸皮肤素的片段、盐类及混合物。
3.根据权利要求1的类脂化糖胺聚糖微米颗粒或纳米颗粒,其中糖胺聚糖为透明质酸。
4.根据权利要求1的类脂化糖胺聚糖微米颗粒或纳米颗粒,其中类脂为磷脂酰乙醇胺。
5.根据权利要求1的类脂化糖胺聚糖微米颗粒或纳米颗粒,其中颗粒的粒径约为2-5微米。
6.根据权利要求1的类脂化糖胺聚糖微米颗粒或纳米颗粒,其中颗粒的粒径约为50-200纳米。
7.根据权利要求1的类脂化糖胺聚糖微米颗粒或纳米颗粒,其中活性成分被包封在颗粒中。
8.根据权利要求7的类脂化糖胺聚糖微米颗粒或纳米颗粒,其中活性成分选自抗感染药、化疗药物、蛋白质、激素、酶、细胞和核酸。
9.根据权利要求8的类脂化糖胺聚糖微米颗粒或纳米颗粒,其中活性成分是用于治疗癌症的化疗药物。
10.一种制备类脂化糖胺聚糖微米颗粒或纳米颗粒的方法,包括至少一种糖胺聚糖与至少一种含有伯氨基的类脂反应,使糖胺聚糖的羧酸基残基与伯氨基交联,其中所述类脂与糖胺聚糖的比例是1:1或5:1-20:1重量/重量,所述方法包括
(a)提供反应容器,其中类脂薄层铺展于容器底部和壁上;
(b)在酸性pH下与交联剂预温育,使糖胺聚糖活化;
(c)将活化的糖胺聚糖加至反应容器中;
(d)类脂和活化的糖胺聚糖的反应混合物缓冲至pH8.6的碱性;
(e)在连续搅拌下,将缓冲后的反应混合物温育足以形成类脂化糖胺聚糖的时间;
(f)将类脂化糖胺聚糖缓冲至中性pH,并根据需要加入其他离子和水溶性添加剂,以提高离子强度,使其相当于生物流体中离子或盐类的生理水平;
(g)经连续离心,每操作在4℃,1.3×105g离心40分钟,分级颗粒:3次操作后的小球是富含微粒的级分,富含微粒的上层再离心3次操作即获得富含纳米粒的级分。
11.根据权利要求10的方法,其中糖胺聚糖选自透明质酸,硫酸角质素,硫酸软骨素,硫酸肝素,硫酸乙酰肝素,硫酸皮肤素,和透明质酸、硫酸角质素、硫酸软骨素、硫酸肝素、硫酸乙酰肝素、硫酸皮肤素的片段、盐类及混合物。
12.根据权利要求11的方法,其中糖胺聚糖是透明质酸。
13.根据权利要求10的方法,其中类脂是磷脂酰乙醇胺。
14.一种制备包封有活性成分的类脂化糖胺聚糖微米颗粒或纳米颗粒的方法,包括在水中重建冻干的权利要求1的类脂化的糖胺聚糖微米颗粒或纳米颗粒,并加入粉末状活性成分,由此使活性成分被包封于类脂化糖胺聚糖微米颗粒或纳米颗粒中。
15.包封于用作递送系统的权利要求1的类脂化糖胺聚糖微米颗粒或纳米颗粒中的生物活性物质在制备用于治疗患有病理学病症的动物的药物的用途。
16.根据权利要求15的用途,其中病理学病症是癌症和所述生物活性物质是抗癌药物。
17.根据权利要求16的用途,其中所述药物为适合于口服施用的形式。
18.根据权利要求16的用途,其中所述药物为适合于静脉内施用的形式。
19.根据权利要求16的用途,其中所述药物为适合于鼻内施用的形式。
20.根据权利要求16的用途,其中所述药物为适合于局部施用的形式。
21.根据权利要求16的用途,其中所述癌症是动物中枢神经系统的癌症。
22.根据权利要求21的用途,其中所述中枢神经系统癌症是神经胶质瘤。
23.根据权利要求16的用途,其中所述癌症是转移癌。
24.根据权利要求15的用途,其中病理学病症是细菌感染和所述生物活性物质是抗菌药。
25.根据权利要求24的用途,其中细菌感染是创伤。
26.根据权利要求24的用途,其中细菌感染是烧伤。
27.根据权利要求24的用途,其中细菌感染位于动物的中枢神经系统。
28.根据权利要求24的用途,其中所述药物为适合于口服施用的形式。
29.根据权利要求24的用途,其中所述药物为适合于静脉内施用的形式。
30.根据权利要求24的用途,其中所述药物为适合于鼻内施用的形式。
31.根据权利要求24的用途,其中所述药物为适合于局部施用的形式。
32.根据权利要求15的用途,其中病理学病症是真菌感染和所述生物活性物质是抗真菌药。
33.根据权利要求32的用途,其中真菌感染是创伤。
34.根据权利要求32的用途,其中真菌感染是烧伤。
35.根据权利要求32的用途,其中真菌感染位于动物的中枢神经系统。
36.根据权利要求32的用途,其中所述药物为适合于口服施用的形式。
37.根据权利要求32的用途,其中所述药物为适合于静脉内施用的形式。
38.根据权利要求32的用途,其中所述药物为适合于鼻内施用的形式。
39.根据权利要求32的用途,其中所述药物为适合于局部施用的形式。
40.根据权利要求15的用途,其中病理学病症是病毒感染和所述生物活性物质是抗病毒药。
41.根据权利要求40的用途,其中病毒感染位于动物的中枢神经系统。
42.根据权利要求40的用途,其中所述药物为适合于口服施用的形式。
43.根据权利要求40的用途,其中所述药物为适合于静脉内施用的形式。
44.根据权利要求40的用途,其中所述药物为适合于鼻内施用的形式。
45.根据权利要求40的用途,其中所述药物为适合于局部施用的形式。
46.根据权利要求15的用途,其中病理学病症是寄生虫感染和所述生物活性物质是抗寄生虫药。
47.根据权利要求46的用途,其中所述药物为适合于口服施用的形式。
48.根据权利要求46的用途,其中所述药物为适合于静脉内施用的形式。
49.根据权利要求46的用途,其中所述药物为适合于鼻内施用的形式。
50.根据权利要求46的用途,其中所述药物为适合于局部施用的形式。
51.根据权利要求15的用途,其中病理学病症是朊病毒感染和所述生物活性物质是适于治疗朊病毒感染的生物活性剂。
52.根据权利要求51的用途,其中所述药物为适合于口服施用的形式。
53.根据权利要求51的用途,其中所述药物为适合于静脉内施用的形式。
54.根据权利要求51的用途,其中所述药物为适合于鼻内施用的形式。
55.权利要求1的类脂化糖胺聚糖微米颗粒或纳米颗粒,其中包封有成像用的标记物。
56.根据权利要求55的微米颗粒或纳米颗粒,其中标记物是放射性同位素。
57.根据权利要求56的微米颗粒或纳米颗粒,其中放射性同位素选自99Tc、127I和67Gd。
58.根据权利要求55的微米颗粒或纳米颗粒,其中标记物是荧光分子。
59.权利要求55所述的类脂化糖胺聚糖微米颗粒或纳米颗粒作为递送系统在制备诊断剂中的应用,其中所述诊断剂被给予患者以对所述患者进行成像。
60.根据权利要求8的类脂化糖胺聚糖微米颗粒或纳米颗粒,其中活性成分是核酸。
61.权利要求60所述的糖胺聚糖微米颗粒或纳米颗粒作为递送系统在制备用于基因传递和短期表达用于治疗目的核酸的试剂中的应用,其中所述核酸以有效量使用并且被配制以包封于所述微米颗粒或纳米颗粒中以对需要其的动物进行给予。
62.根据权利要求15的用途,其中所述微米颗粒或纳米颗粒为适合于眼内、肌内或皮下施用的形式。
63.权利要求1的类脂化糖胺聚糖微米颗粒或纳米颗粒作为递送系统在制备用于治疗病症的药剂中的应用,其中所述类脂化的糖胺聚糖微米颗粒或纳米颗粒包封一种水溶性药物,所述水溶性药物对治疗所述病症有效。
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EP1423095A1 (en) | 2004-06-02 |
WO2003015755A1 (en) | 2003-02-27 |
JP2005505529A (ja) | 2005-02-24 |
CA2456966A1 (en) | 2003-02-27 |
EP1423095B1 (en) | 2016-09-28 |
JP4537057B2 (ja) | 2010-09-01 |
CN1564678A (zh) | 2005-01-12 |
US20130095032A1 (en) | 2013-04-18 |
US20160113882A1 (en) | 2016-04-28 |
ES2607802T3 (es) | 2017-04-04 |
US9259474B2 (en) | 2016-02-16 |
KR20040037062A (ko) | 2004-05-04 |
IL160205A0 (en) | 2004-07-25 |
US8277847B2 (en) | 2012-10-02 |
US20090155178A1 (en) | 2009-06-18 |
US20040241248A1 (en) | 2004-12-02 |
US7544374B2 (en) | 2009-06-09 |
US9526705B2 (en) | 2016-12-27 |
EP1423095A4 (en) | 2010-03-17 |
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