CN111315399A - 用于药物递送的葡萄糖敏感性组合物 - Google Patents
用于药物递送的葡萄糖敏感性组合物 Download PDFInfo
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- CN111315399A CN111315399A CN201880049323.6A CN201880049323A CN111315399A CN 111315399 A CN111315399 A CN 111315399A CN 201880049323 A CN201880049323 A CN 201880049323A CN 111315399 A CN111315399 A CN 111315399A
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- drug delivery
- delivery system
- insulin
- liposomes
- glucose
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- 239000008103 glucose Substances 0.000 title claims abstract description 109
- 238000012377 drug delivery Methods 0.000 title claims abstract description 53
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Abstract
本发明公开了葡萄糖敏感性药物递送系统,其包括包封活性剂的聚合物壳。在暴露于足够浓度的葡萄糖时,壳破裂,释放出活性剂以供吸收。
Description
政府资助声明
本发明在由国立卫生研究院授予的拨款号TR001111的政府资助下完成。政府享有本发明的某些权利。
相关专利申请的交叉引用
本申请要求2017年6月2日提交的美国临时申请62/514,099的优先权,其内容现以其整体并入本文。
技术领域
本申请涉及可口服给药的葡萄糖敏感性组合物。
背景技术
全世界糖尿病患病率的上升是严重的公共健康负担。糖尿病的医疗管理以严格控制血糖水平为中心,以防止与慢性高血糖相关的长期器官损害。为此,患者在日常方案中自我给予胰岛素,通常包括皮下注射商业胰岛素制剂。例如,根据碳水化合物含量服用速效胰岛素,并在每餐前后皮下注射,以减轻餐后血糖偏移。目前的糖尿病自我管理护理标准建议患者量化每餐的碳水化合物并相应地服用胰岛素。然而,这种方法的有效性受到人为计数或计算误差、其他饮食成分或生活方式因素的复杂影响以及患者依从性差的限制,导致餐后血糖水平控制不充分。此外,注射胰岛素与高度的人为误差和患者的依从性差,以及诸如疼痛、组织侵犯、感染和神经损伤等并发症有关。
为了改善糖尿病患者的生活质量,最近几十年的努力集中在开发基于口服、鼻、肺和透皮递送途径的替代策略上。胰岛素口服递送已成为最方便的给药途径之一,并且许多胰岛素制剂已被开发出来,以通过改善肠道吸收和防止胰岛素消化来提高胰岛素口服递送效率。然而,目前的制剂不能满足特定的餐后胰岛素释放的需要,优化的口服胰岛素递送系统将在需要时向身体供应胰岛素。
仍然需要改善的生物制剂(诸如胰岛素)的可口服给药的组合物。仍然需要改善的不需要患者量化食物摄入量的治疗糖尿病和相关病症的方法。仍然需要在食物消化后选择性地释放治疗剂的可口服给药的组合物。仍然需要一种口服胰岛素递送方法,该方法能够对一顿饭消化后肠道葡萄糖水平升高作出反应,从而减少患者计算碳水化合物和胰岛素剂量的需要。
发明内容
本发明公开了一种口服药物递送系统,其包括包封活性剂的葡萄糖响应性硼酸酯聚合物缀合物。在葡萄糖水平升高的情况下,硼酸酯裂解,聚合物壳破裂,释放出其内容物。该系统可包括负载有治疗剂(例如胰岛素)的脂质体。该系统可包括一个或多个靶向部分,以便利地将制剂沿着肠道递送至所需位置。
附图简要说明
图1包括用于餐后血糖调节的具有葡萄糖敏感性HA壳的葡萄糖响应性口服胰岛素递送系统的示意图。(A)负载有胰岛素的脂质体的示意图,该脂质体具有葡萄糖反应性可分离HA壳,用于由餐后肠道中评估的葡萄糖浓度触发的口服胰岛素递送。(B)葡萄糖反应性HA壳的形成及反应机理示意图。
图2包括葡萄糖反应性HA-Fc-脂质体的表征。(A)Ins-脂质体、Fc-脂质体和HA-Fc-脂质体的粒径和zeta电位。(B)HA-Fc-脂质体的TEM图像。比例尺:100nm。(C)利用动态光散射(DLS)测得的HA-Fc-脂质体的水动力粒径分布。(D)在pH 7.4或2.5条件下,胰岛素从Fc-脂质体和HA-Fc-脂质体的体外释放。误差条指示SD(n=3)。(E)TEM图像和(F)用葡萄糖(10mM)孵育2小时后HA-Fc-脂质体的粒径分布。比例尺为100nm。
图3描绘了体外葡萄糖触发的HA壳从HA-Fc-脂质体上分离和跨上皮转运。(A)在pH6.0条件下,不同葡萄糖浓度下Rho-HA-PBA从HA-Fc-脂质体或HA_CL-Fc-脂质体中的体外分离。(B)HA-Fc-脂质体在0mM、5mM和10mM葡萄糖溶液中随时间的zeta电位变化。(C)利用Caco-2细胞单层通透性试验进行体外跨上皮转运研究的示意图。(D)不同的负载有胰岛素的脂质体制剂(含或不含10mM葡萄糖)的体外跨上皮转运。误差条指示SD(n=3)。**P<0.01(双尾学生氏t检验)。
图4描绘了用于1型糖尿病治疗的体内研究。(A)给禁食STZ诱导的1型糖尿病小鼠口服不同制剂:1)Fc-脂质体+葡萄糖;2)HA-Fc-脂质体;3)HA-Fc-脂质体+葡萄糖;4)HA-CL-Fc-脂质体+葡萄糖。给药后2小时收集肠,用于切片并成像。绿色荧光指示FITC标记的胰岛素,蓝色荧光指示Hoechst 33342染色的细胞核。比例尺:20μm。(B)体内FITC-胰岛素吸收中荧光强度的定量分析。所有荧光强度被标准化为Fc-脂质体+葡萄糖组。*P<0.05(双尾学生氏t检验)。(C)口服给予胰岛素溶液、负载有胰岛素的脂质体、Fc-脂质体、HA-Fc-脂质体和用葡萄糖预处理的HA-Fc-脂质体后,禁食糖尿病小鼠的血糖水平。给予用葡萄糖(10mM)预处理的HA-Fc-脂质体与HA-Fc-脂质体相比,*P<0.05。(D)口服不同制剂的禁食小鼠的血糖水平:1)葡萄糖;2)胰岛素溶液+葡萄糖;3)Fc-脂质体+葡萄糖;4)HA-Fc-脂质体+葡萄糖;5)HA_CL-Fc-脂质体+葡萄糖。口服胰岛素制剂(10U/kg)30min后,口服葡萄糖溶液(1g/kg)。(E)治疗后糖尿病小鼠的血浆人胰岛素浓度。给予HA-Fc-脂质体+葡萄糖与HA_CL-Fc-脂质体+葡萄糖相比,*P<0.05并且**P<0.01。误差条指示SD(n=5)。
图5描绘了多巴胺(1mg/mL)和DSPE-PEG-CA(10mg/mL)在水中的UV-Vis光谱。
图6描绘了在与Caco-2细胞孵育24小时后,空HA-Fc-脂质体的细胞毒性研究。误差条指示SD(n=6)。
图7描绘了HA-PBA在水中的平衡:分子内B-O键的形成导致促进硼酸酯形成的硼原子的四面体几何结构。
图8描绘了静脉注射胰岛素溶液或负载有胰岛素的Fc-脂质体(胰岛素剂量:5U/kg)后的糖尿病小鼠的血糖变化。误差条指示SD(n=5)。
图9描绘了在pH 2.5和pH 7.4的条件下,Fc-脂质体和HA-Fc-脂质体的zeta电位。误差条指示SD(n=3)。
具体实施方式
在本方法和系统公开和描述前,应理解所述方法和系统不局限于特定合成方法、特定成分或特定组合物。另外应当了解,本文使用的术语只是为了描述特定实施例的目的,并非旨在进行限制。
如在本说明书和所附权利要求书中所用,单数形式“一个”“一种”和“所述”包括复数指代物,除非上下文另外明确规定。范围可在本文中表示为从“约”一个特定值和/或至“约”另一个特定值。当表达此类范围时,另一个实施例包括从一个特定值和/或至另一个特定值。相似地,在利用前词“约”将值表示为近似值时,应当理解,该特定值形成另一个实施例。还应当理解,每个范围的端点在相对于另一个端点和独立于另一个端点方面都是显著的。
“任选的”或“任选地”意指随后描述的事件或情况可能发生或可能不发生,并且该描述包括其中所述事件或情况发生的情形和不发生的情形。
在本说明书的说明和权利要求书中,字词“包括”和该字词的变体诸如“包含”和“具有”意指“包括但不限于”,并不旨在排除例如其他添加剂、成分、整体或步骤。“示例性的”意指“一个实例”,并且不是旨在表达优选的或理想实施例的指示。“诸如”不是在限制性意义上使用,而是用于解释目的。
药学上可接受的盐是保留母体化合物所期望的生物活性并不会产生不期望的毒理学作用的盐。这些盐的实例是由无机酸(例如盐酸、氢溴酸、硫酸、磷酸和硝酸等)形成的酸加成盐;由有机酸(例如乙酸、草酸、酒石酸、琥珀酸、马来酸、富马酸、葡糖酸、柠檬酸、苹果酸、甲磺酸、对甲苯磺酸、萘磺酸和聚半乳糖醛酸等)形成的盐;由元素阴离子(如氯、溴和碘)形成的盐;由金属氢氧化物(例如氢氧化钠、氢氧化钾、氢氧化钙、氢氧化锂和氢氧化镁)形成的盐;由金属碳酸盐(例如碳酸钠、碳酸钾、碳酸钙和碳酸镁)形成的盐;由金属碳酸氢盐(例如碳酸氢钠和碳酸氢钾)形成的盐;由金属硫酸盐(例如硫酸钠和硫酸钾)形成的盐;和由金属硝酸盐(例如硝酸钠和硝酸钾)形成的盐。可以使用本领域熟知的方法制备药学上可接受的和非药学上可接受的盐,例如,通过将足够碱性的化合物(诸如胺)与包含生理学上可接受的阴离子的合适的酸反应。也可以制备羧酸的碱金属(例如钠、钾或锂)或碱土金属(例如钙)盐。
如在本文中所使用的术语“烷基”是支化或非支化的烃基,诸如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基、庚基、辛基、壬基、癸基、十二烷基等。烷基基团还可以是被取代的或未被取代的。除非另有说明,术语“烷基”包括被取代的或未被取代的烷基基团两者。烷基基团可以被一个或多个基团取代,其包括但不限于烷氧基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、醛、氨基、羧酸、酯、醚、卤化物、羟基、酮、硝基、甲硅烷基、磺基-氧代或硫醇。不含有碳-碳双键或碳-碳三键的烷基基团被称为饱和的烷基基团,而含有一个或多个这类键的烷基基团被称为不饱和的烷基基团。可以将具有双键的不饱和烷基基团称为烯基基团,可以将具有三键的不饱和烷基称为炔基基团。除非另有相反的说明,术语烷基包括饱和基团和不饱和基团两者。
如在本文中所使用的术语“环烷基”是由至少三个碳原子组成的不基于芳香族碳的环。环烷基基团的实例包括但不限于环丙基、环丁基、环戊基、环己基等。术语“杂环烷基”是如上定义的环烷基基团,其中环的至少一个碳原子被杂原子(诸如,但不限于氮、氧、硫、硒或磷)取代。环烷基基团和杂环烷基基团可以是被取代的或未被取代的。除非另有说明,否则术语“环烷基”和“杂环烷基”包括被取代的和未被取代的环烷基基团和杂环烷基基团两者。环烷基基团和杂环烷基基团可以被一个或多个基团取代,其包括但不限于烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、醛、氨基、羧酸、酯、醚、卤化物、羟基、酮、硝基、甲硅烷基、磺基-氧代或硫醇。不含有碳-碳双键或碳-碳三键的环烷基基团被称为饱和的环烷基基团,而含有一个或多个这类键(但仍不是芳香族的)的环烷基基团被称为不饱和的环烷基基团。除非另有相反的说明,术语环烷基包括饱和非芳香族环系和不饱和非芳香族环系两者。
除非另有相反的说明,化学键仅以实线表示而不以楔形或虚线表示的式考虑了每种可能的异构体,例如每种对映体、非对映体和内消旋化合物,以及异构体的混合物,诸如外消旋或部分消旋混合物。一种用楔形和虚线描绘键的化合物,既考虑了具体描绘的立体异构体,也考虑了外消旋混合物。术语“对映体富集”意指所描绘的对映体以大于未描绘的对映体的量存在。
如在本文中所使用的术语“芳基”是由碳原子组成的芳香环。芳基基团的实例包括但不限于苯基和萘基等。术语“杂芳基”是如上定义的芳基基团,其中环的至少一个碳原子被杂原子(诸如但不限于氮、氧、硫、硒或磷)取代。芳基基团和杂芳基基团可以是被取代的或未被取代的。除非另有说明,否则术语“芳基”和“杂芳基”包括被取代的和未被取代的芳基基团和杂芳基基团两者。芳基基团和杂芳基基团可以被一个或多个基团取代,其包括但不限于烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、醛、氨基、羧酸、酯、醚、卤化物、羟基、酮、硝基、甲硅烷基、磺基-氧代或硫醇。
示例性的杂芳基环和杂环基环包括:苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH咔唑基、咔啉基、苯并二氢吡喃基、苯并吡喃基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3b]四氢呋喃、呋喃基、呋咕基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、吲哚啉基、吲哚嗪基、吲哚基、3H-吲哚基、靛红酰基、异苯并呋喃基、异苯并二氢吡喃基、异吲唑基、异吲哚啉基、异吲哚基、异喹啉基、异噻唑基、异噁唑基、亚甲二氧基苯基、吗啉基、萘啶基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、氧代吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并噁唑、吡啶并咪唑、吡啶并噻唑、吡啶基(pyridinyl)、吡啶基(pyridyl)、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、喹宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、苯硫基和呫吨基。
术语“烷氧基”“环烷氧基”“杂环烷氧基”“芳氧基”和“杂芳氧基”具有上述烷基、环烷基、杂环烷基、芳基和杂芳基的含义,进一步提供所述基团是通过氧原子连接的。
如在本文中所使用的术语“被取代的”预期包括有机化合物的所有可允许的取代基。从广义方面,可允许的取代基包括有机化合物的无环和环状的、支化和非支化的、碳环和杂环的及芳香族和非芳香族的取代基。示例性取代基包括例如下面描述的那些。对于合适的有机化合物,可允许的取代基可以是一个或多个并且是相同或不同的。出于本公开的目的,杂原子(诸如氮)可以具有氢取代基和/或本文所述的满足杂原子价态的有机化合物的任何可允许的取代基。本公开并不旨在以任何方式受限于有机化合物的可允许的取代基。此外,术语“取代”或“被取代”包括隐含的条件,即这种取代与被取代的原子和取代基的可允许的价态相符,并且所述取代产生稳定的化合物,例如不会诸如通过重排、环化、消除等自发进行转化的化合物。除非特别说明,否则被称为“被取代的”取代基意指取代基被以下中的一种或多种取代:烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、醛、氨基、羧酸、酯、醚、卤化物、羟基、酮、硝基、甲硅烷基、磺基-氧代或硫醇。
除非另有相反的说明,术语“羧酸”和“羧酸酯”可以互换使用。本领域技术人员理解,官能基团在两种形式之间互换取决于其局部环境的pH值。
如本文所使用的,“透明质酸”包括中性和阴离子(即盐)形式的透明质酸。
如本文所使用的,术语“胰岛素”包括所有治疗上可接受的制剂形式,包括常规胰岛素、德谷胰岛素、赖脯胰岛素、门冬胰岛素、赖谷胰岛素、地特胰岛素、甘精胰岛素、NPH胰岛素、动物胰岛素。也可以使用不同胰岛素形式的组合。
如本文所使用的,并且除非另有说明,否则“脂质”应理解为脂肪酸、脂肪酸盐、脂肪醇或磷脂。脂质包括鞘脂,包括但不限于神经鞘髓磷脂;糖鞘脂,包括但不限于神经节苷脂、红细胞糖苷酯和脑苷脂;和表面活性剂胺,包括但不限于硬脂酰胺、油胺和亚油酰胺。
如本文所使用的,并且除非另有说明,否则“磷脂”应理解为甘油的两性衍生物,其中其一个羟基被磷酸酯化,另两个羟基被长链脂肪酸酯化,所述长链脂肪酸可以是彼此相等的或彼此不同的,并且可以是饱和的或不饱和的。中性磷脂通常是其中其他磷酸羟基被由极性基团(通常为羟基或氨基)取代的醇所酯化并且其净电荷为零的磷脂。带电荷的磷脂通常是其中其他磷酸羟基被由极性基团取代的醇所酯化并且其净电荷为正或负的磷脂。
本发明公开了可用于执行所公开的方法和系统的成分。本文公开了这些和其他成分,并且应当理解,当公开这些成分的组合、子集、相互作用、分组等时,虽然可能未明确公开对这些中每种不同的单个和集体组合排列的特定提及,但对于所有方法和系统,每一种在本文中都有特别考虑和描述。这适用于本申请的所有方面,包括但不限于所公开方法中的步骤。因此,如果存在可以执行的各种附加步骤,则应当理解,这些附加步骤中的每个可用本发明所公开的方法的任何特定实施例或实施例的组合来执行。
本发明公开了用于口服药物递送的葡萄糖响应性组合物。所述药物递送系统包括被聚合物壳包封的核。所述治疗剂包含在所述核内或所述核上,由所述聚合物壳保护其免受胃的酸性条件的影响。一旦进入小肠,在那里暴露于较高浓度的葡萄糖和不同的pH水平,所述聚合物壳从核分离,释放出治疗剂以供吸收。可以通过硼酸酯用所述聚合物包封所述核。在一些实施例中,通过在聚合物和存在于所述核中的二醇部分之间形成的氨基硼酸酯用聚合物包封所述核。
当所述聚合物壳遇到葡萄糖含量足够高的环境时,被包封的核被释放。例如,所述壳可以保持完整,直到所述葡萄糖浓度至少为0.1mM、至少0.25mM、至少0.5mM、至少0.75mM、至少1mM、至少2.5mM或至少5mM。
所述药物递送系统可包括氨基硼酸酯,其部分式为:
其中R1、R2、R3和R4独立地选自氢、C1-8烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、C3-8环烷基和C1-8杂芳基,其可以是被取代的或未被取代的,并且其中R1、R2、R3和R4中的任何两个或多个可以一起形成环。在一些实施例中,如上文所定义,R1和R3中的每一个为氢,R2和R4中的每一个为非氢基团。例如,R2和R4可以一起形成苯环,并且R1和R3是氢。在另一个实施例中,R1、R2、R3和R4中的每一个为甲基。在又一个实施例中,R1、R2、R3和R4中的每一个为氢。在一些实施例中,R2、R3和R4中的每一个为氢,并且R1为C1-8烷基。在其他实施例中,R3和R4分别为氢,并且R1和R2分别为独立的C1-8烷基并可以一起形成环。在其他情况下,R1和R2分别为氢,R3和R4分别为独立的C1-8烷基并可以一起形成环。
一般来说,任何生物相容性聚合物都可以用于所述壳。优选地,所述生物相容性聚合物包括用于连接所述硼酸酯的羧酸部分,然而,也可以使用其他连接方式。示例性聚合物包括透明质酸、聚(γ-谷氨酸)、聚(α-谷氨酸)、聚(天冬氨酸)、硫酸软骨素、羧甲基纤维素及其组合。用于该组合物的聚合物的分子量可以为100,000-10,000,000、100,000-1,000,000、100,000-750,000、250,000-750,000或200,000-500,000。
透明质酸是所述壳的优选的聚合物。用于该组合物的透明质酸聚合物的分子量可以为100,000-10,000,000、100,000-1,000,000、100,000-750,000、250,000-750,000或200,000-500,000。透明质酸是由重复的D-葡萄糖酸和N-乙酰-D-葡萄糖胺二糖单元组成的糖胺聚糖:
透明质酸中的羧酸基作为所述硼酸酯的连接点。掺入后,所述透明质酸将包括具有以下式的亚基:
其中R1、R2、R3和R4具有上述含义。本领域技术人员将理解,其他含羧酸聚合物可以类似方式连接到所述硼酸酯。所述聚合物/硼酸酯可通过经修饰以含有所述硼酸酯的羧酸酯部分的百分比来表征。在一些实施例中,至少2%、至少4%、至少6%、至少8%、至少10%、至少12%、至少14%、至少16%、至少18%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%或至少50%的所述羧酸酯基被修饰以包含所述硼酸酯。在一些实施例中,至少2%、至少4%、至少6%、至少8%、至少10%、至少12%、至少14%、至少16%、至少18%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%或至少50%的所述透明质酸的亚基将如上所描绘被修饰。在其他实施例中,2-50%、2-25%、2-20%、4-20%、6-20%、8-20%、10-20%、12-20%、14-20%、10-18%、10-16%或12-16%的所述羧酸酯基被修饰以包含所述硼酸酯。在一些实施例中,10-50%、15-50%、20-50%、25-50%、30-50%、40-50%、10-30%、15-30%、20-30%、25-30%的所述羧酸酯基被修饰以包含所述硼酸酯。在进一步的实施例中,50-100%、50-90%、50-80%、50-70%、50-60%、60-100%、70-100%、80-100%或90-100%的所述羧酸酯基被修饰以包含所述硼酸酯。在一些优选的实施例中,10-20%或12-16%的所述羧酸酯基被修饰以包含所述硼酸酯。
所述硼酸酯可使用常规酰胺形成技术由氨基硼酸制备。所述硼酸具有通式:
其中R1、R2、R3和R4具有上述含义。在一些情况下,所述聚合物中的羧酸基团通过1-乙基-3-(3-二甲氨基丙基)碳化二亚胺(EDC)和N-羟基琥珀酰亚胺(NHS)在水中的结合而被激活,然后所述硼酸可以被添加到所述系统中。所述反应完成后,所述溶剂可通过蒸发或冻干去除。
在某些实施例中,所述核包含脂质体,其中可负载一种或多种治疗剂。可使用所述组合物给药的合适的治疗剂包括小分子药物和治疗蛋白质,其包括疫苗和单克隆抗体。
治疗蛋白的示例性类别包括基于抗体的药物、Fc融合蛋白、抗凝剂、血液因子、骨形态发生蛋白、工程蛋白支架、酶、生长因子、激素、干扰素、白介素和溶栓剂。示例性治疗蛋白包括胰岛素、普兰林肽、生长激素、促生长素、美卡舍明、因子Ⅷ、因子Ⅸ、抗凝血酶Ⅲ、蛋白质C浓缩物、葡萄糖脑苷脂酶、阿葡糖苷酶、拉罗尼酶、艾杜硫酶、加硫酶、阿加糖酶、α-1蛋白酶抑制剂、乳糖酶、胰腺酶、腺苷脱氨酶、汇集免疫球蛋白、人类白蛋白、红血球生成素、达贝泊汀、非格司亭、乙二醇化非格司亭、沙格司亭、奥普瑞白介素、FSH、HCG、促黄体素、干扰素、阿地白介素、阿替普酶、瑞替普酶、替奈普酶、尿激酶、因子Ⅶa、屈曲可净、鲑降血钙素、特立帕肽、艾塞那肽、奥曲肽、地博特明、人骨蛋白、组氨瑞林、帕利夫明、贝卡普勒明、胰蛋白酶、奈西立肽、天冬酰氨酶、拉布立酶、来匹卢定、比伐卢定、链激酶和阿尼普酶。在特别优选的实施例中,所述治疗蛋白是胰岛素,诸如常规胰岛素、德谷胰岛素、赖脯胰岛素、门冬胰岛素、赖谷胰岛素、地特胰岛素、甘精胰岛素、NPH胰岛素、动物胰岛素及其组合。
本文公开的组合物可用于治疗各种葡萄糖相关病症。例如,所述组合物可用于治疗1型糖尿病、2型糖尿病、妊娠糖尿病以及其他急性和慢性高血糖病症。
示例性小分子药物包括抗癌剂。本文所公开的组合物可用于治疗多种不同的癌症,包括急性淋巴细胞白血病(ALL)、急性髓性白血病(AML)、肾上腺皮质癌、艾滋病相关癌、卡波西肉瘤、艾滋病相关淋巴瘤、原发性CNS淋巴瘤、肛门癌、阑尾癌、类癌瘤、星形细胞瘤、非典型畸胎/横纹肌样瘤、基底细胞癌、皮肤癌(非黑色素瘤)、胆道癌、肝外膀胱癌、膀胱癌、骨癌(包括尤因肉瘤和骨肉瘤及恶性纤维组织细胞瘤)、脑肿瘤、乳腺癌、支气管肿瘤、伯基特淋巴瘤(非霍奇金)、心脏肿瘤、胚胎肿瘤、生殖细胞肿瘤、淋巴瘤、原发性-宫颈癌、胆管癌、脊索瘤、慢性淋巴细胞白血病(CLL)、慢性髓性白血病(CML)、慢性骨髓增殖性疾病、结肠直肠癌、颅咽管瘤、皮肤T细胞淋巴瘤、原位导管癌(DCIS)、胚胎肿瘤、子宫内膜癌、室管膜瘤、食道癌、嗅神经母细胞瘤、尤文肉瘤、颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、眼癌、眼内黑色素瘤、视网膜母细胞瘤、卵管癌、骨纤维组织细胞瘤、恶性骨肉瘤、胆囊癌、胃癌、胃肠道类癌肿瘤、胃肠道间质瘤(GIST)、生殖细胞肿瘤、中枢神经系统、颅外、性腺外、卵巢-睾丸、妊娠滋养细胞疾病、胶质瘤、毛细胞白血病、头颈癌、心脏肿瘤、肝细胞癌、组织细胞增多症、朗格汉斯细胞、霍奇金淋巴瘤、下咽癌、胰岛细胞瘤、胰腺神经内分泌肿瘤、卡波西肉瘤、肾-朗格汉斯细胞组织细胞增多症、喉癌、喉癌和乳头状瘤病、白血病、唇癌和口腔癌、肝癌(原发性)、肺癌、淋巴瘤-巨球蛋白血症、-非霍奇金淋巴瘤、男性乳腺癌、骨和骨肉瘤的恶性纤维组织细胞瘤、黑色素瘤、眼内(眼)、Merkel细胞癌、间皮瘤、恶性间皮瘤、转移性鳞状颈癌伴隐匿性原发性、涉及NUT基因的中线癌、口腔癌、多发性内分泌肿瘤综合征、多发性骨髓瘤/浆细胞肿瘤、蕈样真菌病、骨髓增生异常综合征、骨髓增生异常/骨髓增殖性肿瘤和慢性骨髓增生性肿瘤、鼻腔和鼻窦癌、鼻咽癌、神经母细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌、口腔癌、唇和口腔癌及口咽癌、骨肉瘤和骨的恶性纤维组织细胞瘤、卵巢癌、胰腺癌和胰腺神经内分泌肿瘤(胰岛细胞瘤)、乳头状瘤病、副神经节瘤、副鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、咽癌、嗜铬细胞瘤、垂体瘤、浆细胞瘤/多发性骨髓瘤、胸膜肺母细胞瘤、妊娠和乳腺癌、原发性中枢神经系统(CNS)淋巴瘤、原发性腹膜癌、前列腺癌、直肠癌、肾细胞(肾)癌、视网膜母细胞瘤、横纹肌肉瘤、涎腺癌、涎腺肿瘤、骨肉瘤、子宫肉瘤、血管瘤、Sézary综合征、皮肤癌、小细胞肺癌、小肠癌、软组织肉瘤、鳞状细胞癌、原发性鳞癌、转移性鳞癌、胃癌、T细胞淋巴瘤、皮肤癌、睾丸癌、喉癌、胸腺瘤和胸腺癌、甲状腺癌、输尿管和肾盂癌、移行细胞癌、尿道癌、子宫癌、子宫内膜和子宫肉瘤、阴道癌、外阴癌、巨球蛋白血症或Wilms肿瘤。
可使用脂质体给药的示例性抗癌剂包括阿比特龙、甲氨喋呤、Abraxane(紫杉醇白蛋白稳定的纳米微粒制剂)、贝伦妥单抗-维多汀、Ado-曲妥珠单抗、艾美坦辛、阿霉素、阿法替尼、依维莫司、Akynzeo(奈妥吡坦和盐酸帕洛诺司琼)、咪喹莫特、Aldesleukin(阿地白介素)、艾乐替尼、阿伦单抗、美法仑、培美曲塞、帕洛诺司琼、苯丁酸氮芥、氨基乙酰丙酸、阿那曲唑、阿瑞匹坦、帕米磷酸、依西美坦、奈拉滨、三氧化二砷、奥法木单抗、菊欧文氏菌天冬酰胺酶、阿特珠单抗、贝伐单抗、阿西替尼、阿扎胞苷、BEACOPP、卡莫司汀、贝利司他、苯达莫司汀、BEP、蓓萨罗丁、托西莫单抗、比卡鲁胺、博来霉素、博纳吐单抗、硼替佐米、博舒替尼、白消安、卡巴他赛、卡博替尼-阿伦单抗、伊立替康、卡培他滨、CAPOX、氟尿嘧啶、卡铂(Carboplatin)、卡铂-紫杉酚、卡非佐米、洛莫司汀、CEM、柔红霉素、Cervarix(重组HPV双价疫苗)、西妥昔单抗、瘤可宁、CHOP、顺铂、氯法拉滨、CMF、考比替尼、卡博替尼、COPDAC、COPP、COPP-ABV、更生霉素、克唑替尼、CVP、异环磷酰胺、雷莫芦单抗、阿糖胞苷、环磷酰胺、达拉菲尼、达卡巴嗪、地西他滨、达雷木单抗、达沙替尼、道诺霉素、去纤核苷酸钠、去纤苷、地加瑞克、地尼白介素-白喉毒素连接物、地诺单抗、DepoCyt(阿糖胞苷脂质体)、地塞米松、右雷佐生、地妥昔单抗、多西他赛、多柔比星、表柔比星、埃罗妥珠单抗、奥沙利铂、艾曲波帕乙醇胺、Empliciti(埃罗妥珠单抗)、恩杂鲁胺、EPOCH、艾日布林、维莫德吉、埃罗替尼、Erwinaze(菊欧文氏菌天冬酰胺酶)、凡毕复(磷酸依托泊苷)、依托泊苷、磷酸依托泊苷、易维特(盐酸雷洛昔芬)、优维宁(盐酸美法仑)、5-FU、法乐通(托瑞米芬)、Farydak(帕比司他)、Faslodex(氟维司群)、FEC、来曲唑、非格司亭、氟达拉滨、氟他米特、甲氨蝶呤、Folfiri、Folfiri-贝伐单抗、Folfiri-西妥昔单抗、Folfirinox、Folfox、普拉曲沙、FU-LV、氟维司群、加卫苗(重组HPV四价疫苗)、阿妥珠单抗、吉非替尼、吉西他滨、吉妥珠单抗-奥佐米星、伊马替尼、羧肽酶、乙酸戈舍瑞林、艾日布林、曲妥珠单抗、拓扑替康、羟基脲帕博西尼、替伊莫单抗-Tiuxetan、依鲁替尼、ICE、帕纳替尼、善唯达、艾代拉利司、Ifex(异环磷酰胺)、异环磷酰胺、IL-2(阿地白介素)、伊马替尼、依鲁替尼、Imlygic、Talimogene Laherparepvec、干扰素α-2b、重组白介素-2(阿地白介素)、Intron A(重组干扰素α-2b)、伊匹单抗、吉非替尼、罗米地辛、伊沙匹隆、伊沙佐米、卢索替尼、雷洛昔芬、帕利夫明、派姆单抗、兰瑞肽、拉帕替尼、来那度胺、乐伐替尼、来曲唑、亚叶酸、亮丙瑞林、奥拉帕尼、长春新碱、甲基苄肼、氮芥、甲地孕酮、曲美替尼、巯嘌呤、美司钠、替莫唑胺、甲氨蝶呤、丝裂霉素C、米托蒽醌、MOPP、普乐沙福、氮芥、吉妥珠单抗-奥佐米星、长春瑞滨、耐昔妥单抗、Neosar(环磷酰胺)、奈妥吡坦和盐酸帕洛诺司琼、优保津(非格司亭)、多吉美(甲苯磺酸索拉非尼)、尼罗替尼、Ninlaro(柠檬酸伊沙佐米)、纳武单抗、Nolvadex(柠檬酸泰莫西芬)、Nplate(罗米司亭)、阿妥珠单抗、Odomzo(索尼吉布)、OEPA、奥拉帕尼、高三尖杉酯碱、Oncaspar(培门冬酶)、盐酸昂丹司琼、Onivyde(盐酸伊立替康脂质体)、Ontak(地尼白介素-白喉毒素连接物)、Opdivo(纳武单抗)、OPPA、奥斯替尼、奥沙利铂、紫杉醇、紫杉醇白蛋白稳定的纳米颗粒制剂、帕博西尼、帕利夫明、盐酸帕洛诺司琼、盐酸帕洛诺司琼和奈妥吡坦、帕米磷酸二钠、帕尼单抗、帕比司他、Paraplat(卡铂)、Paraplatin(伯尔定)、盐酸帕唑帕尼、培门冬酶、聚乙二醇干扰素α-2b、PEG-内含子(聚乙二醇干扰素α-2b)、派姆单抗、培美曲塞二钠、Perjeta(帕妥珠单抗)、帕妥珠单抗、Platinol(顺铂)、Platinol-AQ(顺铂)、普乐沙福、泊马度胺、Pomalyst(泊马度胺)、盐酸帕纳替尼、Portrazza(耐昔妥单抗)、普拉曲沙、强的松、盐酸甲基苄肼、Proleukin(阿地白介素)、Prolia(地诺单抗)、Promacta(艾曲波帕乙醇胺)、普列威(Sipuleucel-T)、Purinethol(巯基嘌呤)、Purixan(巯嘌呤)、镭223二氯化物、盐酸雷洛昔芬、拉布立酶、R-CHOP、R-CVP、重组人乳头瘤病毒(HPV)二价疫苗、重组人乳头瘤病毒(HPV)九价疫苗、重组人乳头瘤病毒(HPV)四价疫苗、重组干扰素α-2b、瑞戈非尼、R-EPOCH、Revlimid(来那度胺)、Rheumatrex(甲氨蝶呤)、利妥昔单抗、盐酸罗拉吡坦、罗米地辛、罗米司亭、红比霉素(盐酸道诺霉素)、磷酸卢索替尼、司兰索胸膜内气溶胶(Talc)、司妥昔单抗、Sipuleucel-T、索马杜林储库型(乙酸兰瑞肽)、索尼吉布、甲苯磺酸索拉非尼、施达赛(达沙替尼)、STANFORD V、无菌滑石粉(Talc)、Steritalc(Talc)、Stivarga(瑞戈非尼)、苹果酸舒尼替尼、索坦(苹果酸舒尼替尼)、Sylatron(聚乙二醇干扰素α-2b)、Sylvant(司妥昔单抗)、Synovir(萨力多胺)、Synribo(高三尖杉酯碱)、Tabloid(硫鸟嘌呤)、TAC、Tafinlar(达拉菲尼)、Tagrisso(奥斯替尼)、Talimogene Laherparepvec、柠檬酸泰莫西芬、Tarabine PFS(阿糖胞苷)、Tarceva(盐酸埃罗替尼)、Targretin(蓓萨罗丁)、泰息安(尼罗替尼)、Taxol(紫杉醇)、泰索帝(多西他赛)、Tecentriq(阿特珠单抗)、Temodar(替莫唑胺)、替莫唑胺、坦罗莫司、萨力多胺、Thalomid(萨力多胺)、硫鸟嘌呤、塞替派、Tolak(氟尿嘧啶-局部用)、盐酸拓扑替康、托瑞米芬、Torisel(坦罗莫司)、托西莫单抗和碘I131托西莫单抗、Totect(盐酸右雷佐生)、曲贝替定、曲美替尼、Treanda(盐酸苯达莫司汀)、三氟尿苷和盐酸替比嘧啶、Trisenox(三氧化砷)、泰立沙(二甲苯磺酸拉帕替尼)、Unituxin(地妥昔单抗)、三乙酸尿苷、凡得他尼、VAMP、Varubi(盐酸罗拉吡坦)、Vectibix(帕尼单抗)、Velban(硫酸长春花碱)、万珂(硼替佐米)、Velsar(硫酸长春花碱)、维罗非尼、Venclexta(维特克拉)、维特克拉、Viadur(乙酸亮丙瑞林)、Vidaza(阿扎胞苷)、硫酸长春花碱、Vincasar PFS(硫酸长春新碱)、硫酸长春新碱、硫酸长春新碱脂质体、酒石酸长春瑞滨、维莫德吉、Vistogard(三乙酸尿苷)、Voraxaze(羧肽酶)、伏立诺他、福退癌(盐酸帕唑帕尼)、Wellcovorin(亚叶酸钙)、Xalkori(克唑替尼)、希罗达(卡培他滨)、XELIRI、XELOX、Xgeva(地诺单抗)、Xofigo(镭223二氯化物)、Xtandi(恩杂鲁胺)、Yervoy(伊匹单抗)、Yondelis(曲贝替定)、Zaltrap(Ziv-阿柏西普)、Zarxio(非格司亭)、Zelboraf(维罗非尼)、泽娃灵(替伊莫单抗-Tiuxetan)、Zinecard(盐酸右雷佐生)、Ziv-阿柏西普、枢复宁(盐酸昂丹司琼)、诺雷得(乙酸戈舍瑞林)、唑来膦酸、Zolinza(伏立诺他)、择泰(唑来膦酸)、Zydelig(艾代拉利司)、Zykadia(色瑞替尼)和Zytiga(醋酸阿比特龙)及其组合。
所述脂质体可包含常规脂质(例如,所述主脂质)和经修饰以锚定所述聚合物硼酸酯壳的脂质的混合物。脂质体的传统脂质是众所周知的,并且包括磷脂酸(“PA”)、磷脂酰胆碱(“PC”)、磷脂酰甘油(“PG”)、磷脂酰乙醇胺、磷脂酰肌醇(“PI”)、磷脂酰丝氨酸(“PS”)、鞘磷脂(包括脑鞘磷脂)、卵磷脂、溶血卵磷脂、溶血磷脂酰乙醇胺、脑苷脂、二花生酰基磷脂酰胆碱(“DAPC”)、二癸酰基-L-α-磷脂酰胆碱(“DDPC”)、二芥酰基磷脂酰胆碱(“DEPC”)、二月桂酰基磷脂酰胆碱(“DLPC”)、二亚油酰基磷脂酰胆碱、二肉豆蔻酰基磷脂酰胆碱(“DMPC”)、二油酰基磷脂酰胆碱(“DOPC”)、二棕榈酰基磷脂酰胆碱(“DPPC”)、二硬脂酰基磷脂酰胆碱(“DSPC”)、1-棕榈酰基-2-油酰基磷脂酰胆碱(“POPC”)、二花生酰基磷脂酰甘油(“DAPG”)、二癸酰基-L-α-磷脂酰甘油(“DDPG”)、二芥酰基磷脂酰甘油(“DEPG”)、二月桂酰基磷脂酰甘油(“DLPG”)、二亚油酰基磷脂酰甘油、二肉豆蔻酰基磷脂酰甘油(“DMPG”)、二油酰基磷脂酰甘油(“DOPG”)、二棕榈酰基磷脂酰甘油(“DPPG”)、二硬脂酰基磷脂酰甘油(“DSPG”)、1-棕榈酰基-2-油酰基磷脂酰甘油(“POPG”)、二花生酰基磷脂酰乙醇胺(“DAPE”)、二癸酰基-L-α-磷脂酰乙醇胺(“DDPE”)、二芥酰基磷脂酰乙醇胺(“DEPE”)、二月桂酰基磷脂酰乙醇胺(“DLPE”)、二亚油酰基磷脂酰乙醇胺、二肉豆蔻酰基磷脂酰乙醇胺(“DMPE”)、二油酰基磷脂酰乙醇胺(“DOPE”)、二棕榈酰基磷脂酰乙醇胺(“DPPE”)、二硬脂酰基磷脂酰乙醇胺(“DSPE”)、1-棕榈酰基-2-油酰基磷脂酰乙醇胺(“POPE”)、二花生酰基磷脂酰肌醇(“DAPI”)、二癸酰基-L-α-磷脂酰肌醇(“DDPI”)、二芥酰基磷脂酰肌醇(“DEPI”)、二月桂酰基磷脂酰肌醇(“DLPI”)、二亚油酰基磷脂酰肌醇、二肉豆蔻酰基磷脂酰肌醇(“DMPI”)、二油酰基磷脂酰肌醇(“DOPI”)、二棕榈酰基磷脂酰肌醇(“DPPI”)、二硬脂酰基磷脂酰肌醇(“DSPI”)、1-棕榈酰基-2-油酰基磷脂酰肌醇(“POPI”)、二花生酰基磷脂酰丝氨酸(“DAPS”)、二癸酰基-L-α-磷脂酰丝氨酸(“DDPS”)、二芥酰基磷脂酰丝氨酸(“DEPS”)、二月桂酰基磷脂酰丝氨酸(“DLPS”)、二亚油酰基磷脂酰丝氨酸、二肉豆蔻酰基磷脂酰丝氨酸(“DMPS”)、二油酰基磷脂酰丝氨酸(“DOPS”)、二棕榈酰基磷脂酰丝氨酸(“DPPS”)、二硬脂酰基磷脂酰丝氨酸(“DSPS”)、1-棕榈酰基-2-油酰基磷脂酰丝氨酸(“POPS”)、二花生酰基鞘磷脂、二癸酰基鞘磷脂、二芥酰基鞘磷脂、二月桂酰基鞘磷脂、二亚油酰基鞘磷脂、二肉豆蔻酰基鞘磷脂、鞘磷脂、二油酰基鞘磷脂、二棕榈酰基鞘磷脂、二硬脂酰基鞘磷脂、1-棕榈酰基-2-油酰基鞘磷脂及其混合物。
在一些情况下,所述主脂质可以包括不同脂质化合物的混合物。在一些情况下,所述主脂质可包括胆碱脂质成分(即,一种或多种包括胆碱残基的脂质化合物)和乙醇胺脂质成分(即,一种或多种包括乙醇胺基的脂质化合物,其可在胺位置官能化)。(a)胆碱脂质成分和(b)乙醇胺脂质成分的重量比可以是99:1至1:99、25:1至1:25、10:1至1:10、5:1至1:5、2:1至1:2、1:1至1:100、1:1至1:50、1:1至1:25、1:1至1:10、1:1至1:5、1:1至1:2、100:1至1:1、50:1至1:1、25:1至1:1、10:1至1:1、5:1至1:1或2:1至1:1。
所述脂质体还可以包括胆固醇和/或胆固醇衍生物(即在羟基位置已官能化的胆固醇)。在其他实施例中,所述脂质体中不存在胆固醇和/或胆固醇衍生物。示例性胆固醇衍生物包括聚乙二醇化胆固醇、中性酯、阳离子酯和阴离子酯。阳离子酯可通过与含有胺的羧酸(例如赖氨酸、精氨酸、3-二甲氨基丙酸或3-氨基丙酸)酯化而获得。阴离子酯可通过与含羧酸的磺酸或羧酸(例如谷氨酸、天冬氨酸、琥珀酸或柠檬酸)酯化而获得。当存在时,所述胆固醇和/或胆固醇衍生物可以由0.1-20重量%、0.5-20重量%、0.5-15重量%、0.5-10重量%、1-10重量%、2-10重量%、2.5-10重量%、2.5-7.5重量%和2.5-5重量%的脂质体构成。在优选的实施例中,相对于所述脂质体的总重量,所述胆固醇和/或胆固醇衍生物以2-6重量%的量存在。如本文参考胆固醇和其他脂质体成分所使用的,所述脂质体的总重量是指被所述聚合物包封之前的重量。除非另有相反的说明,所述脂质体中成分的重量比等于用于制备所述脂质体的混合物中成分的重量比。
被修饰以锚定所述聚合物硼酸酯壳的脂质包括具有双羟基(二醇)官能基团(诸如1,2二醇和1,3二醇)的脂质。这种被修饰的脂质可以被称为“聚合物锚定物”。术语聚合物锚定物可以指自由二醇或硼酸酯缀合物。聚合物锚定物通常由以下式表示:
脂质-接头-二醇。
在一些实施例中,所述聚合物锚定物可具有以下任一式:
其中Ra和Rb独立地选自C6-32烷基-C(O)-,n为5-1000的整数,并且X和X1为具有二醇的基团。在某些实施例中,n为3-1,000、5-1,000、8-1,000、10-1,000、15-1,000、20-1,000、25-1,000、30-1,000、35-1,000、40-1,000、45-1,000、50-1,000、60-1,000、70-1,000、80-1,000、90-1,000、100-1,000、125-1,000、150-1,000、175-1,000、200-1,000、300-1,000、400-1,000或500-1,000。在某些实施例中,Ra和Rb独立地选自C6-18烷基-C(O)-或C6-32烯基-C(O)。上述任何乙醇胺脂质化合物可以用于获得锚定物脂质。
优选的X和X1基团包括具有以下式的邻苯二酚:
其中n为0-10的整数,优选1-6、更优选1-4、甚至更优选1-2的整数,m为0-3的整数,并且Rc独立地选自Rc1、ORc1、N(Rc1)2、SiRc1 3、SRc1、SO2Rc1、SO2N(Rc1)2、C(O)Rc1;C(O)ORc1、OCORc1;C(O)N(Rc1)2、OC(O)N(Rc1)2、N(Rc1)C(O)N(Rc1)2、F、Cl、Br、I、氰基和硝基,其中Rc1在每种情况下独立地选自氢、C1-8烷基、C2-8烯基、C2-8炔基、芳基、C1-8杂芳基、C3-8环烷基或C1-8杂环基;并且其中任何两个或多个Rc基团可以一起形成环。
在某些实施例中,所述聚合物锚定物/硼酸酯复合体可以由以下式表示:
其中Ra和Rb独立选自C6-32烷基-C(O)-,n为3-1,000、5-1,000、8-1,000、10-1,000、15-1,000、20-1,000、25-1,000、30-1,000、35-1,000、40-1,000、45-1,000、50-1,000、60-1,000、70-1,000、80-1,000、90-1,000、100-1,000、125-1,000、150-1,000、175-1,000、200-1,000、300-1,000、400-1,000或500-1,000;并且Z和Z1为:
其中R1、R2、R3和R4独立地选自氢、C1-8烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、C3-8环烷基和C1-8杂芳基,其可以是被取代的或未被取代的,并且其中R1、R2、R3和R4中的任何两个或多个可以一起形成环;
n为0-10的整数,m为0-3的整数,并且Rc独立地选自Rc1、ORc1、N(Rc1)2、SiRc1 3、SRc1、SO2Rc1、SO2N(Rc1)2、C(O)Rc1;C(O)ORc1、OCORc1;C(O)N(Rc1)2、OC(O)N(Rc1)2、N(Rc1)C(O)N(Rc1)2、F、Cl、Br、I、氰基和硝基,其中Rc1在每种情况下独立地选自氢、C1-8烷基、C2-8烯基、C2-8炔基、芳基、C1-8杂芳基、C3-8环烷基或C1-8杂环基;并且其中任何两个或多个Rc基团可以一起形成环。
在一些实施例中,所述聚合物锚定物可由以下式表示:
或其药学上可接受的盐(例如钠),其中R1和R2选自酰基,n选自2-10,m选自0-10,o选自0-10,Z为PEG,并且X是含有1,2二醇或1,3二醇的部分。在某些实施例中,Z包括含有邻苯二酚的基团。合适的酰基包括C6-24酰基、C6-18酰基、C6-14酰基;所述酰基可包含一个或多个烯键。在某些情况下,R1和R2可独立地选自油酰、硬脂酰、棕榈酰和肉豆蔻酰。具有至少3、5、8、10、15、20、25、30、35、40、45、50、60、70、80、90、100、125、150、175或200个单体单元的PEG链可用于接头部分,例如,所述聚合物锚定物可包括3-1,000、5-1,000、8-1,000、10-1,000、15-1,000、20-1,000、25-1,000、30-1,000、35-1,000、40-1,000、45-1,000、50-1,000、60-1,000、70-1,000、80-1,000、90-1,000、100-1,000、125-1,000、150-1,000、175-1,000、200-1,000、300-1,000、400-1,000或500-1,000个单体单元。在某些实施例中,所述聚合物锚定物可具有以下式:
或其药学上可接受的盐,其中R1、R2、n、m、o和Z具有上述含义。在一些情况下,R1和R2都可以是硬脂酰,n可以是2,Z可以是PEG,m可以是1,并且o可以是2。
相对于脂质体的总重量,所述聚合物锚定物在所述脂质体中的存在量为0.05-10重量%、0.1-10重量%、0.1-7.5重量%、0.1-5重量%、0.1-4重量%、0.1-3重量%、0.1-2重量%、0.1-1重量%、0.5-10重量%、0.5-7.5重量%、0.5-5重量%、0.5-4重量%、0.5-3重量%、0.5-2重量%或0.5-1重量%。在某些优选的实施例中,所述聚合物锚定物以相对于所述脂质体总重量的0.5-2重量%的量存在。
在某些实施例中,所述药物递送系统可进一步包括一个或多个靶向因子,以促进所述治疗剂的吸收。例如,所述组合物可包括人IgG Fc片段。其他合适的靶向因子包括转铁蛋白(Tf)和抗细胞间粘附分子-1(ICAM-1)。所述靶向因子可使用因子锚定物连接到所述脂质体的表面上,其通常由以下式表示:
脂质-接头-靶向因子
利用常规生物缀合化学方法,脂质可以通过靶向因子被修饰。例如,可以用与靶向因子反应形成共价键的官能团来修饰脂质。非限制性官能团包括琥珀酰亚胺酯、琥珀酰亚胺碳酸酯、琥珀酰亚胺氨基甲酸酯、五氟苯酯、噻唑烷-2-硫酮、酸酐、醛、迈克尔受体(诸如乙烯基砜)、马来酰亚胺、炔(与叠氮化物修饰的因子反应)或叠氮化物(与炔修饰的因子反应)。当存在时,相对于脂质体的总重量,所述因子锚定物在所述脂质体中的存在量为0.05-10重量%、0.1-10重量%、0.1-7.5重量%、0.1-5重量%、0.1-4重量%、0.1-3重量%、0.1-2重量%、0.1-1重量%、0.5-10重量%、0.5-7.5重量%、0.5-5重量%、0.5-4重量%、0.5-3重量%、0.5-2重量%或0.5-1重量%。在某些优选的实施例中,所述因子锚定物以相对于所述脂质体总重量的0.5-2重量%的量存在。所述靶向因子本身不包括在所述因子锚定物相对重量的计算中。
在一些实施例中,所述聚合物锚定物和因子锚定物各自包括亲水性部分,例如聚乙二醇。在一些实施例中,所述因子锚定物中的PEG部分比所述聚合物锚定物中的PEG部分短,以便所述靶向因子被所述聚合物很好地包封。例如,与聚合物锚定物中的环氧乙烷单元的数量相比,所述因子锚定物中的环氧乙烷单元的数量可以不超过其95%、不超过其90%、不超过其85%、不超过其80%、不超过其75%、不超过其70%、不超过其65%、不超过其60%、不超过其55%、不超过其50%、不超过其45%、不超过其40%、不超过其35%、不超过其30%、不超过其25%、不超过其20%、不超过其15%,不超过其10%或不超过其5%。
所述因子可通过所述靶向因子与具有下式的化合物的反应来配置:
或其药学上可接受的盐,其中R1’和R2’独立地选自酰基,n’选自2-10,m’选自0-10,o’选自0-10,Z’为PEG,并且Y是能够与所述靶向部分反应以形成共价键的部分。在一些实施例中,Y可以是琥珀酰亚胺酯、琥珀酰亚胺碳酸酯、琥珀酰亚胺氨基甲酸酯、五氟苯酯、噻唑烷-2-硫酮、酸酐、醛、迈克尔受体(诸如乙烯基砜)、马来酰亚胺、炔(与叠氮化物修饰的因子反应)或叠氮化物(与炔修饰的因子反应)。
合适的酰基包括C8-24酰基、C6-18酰基、C6-14酰基;所述酰基可包含一个或多个烯键。在某些情况下,R1’和R2’可独立地选自油酰、硬脂酰、棕榈酰和肉豆蔻酰。具有至少3、5、8、10、15、20、25、30、35、40、45、50、60、70、80、90、100、125、150、175或200个单体单元的PEG链可用于接头部分,例如,所述接头可包括5-200、10-150、20-150、20-100或25-75个单体单元。在某些实施例中,所述靶向因子可与具有以下式的化合物反应:
或其药学上可接受的盐,其中R1’、R2’、n’、m’、o’和Z’具有上述含义。例如,R1’和R2’都可以是硬脂酰,n’可以是2,Z’可以是PEG,m’可以是1,并且o’可以是2。在一些情况下,当与所述聚合物锚定物缀合时,所述靶向因子可处于其天然状态。在其他情况下,所述靶向因子的反应性可以增加,例如,通过使所述因子与诸如特劳特试剂之类的硫醇化剂反应。在其他情况下,可以使用像克莱兰试剂这样的还原剂。一般情况下,在脂质体形成后最好将所述因子和因子锚定物缀合,但在一些情况下,所述缀合可在脂质体形成之前发生。
脂质体可以通过常规方法形成。在优选的方法中,所述脂质溶解或分散在挥发性溶剂中,然后蒸发形成膜。含有所述治疗剂的水溶液可以被添加到膜上,然后进行机械分散,例如使用超声波。所述混合物可以通过一个或多个过滤器挤压以产生所述脂质体。如果尚未连接,则可使用常规马来酰亚胺硫醇化学法将靶向因子缀合到所述脂质体。所述脂质体可与所述聚合物硼酯复合体结合,在室温下搅拌得到所述聚合物包封的脂质体。
用于测定平均粒径和粒径分布的装置是可商购获得的。它们通常使用动态光散射和/或单粒子光学传感技术,例如可从Particle Sizing Systems(美国圣巴巴拉)获得的AccusizerTM和NicompTM系列仪器,或从Malvern instruments(英国)获得的ZetasizerTM仪器,或是从Horiba(日本京都)获得的粒径分布分析仪。动态光散射是测定包封的脂质体粒径的优选的方法。对于包封的脂质体的总体而言,在本发明的组合物中定义平均脂质体粒径的优选的方法是Z平均,即通过动态光散射(DLS)测量的脂质体总集合的强度加权平均流体动力学尺寸。所述Z平均来自对测量的相关曲线的累积量分析,其中假设单个粒径(脂质体粒径)并且对自相关函数应用单指数拟合。所述累积量分析算法不产生分布,但除了强度加权Z平均外,给出了多分散性指数。
本文公开的所述包封的脂质体可以制备成各种不同的粒径。如通过动态光散射方法所测量的,优选的尺寸包括1-10,000nm、1-5,000nm、1-2,500nm、1-1,000nm、1-750nm、1-500nm、1-250nm、5-250nm、25-250nm、50-250nm或75-150nm。在其他情况下,如通过动态光散射方法所测量的,所述包封的脂质体可具有的粒径为100-10,000nm、250-10,000nm、500-10,000nm、100-5,000nm、250-5,000nm、500-5,000nm、100-2,500nm、250-2,500nm、500-2,500nm、100-1,000nm、250-1,000nm或500-1,000nm。
一般情况下,所述靶向蛋白位于所述脂质体的表面,并被所述透明质酸壳包封。在一些实施例中,新生儿Fc受体(FcRn)靶向的脂质体核负载有胰岛素(图1A)。FcRn在小肠上皮细胞的顶端区域表达,它可以通过所述Fc部分结合IgG,从而促进蛋白质穿过肠上皮转运进入循环。这种特异性结合以pH依赖性的方式发挥作用,在十二指肠肠上皮细胞的顶端(pH5.5-6.5)表现出高亲和力,但在基底外侧(pH 7.4)不表现出高亲和力。
氨基硼酸缀合的HA壳通过在氨基硼酸和脂质体表面的二醇基之间形成硼酸酯来包被所述脂质体核,可防止所述治疗剂在胃肠道的渗漏和消化,另外还作为葡萄糖响应性部分用于按需吸收。在餐后消化过程中肠内葡萄糖浓度升高时,由于葡萄糖与氨基硼酸的竞争性结合(图1B),所述HA壳分离,暴露了促进治疗性负载的脂质体核的肠吸收的靶向因子组,最终在血流中释放制剂。
葡萄糖响应性的负载有胰岛素的脂质体的制备与表征。
首先采用脂质膜水化法制备所述负载有胰岛素的脂质体(Ins脂质体)。为了制备表面带有邻苯二酚(CA)基团的脂质体,首先将多巴胺与DSPE-PEG-CM(1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺-N-[羧基(聚乙二醇)])的羧基缀合,以利用碳化二亚胺化学法制备DSPE-PEG-CA。通过UV-Vis光谱验证了缀合的成功(图5)。所获得的Ins-脂质体的平均直径约为69nm,并且zeta电位为-2.6mV(图2A)。Ins-脂质体的胰岛素的包封率(EE)和负载容量(LC)分别为20.7%和17.1%。利用马来酰亚胺硫醇化学法将多克隆IgG Fc片段与Ins-脂质体表面的PEG链共价缀合。用2-亚氨基硫烷对Fc进行硫醇基修饰。缀合后,Fc-脂质体的水动力直径增加到77nm,表面电荷变化较小,为-6.6mV。通过PBA和邻苯二酚基团的结合,将所述HA壳进一步包被在所述Fc-脂质体上。由此得到的具有HA壳的脂质体(HA-Fc-脂质体)的尺寸增大了约94nm(图2C)。所述HA-Fc-脂质体的zeta电位从-6.6mV显著变化到-28.1mV,证实了HA壳的成功形成。透射电镜(TEM)图像清楚地显示了HA-Fc-脂质体的核-壳结构(图2B)。空白HA-Fc-脂质体对人肠上皮性大肠腺癌(Caco-2)细胞无明显的细胞毒性(图6)。
所述HA壳不仅可以作为葡萄糖响应性部分,而且可以防止胰岛素在上消化道的渗漏和消化。在37℃、pH 7.4下,观察到胰岛素从Fc-脂质体中快速释放。如图2D所示,约50%的胰岛素在2小时内释放。但是,在相同条件下,HA-Fc-脂质体中的胰岛素渗漏可忽略不计,这可归因于HA包被。重要的是,在pH 2.5的条件下,所述HA-Fc-脂质体中的胰岛素水平几乎完全保持不变,表明这种胰岛素载体在胃的酸性条件下具有很高的稳定性。
实例
以下实例仅用于说明本发明,并不旨在以任何方式限制本发明的范围。本领域技术人员将能够通过修改以下公开的工艺制备本文所述的其他组合物。
HA壳的葡萄糖响应性分离。
基于邻苯二酚和PBA的络合作用,通过形成硼酸酯,将PBA修饰的HA聚合物(HA-PBA)用于包被Fc-脂质体的表面(25)。由于分子内的配位作用可以在温和的酸性条件下稳定硼酸酯的形成(图7),硼酸酯的形成在肠液中是动态稳定的(pH 5.5-8.0)。但是,由于葡萄糖与PBA的竞争性结合,这种硼酸酯在葡萄糖存在下会被破坏,从而使所述HA壳具有葡萄糖响应性。为了验证高葡萄糖浓度下HA壳的分离,将含罗丹明标记HA-PBA(Rho-HA-PBA)的HA-Fc-脂质体在PBS缓冲液中随葡萄糖浓度的增加而孵育。为了进行比较,我们还制备了被丙烯酸修饰的Rho-HA-PBA壳包被的脂质体,并在UV照射下与N,N’-亚甲基双丙烯酰胺进一步交联。被交联的HA壳包被的脂质体(HA_CL-Fc-脂质体)对葡萄糖无响应,可作为对照。如图3A所示,在与5、10、20和50mM葡萄糖孵育30分钟后,观察到Rho-HA-PBA的显著释放。TEM图像的形态学变化和尺寸的减小进一步证实,与10mM葡萄糖孵育足以使所述HA壳完全分离(图2E和F)。然而,在所有葡萄糖条件下,从HA_CL-Fc-脂质体中观察到不明显的释放。Zeta电位结果进一步证实了所述HA壳的分离和Fc基团的后续暴露。如图3B所示,经10mM葡萄糖孵育30分钟后,表面电荷从-25.9mV增加到-9.7mV,说明Fc-脂质体核的迅速释放。为了确定释放的胰岛素对血糖的影响,收集负载有胰岛素的Fc-脂质体并静脉注射到链脲佐菌素(STZ)诱导的成年1型糖尿病C57BL/6J小鼠(胰岛素剂量:5U/kg)。Fc-脂质体能够产生与注射天然胰岛素相当的低血糖反应(图8),证实生物活性胰岛素的成功释放。
在胃的强酸性条件下(pH 1.2-3.0),由于硼酸酯的形成受到抑制,所述HA-PBA不能与所述Fc-脂质体核表面的邻苯二酚基团形成络合作用。然而,由于Fc-脂质体表面基团在酸性条件下质子化,使得Fc-脂质体的负表面电荷在pH 2.5下转化为正电荷(图9),其通过静电作用保持完整的HA壳。综合起来,所述HA壳显示出可以防止胰岛素在胃中的渗漏和消化。
体外跨上皮转运。
然后采用人肠上皮性大肠腺癌(Caco-2)细胞单层通透性试验评价负载有胰岛素的脂质体的体外跨上皮转运效率。如图3C所示,FITC标记的负载有胰岛素的脂质体被添加到细胞单层的顶腔中,在37℃下与葡萄糖一起或不与葡萄糖一起孵育2小时。通过测量基底外侧腔中FITC标记的胰岛素的荧光强度来测定跨上皮转运效率。由于FcRn在Caco-2细胞表面高表达,与Ins-脂质体相比,FcRn介导的转胞吞作用使Fc-脂质体具有更高的跨上皮渗透性(图3D)。与具有交联的HA壳的脂质体(HA_CL-Fc-脂质体)不同,与葡萄糖共孵育也增加了HA-Fc-脂质体的转运,说明所述Fc基团是在葡萄糖触发的所述HA壳分离后暴露的。
体内肠道吸收。
将STZ诱导的1型糖尿病小鼠分为4组,依次口服管饲法给药:1)Fc-脂质体+葡萄糖;2)HA-Fc-脂质体;3)HA-Fc-脂质体+葡萄糖;4)HA_CL-Fc-脂质体+葡萄糖。口服脂质体30分钟后,口服葡萄糖溶液(1g/kg)来模拟餐后情况。给药后2小时收集十二指肠切片,用荧光显微镜成像。如图4A所示,FITC标记的胰岛素的绿色荧光在Fc-脂质体+葡萄糖治疗组的绒毛中广泛观察到,但在HA-Fc-脂质体治疗的小鼠中很少观察到。此外,葡萄糖溶液的额外摄入导致经HA-Fc-脂质体+葡萄糖处理的小鼠绒毛中FITC荧光的明显分布。在HA_CL-Fc-脂质体+葡萄糖处理的小鼠切片中,没有发现预期的荧光信号。定量数据进一步表明,与HA_CL-Fc-脂质体+葡萄糖治疗组相比,口服HA-Fc-脂质体+葡萄糖导致上皮细胞基底外侧绒毛中FITC标记的胰岛素的量增加5倍(图4B)。
葡萄糖响应性口服胰岛素递送用于1型糖尿病治疗。
通过口服负载有胰岛素的脂质体(含或不含Fc)对糖尿病小鼠的降糖作用进行评估(胰岛素剂量:10U/kg)。口服Fc-脂质体在治疗后的最初12小时内诱导血糖水平显著下降(图4C)。然而,口服游离胰岛素并没有诱导低血糖反应,而Ins-脂质体或HA-Fc-脂质体的治疗可使血糖水平降低到最低水平。值得注意的是,与Fc-脂质体相比,先前经10mM葡萄糖处理的HA-Fc-脂质体的口服给药也显示出类似的血糖控制作用,表明暴露的Fc在葡萄糖触发的HA壳分离后改善了所述脂质体的肠道吸收。
接下来,我们通过口服葡萄糖溶液以模拟餐后情况来评估脂质体的葡萄糖响应性肠吸收。给小鼠口服不同浓度的负载有胰岛素的制剂30分钟后,口服葡萄糖溶液(1g/kg)。如图4D所示,口服葡萄糖溶液导致餐后高血糖,治疗8小时后血糖水平降至初始水平。负载有胰岛素的Fc-脂质体的预处理显著地抑制了餐后血糖的升高,口服葡萄糖2小时后血糖水平恢复到初始水平,并在8小时内保持在如此低的水平。由于HA壳分离(其由口服葡萄糖后肠内的高浓度葡萄糖触发)后,Fc介导的对负载有胰岛素的脂质体的肠吸收,葡萄糖响应性HA-Fc-脂质体的治疗同样表现出降血糖作用。然而,在给予HA_CL-Fc-脂质体的组中观察到显著的餐后血糖持续升高,这进一步证实了该胰岛素递送系统的降血糖作用依赖于肠内葡萄糖触发的HA壳分离。相应地,用HA-Fc-脂质体处理的小鼠的血浆胰岛素浓度持续高于用HA_CL-Fc-脂质体处理的小鼠(图4E)。
方法
材料。除非另有说明,所有化学品均购自Sigma-Aldrich,并在收到时使用。透明质酸钠(分子量:300kDa)购自福瑞达生物化工有限公司(中国山东)。人重组胰岛素(锌盐,27.5IU/mg)购自Life Technology。纯化的人多克隆IgG Fc购自Bethyl Laboratories。1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺-N-[马来酰亚胺(聚乙二醇)](DSPE-PEG-MAL)(MW=2000)和1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺-N-[羧基(聚乙二醇)](DSPE-PEG-CM)(MW=2000)购自Laysan Bio,Inc。
葡萄糖响应性透明质酸(HA-PBA)、丙烯酸酯修饰的HA-PBA和罗丹明标记的HA-PBA的合成与表征。根据文献合成了丙烯酸酯修饰的HA和罗丹明标记的HA(37,38)。在1-乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐(EDC)和N-羟基琥珀酰亚胺(NHS)存在下,将2-氨基苯硼酸与HA缀合。简言之,0.5g HA(分子量:约300kDa)在水中溶解,加入EDC(0.58g)和NHS(0.35g),在室温下搅拌15分钟。然后在混合物中加入2-氨基苯硼酸盐酸盐(0.17g),并在室温下反应过夜。将反应液用去离子水彻底透析3天。然后,通过冻干得到HA-PBA,并用1H NMR对其进行了表征。通过比较6.91-7.40ppm质子峰下面积与1.99ppm质子峰下面积之比,计算出修饰度为14.4%。1H NMR(400MHz,D2O,δ):7.40(s,H,苯基-H)、7.20(s,2H,苯基-H)、6.91(s,H,苯基-H)。采用类似的方法合成了丙烯酸酯修饰的HA-PBA和罗丹明标记的HA-PBA。
邻苯二酚修饰的DSPE-PEG-CM(DSPE-PEG-CA)的合成与表征。将DSPE-PEG-CM(200mg)、EDC(57.5mg)和NHS(34.5mg)混合,溶解于20mL去离子水中,并在室温下搅拌30分钟。然后向所述混合物中加入盐酸多巴胺(57mg),并在室温下搅拌8小时。用去离子水透析2天除去未反应的多巴胺,将所得的DSPE-PEG-CA冻干,4℃保存至使用。通过使用Nanodrop2000C光谱仪(Thermo Scientific)测量邻苯二酚基团的UV-Vis吸收,验证了缀合的成功。
负载有胰岛素的葡萄糖响应性脂质体的制备。首先,采用脂质膜水化法制备所述负载有胰岛素的脂质体。简单地说,将蛋磷脂酰胆碱(EPC)、二油酰基磷脂酰乙醇胺(DOPE)、DSPE-PEG-MAL、DSPE-PEG-CA和胆固醇(重量比=9:9:1:1:4)的混合物溶解在氯仿中。将所述溶液蒸干形成所述脂质膜。用含胰岛素(胰岛素:脂质,1:1,w:w)的HEPES缓冲液(5mM)对所形成的脂质膜进行水化,用探针式超声波仪分散,并通过孔径分别为0.45和0.20μm的膜过滤器连续挤压3次。以21,000rpm的转速离心除去未包封的胰岛素,所得Ins-脂质体用含5mM EDTA的PBS缓冲液洗涤3次。通过采用Coomassie Plus蛋白质测定来测量未包封的胰岛素的量来确定Ins-脂质体中胰岛素的包封率(EE)和负载容量(LC)。
采用马来酰亚胺硫醇化学法,将Fc与Ins-脂质体表面的PEG链缀合来制备Fc-脂质体。简言之,86μg纯化的人多克隆IgG Fc在含有5mM EDTA的PBS中与4.8μL特劳特试剂(0.5mg/mL)反应1小时,然后将被修饰的Fc加入所述Ins-脂质体中,在4℃下混合1小时。所得Fc-脂质体经21,000rpm离心收集,用PBS缓冲液洗涤3次。
将获得的Fc-脂质体溶液加入所述HA-PBA溶液(HA-PBA:脂质,1:10,w:w)中,混合2小时,以21,000rpm离心获得所述HA-Fc-脂质体,用PBS缓冲液洗涤。在Zetasizer(Nano-ZS,Malvern)上测量了zeta电位和粒径分布。用JEOL 2000FX TEM仪器得到HA-Fc-脂质体的透射电镜(TEM)图像。
通过经UV辐射来交联HA壳而制备了具有非葡萄糖响应性HA壳的脂质体(HA_CL-Fc-脂质体)。将所述Fc-脂质体加入丙烯酸酯修饰的HA-PBA溶液(HA-PBA:脂质,1:10,w:w)中搅拌2小时,然后向所述混合物中加入交联剂N,N-亚甲基双丙烯酰胺(MBA)(MBA:HA-PBA,1:5,w:w)和光引发剂Irgacure 2959(0.1%,w:v)。采用BlueWave 75UV Curing Spot Lamp(DYMAX)经UV辐射60秒自由基聚合后,以21,000rpm离心得到HA_CL-Fc-脂质体,并用PBS缓冲液洗涤。
HA壳的体外分离。为评价HA-PBA壳的葡萄糖响应性分离,将HA-Fc-脂质体或含罗丹明标记的HA-PBA的HA_CL-Fc-脂质体在不同葡萄糖浓度(1、5、10、20和50mM)、pH 6.0下37℃孵育1小时,分离的Rho-HA-PBA经21,000rpm离心分离。用微板检测仪(Infinite M200PRO,Tecan)测定了自由Rho-HA-PBA在激发波长为552nm时在575nm处的荧光强度。
体外胰岛素释放。为了评价胰岛素的体外释放特性,将FITC-负载有胰岛素的HA-Fc-脂质体或Fc-脂质体悬浮于Tris-HCl缓冲液(10mM,pH 7.4)或Tris-HCl缓冲液(10mM,pH2.5)中。在预先安排的时间间隔内,以21,000rpm离心收集释放的胰岛素。在激发波长495nm时,测定游离FITC-胰岛素在519nm处的荧光强度。
细胞培养。Caco-2细胞从美国北卡罗来纳大学莱恩伯格综合癌症中心(UNCLineberger Comprehensive Cancer Center)的组织培养所(Tissue Culture Facility)获得,在5%CO2和90%湿度下,在Dulbecco改良的Eagle培养基中加入10%(v/v)胎牛血清(FBS)、青霉素(100U/mL)和链霉素(100μg/mL),在37℃培养箱(Thermal Scientific)中培养。用胰蛋白酶-EDTA(0.25%,w/w)定期传代培养细胞,每次实验前用血球计测定细胞密度。
体外细胞毒性。用3-(4,5)-二甲基噻嗪(-z-y1)-3,5-二苯基四唑氮唑(MTT)试验和Caco-2细胞评价葡萄糖响应性HA-Fc-脂质体的细胞毒性。在试验之前,去除96孔板中的介质。用PBS洗涤后,将裸HA-Fc-脂质体系列稀释液加入孔中。孵育24小时后,每孔加入噻唑蓝溶液(5mg/mL),再孵育4小时,除去培养基后,将紫色甲瓒晶体溶解于150μL二甲基亚砜中。用微板检测仪读取板在570nm处的吸光度。
体外转胞吞作用研究。为了进一步研究负载有胰岛素的脂质体在上皮细胞中的转运,将所述Caco-2细胞单层接种于Transwell板(Costar)上孵育21天。在研究之前,用在顶腔的预先加热的Hanks平衡盐溶液(HBSS)(pH 6.0)和在基底外侧腔的HBSS(pH7.4)替换培养基,并在37℃下平衡1小时。之后,用200μL FITC-胰岛素+葡萄糖(10mM)、Ins-脂质体+葡萄糖、Fc-脂质体+葡萄糖、HA-Fc-脂质体、HA-Fc-脂质体+葡萄糖、HA_CL-Fc-脂质体+葡萄糖分别替换所述顶端溶液。在37℃下孵育2小时后,收集基底外侧溶液,在激发波长为495nm时,使用微板检测仪测定了在519nm处的转运的FITC-胰岛素的量。
体内吸收。该动物研究方案得到北卡罗来纳州立大学机构动物护理和使用委员会以及北卡罗来纳大学教堂山分校的批准。STZ诱导的成年糖尿病小鼠(雄性C57B6,美国Jackson实验室)给药前禁食6小时。小鼠经口服管饲法给予下列制剂:Fc-脂质体、HA-Fc-脂质体和HA_CL-Fc-脂质体(4mL/kg)。30分钟后,实验组进一步口服葡萄糖溶液(1g/kg)。2小时后处死小鼠,取十二指肠组织冰冻切片,用Hoechst 33342进行细胞核染色,通过荧光显微镜观察组织切片。
使用链脲佐菌素(STZ)诱导的糖尿病小鼠进行体内研究。以STZ诱导的成年糖尿病小鼠(雄性C57B6,美国Jackson实验室)为研究对象,评价葡萄糖响应性负载有胰岛素的脂质体用于治疗糖尿病的体内疗效。该动物研究方案得到北卡罗来纳州立大学机构动物护理和使用委员会以及北卡罗来纳大学教堂山分校的批准。给药前监测小鼠血糖水平两天,并且所有小鼠给药前禁食6小时。为每组选择小鼠(n=5),使每组的平均初始血糖水平在300-500mg/dL之间。小鼠经口服管饲法给予下列制剂:胰岛素溶液、Fc-脂质体、HA-Fc-脂质体和HA_CL-Fc-脂质体(胰岛素剂量:10U/kg)。30分钟后,实验组进一步口服葡萄糖溶液(1g/kg)。每只小鼠的血糖水平都是通过使用Clarity GL2Plus血糖仪(Clarity Diagnostics,博卡拉顿,佛罗里达州)监测的。采用InvitrogenTM NovexTM EASIATM胰岛素人ELISA试剂盒测量血浆胰岛素浓度。
统计分析。所有结果均为平均值±标准差。采用双尾学生氏t检验进行统计分析。描述实验组与对照组之间的差异*P值<0.05被认为具有统计学意义。
所附权利要求书的组合物和方法不限于本文所述的具体组合物和方法的范围,这些组合物和方法旨在说明权利要求书的一些方面,并且功能上等效的任何组合物和方法都旨在落入权利要求书的范围内。除本文示出和描述的那些组合物和方法以外,对组合物和方法的各种修改都旨在落入所附权利要求书的范围内。此外,虽然仅具体描述了本文所公开的某些代表性组合物和方法步骤,但是即使没有具体叙述,组合物和方法步骤的其他组合也旨在落入所附权利要求书的范围内。因此,本文可以明确地提及步骤、元件、部件或成分的组合或更少,但是,即使未明确说明,也包括步骤、元件、部件和成分的其他组合。如本文所用的术语“包含”及其变体与术语“包括”及其变体同义使用,并且为开放的非限制性术语。尽管本文已经使用术语“包含”和“包括”来描述各种实施例,但是可使用术语“基本上由…组成”和“由…组成”来代替“包含”和“包括”以提供更具体的实施例,并且也得到公开。除了在实施例中的或另有说明的情况以外,在说明书和权利要求书中使用的所有表示成分的量、反应条件等的数字应当至少理解为根据有效数字的位数和普通的四舍五入方法来解释,而非试图对等同原则在权利要求书范围的应用作限制。
Claims (52)
1.一种葡萄糖敏感性药物递送系统,所述药物递送系统包含核和聚合物壳,所述核包含活性剂,所述聚合物壳包封所述核,其中所述核通过硼酸酯连接到所述壳。
3.根据权利要求2所述的药物递送系统,其中R1和R3为氢且R2和R4一起形成苯环。
4.根据权利要求1至权利要求3中任一项所述的药物递送系统,其中所述聚合物壳包含透明质酸、聚(γ-谷氨酸)、聚(α-谷氨酸)、聚(天冬氨酸)、硫酸软骨素、羧甲基纤维素或其组合,其中聚合物中的至少一部分羧酸酯基被修饰以包含所述硼酸酯。
5.根据权利要求4所述的药物递送系统,其中至少2%、至少4%、至少6%、至少8%、至少10%、至少12%、至少14%、至少16%、至少18%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%或至少50%的所述羧酸酯基被修饰以包含所述硼酸酯。
6.根据权利要求1至权利要求5中任一项所述的药物递送系统,其中所述聚合物包含透明质酸。
7.根据权利要求1至权利要求6中任一项所述的药物递送系统,其中所述核包含负载有所述活性剂的脂质体。
8.根据权利要求7所述的药物递送系统,其中所述脂质体包含聚合物锚定物,其量为所述脂质体的总重量的0.05-10重量%、0.1-10重量%、0.1-7.5重量%、0.1-5重量%、0.1-4重量%、0.1-3重量%、0.1-2重量%、0.1-1重量%、0.5-10重量%、0.5-7.5重量%、0.5-5重量%、0.5-4重量%、0.5-3重量%、0.5-2重量%或0.5-1重量%。
9.根据权利要求7或权利要求8所述的药物递送系统,其中所述聚合物锚定物包含与磷脂共价结合的二醇。
10.根据权利要求7至权利要求9中任一项所述的药物递送系统,其中所述脂质体包含与所述硼酸酯键合的聚合物锚定物。
11.根据权利要求10所述的药物递送系统,其中与所述硼酸酯键合的所述聚合物锚定物具有式:
其中Ra和Rb独立地选自C6-32烷基-C(O)-或C6-32烯基-C(O)-,n为5-1000的整数,Z和Z1为:
其中R1、R2、R3和R4独立地选自氢、C1-8烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、C3-8环烷基和C1-8杂芳基,其可以是被取代的或未被取代的,并且其中R1、R2、R3和R4中的任何两个或多个可以一起形成环;
n为0-10的整数,m为0-3的整数,并且Rc独立地选自Rc1、ORc1、N(Rc1)2、SiRc1 3、SRc1、SO2Rc1、SO2N(Rc1)2、C(O)Rc1;C(O)ORc1、OCORc1;C(O)N(Rc1)2、OC(O)N(Rc1)2、N(Rc1)C(O)N(Rc1)2、F、Cl、Br、I、氰基和硝基,其中Rc1在每种情况下独立地选自氢、C1-8烷基、C2-8烯基、C2-8炔基、芳基、C1-8杂芳基、C3-8环烷基或C1-8杂环基;并且其中任何两个或多个Rc基团可以一起形成环。
12.根据权利要求7至权利要求11中任一项所述的药物递送系统,其中所述脂质体进一步包含与因子锚定物键合的靶向因子。
13.根据权利要求12所述的药物递送系统,其中所述因子锚定物存在于所述脂质体中,其量为所述脂质体的总重量的0.05-10重量%、0.1-10重量%、0.1-7.5重量%、0.1-5重量%、0.1-4重量%、0.1-3重量%、0.1-2重量%、0.1-1重量%、0.5-10重量%、0.5-7.5重量%、0.5-5重量%、0.5-4重量%、0.5-3重量%、0.5-2重量%或0.5-1重量%。
14.根据权利要求12或权利要求13所述的药物递送系统,其中所述靶向因子包含人IgGFc片段、转铁蛋白(Tf)或抗细胞间粘附分子-1(ICAM-1)。
15.根据权利要求7至权利要求14中任一项所述的药物递送系统,其中所述脂质体包含一种或多种主脂质。
16.根据权利要求15所述的药物递送系统,其中所述主脂质包含一种或多种化合物,所述化合物选自:磷脂酸(“PA”)、磷脂酰胆碱(“PC”)、磷脂酰甘油(“PG”)、磷脂酰乙醇胺、磷脂酰肌醇(“PI”)、磷脂酰丝氨酸(“PS”)、鞘磷脂(包括脑鞘磷脂)、卵磷脂、溶血卵磷脂、溶血磷脂酰乙醇胺、脑苷脂、二花生酰基磷脂酰胆碱(“DAPC”)、二癸酰基-L-α-磷脂酰胆碱(“DDPC”)、二芥酰基磷脂酰胆碱(“DEPC”)、二月桂酰基磷脂酰胆碱(“DLPC”)、二亚油酰基磷脂酰胆碱、二肉豆蔻酰基磷脂酰胆碱(“DMPC”)、二油酰基磷脂酰胆碱(“DOPC”)、二棕榈酰基磷脂酰胆碱(“DPPC”)、二硬脂酰基磷脂酰胆碱(“DSPC”)、1-棕榈酰基-2-油酰基磷脂酰胆碱(“POPC”)、二花生酰基磷脂酰甘油(“DAPG”)、二癸酰基-L-α-磷脂酰甘油(“DDPG”)、二芥酰基磷脂酰甘油(“DEPG”)、二月桂酰基磷脂酰甘油(“DLPG”)、二亚油酰基磷脂酰甘油、二肉豆蔻酰基磷脂酰甘油(“DMPG”)、二油酰基磷脂酰甘油(“DOPG”)、二棕榈酰基磷脂酰甘油(“DPPG”)、二硬脂酰基磷脂酰甘油(“DSPG”)、1-棕榈酰基-2-油酰基磷脂酰甘油(“POPG”)、二花生酰基磷脂酰乙醇胺(“DAPE”)、二癸酰基-L-α-磷脂酰乙醇胺(“DDPE”)、二芥酰基磷脂酰乙醇胺(“DEPE”)、二月桂酰基磷脂酰乙醇胺(“DLPE”)、二亚油酰基磷脂酰乙醇胺、二肉豆蔻酰基磷脂酰乙醇胺(“DMPE”)、二油酰基磷脂酰乙醇胺(“DOPE”)、二棕榈酰基磷脂酰乙醇胺(“DPPE”)、二硬脂酰基磷脂酰乙醇胺(“DSPE”)、1-棕榈酰基-2-油酰基磷脂酰乙醇胺(“POPE”)、二花生酰基磷脂酰肌醇(“DAPI”)、二癸酰基-L-α-磷脂酰肌醇(“DDPI”)、二芥酰基磷脂酰肌醇(“DEPI”)、二月桂酰基磷脂酰肌醇(“DLPI”)、二亚油酰基磷脂酰肌醇、二肉豆蔻酰基磷脂酰肌醇(“DMPI”)、二油酰基磷脂酰肌醇(“DOPI”)、二棕榈酰基磷脂酰肌醇(“DPPI”)、二硬脂酰基磷脂酰肌醇(“DSPI”)、1-棕榈酰基-2-油酰基磷脂酰肌醇(“POPI”)、二花生酰基磷脂酰丝氨酸(“DAPS”)、二癸酰基-L-α-磷脂酰丝氨酸(“DDPS”)、二芥酰基磷脂酰丝氨酸(“DEPS”)、二月桂酰基磷脂酰丝氨酸(“DLPS”)、二亚油酰基磷脂酰丝氨酸、二肉豆蔻酰基磷脂酰丝氨酸(“DMPS”)、二油酰基磷脂酰丝氨酸(“DOPS”)、二棕榈酰基磷脂酰丝氨酸(“DPPS”)、二硬脂酰基磷脂酰丝氨酸(“DSPS”)、1-棕榈酰基-2-油酰基磷脂酰丝氨酸(“POPS”)、二花生酰基鞘磷脂、二癸酰基鞘磷脂、二芥酰基鞘磷脂、二月桂酰基鞘磷脂、二亚油酰基鞘磷脂、二肉豆蔻酰基鞘磷脂、鞘磷脂、二油酰基鞘磷脂、二棕榈酰基鞘磷脂、二硬脂酰基鞘磷脂、1-棕榈酰基-2-油酰基鞘磷脂或其组合。
17.根据权利要求15或权利要求16所述的药物递送系统,其中所述主脂质包含胆碱脂质成分和乙醇胺脂质成分。
18.根据权利要求7至权利要求17中任一项所述的药物递送系统,其中所述脂质体包含胆固醇、一种或多种胆固醇衍生物或其组合。
19.根据权利要求1至权利要求18中任一项所述的药物递送系统,其中所述活性剂包含小分子药物或治疗蛋白。
20.根据权利要求19所述的药物递送系统,其中所述活性剂包含常规胰岛素、德谷胰岛素、赖脯胰岛素、门冬胰岛素、赖谷胰岛素、地特胰岛素、甘精胰岛素、NPH胰岛素、动物胰岛素或其组合。
21.一种治疗高血糖症的方法,所述方法包括向有需要的患者施用根据权利要求20所述的药物递送系统。
22.一种制备根据权利要求1至权利要求20中任一项所述的药物递送系统的方法,所述方法包括制备主脂质和一种或多种锚定物聚合物的干燥混合物,并将所述干燥混合物与包含活性剂的水性组合物结合以提供脂质体,然后用包含硼酸酯的聚合物包封所述脂质体。
25.根据权利要求22至权利要求24中任一项所述的方法,其中所述干混合物进一步包含胆固醇、一种或多种胆固醇衍生物或其组合。
26.根据权利要求22至权利要求25中任一项所述的方法,其中所述干混合物进一步包含一种或多种因子锚定物。
27.根据权利要求26所述的方法,所述方法包括将靶向因子与所述因子锚定物缀合。
28.根据权利要求22至权利要求27中任一项所述的方法,其中所述包含硼酸酯的聚合物包含透明质酸。
30.一种根据权利要求22至权利要求29中任一项所述的方法制备的药物递送系统。
31.一种葡萄糖敏感药物递送系统,所述递送系统包含核和透明质酸壳,其中所述核和透明质酸由硼酸酯结合,其中所述核在葡萄糖存在下从所述透明质酸中释放。
32.根据权利要求31所述的药物递送系统,其中所述硼酸酯由连接到所述核的二醇形成。
34.根据权利要求31至权利要求33中任一项所述的药物递送系统,其中所述硼酸酯由2-氨基苯基硼酸形成。
35.根据权利要求32至权利要求34中任一项所述的药物递送系统,其中所述二醇是1,2二醇。
36.根据权利要求32至权利要求35中任一项所述的药物递送系统,其中所述二醇与磷脂共价结合。
39.根据权利要求37或权利要求38所述的药物递送系统,其中R1和R2均为硬脂酰,n为2,Z为PEG,m为1,并且o为2。
41.根据权利要求37至权利要求40中任一项所述的药物递送系统,其中Z为包含5-200、10-150、20-150、20-100或25-75个单体单元的PEG。
42.根据权利要求31至权利要求41中任一项所述的药物递送系统,其中所述核包含脂质体。
43.根据权利要求31至权利要求42中任一项所述的药物递送系统,其中所述核包含治疗活性剂。
44.根据权利要求43所述的药物递送系统,其中所述治疗活性剂包含治疗蛋白。
45.根据权利要求44所述的药物递送系统,其中所述治疗活性剂包含胰岛素。
46.根据权利要求31至权利要求45中任一项所述的药物递送系统,所述药物递送系统进一步包含连接到所述核的靶向因子。
47.根据权利要求46所述的药物递送系统,其中所述靶向因子包含人IgG Fc片段、转铁蛋白(Tf)或抗细胞间粘附分子-1(ICAM-1)。
49.根据权利要求48所述的药物递送系统,其中Y包含琥珀酰亚胺酯、琥珀酰亚胺碳酸酯、琥珀酰亚胺氨基甲酸酯、五氟苯酯、噻唑烷-2-硫酮、酸酐、醛、迈克尔受体(诸如乙烯基砜)、马来酰亚胺、炔或叠氮化物。
51.根据权利要求48至权利要求50中任一项所述的药物递送系统,其中Z’为包含5-200、10-150、20-150、20-100或25-75个单体单元的PEG。
52.根据权利要求48至权利要求51中任一项所述的药物递送系统,其中R1’和R2’均为硬脂酰,n’为2,Z’为PEG,m’为1,并且o’为2。
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