CN103608354A - 含有pH-响应肽的纳米颗粒 - Google Patents
含有pH-响应肽的纳米颗粒 Download PDFInfo
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- CN103608354A CN103608354A CN201280029868.3A CN201280029868A CN103608354A CN 103608354 A CN103608354 A CN 103608354A CN 201280029868 A CN201280029868 A CN 201280029868A CN 103608354 A CN103608354 A CN 103608354A
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- peptide
- amino acid
- nano particle
- liposome
- acid
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Abstract
本发明提供了能在弱酸性pH环境中释放目标物质的纳米颗粒和包含其的细胞导入剂。所述纳米颗粒包含纳米颗粒成型组分和肽。所述颗粒成型组分形成脂质体或胶束,且所述肽序列具有含有2至8个(任选地为相同的或不同的)以His(组氨酸)起始并以酸性氨基酸终止的单位。
Description
技术领域
本发明涉及弱酸性pH响应肽和含有该肽的纳米颗粒。本发明进一步涉及含有该纳米颗粒的物质导入剂。
发明背景
在癌症化疗中,已经进行了尝试来开发DDS,以提高特异性;然而,这些尝试中几乎没有专注于肿瘤环境的尝试。具体来说,肿瘤组织位于具有小于生理条件下pH(pH约7.4)的pH(pH约6.5)的特殊环境中。然而,必须开发出可以以肿瘤组织特异性方式起作用的药物递送载体,以这种方式从而响应该小pH变化。到目前为止,为了在增加血液循环性能的同时避免与血液中的血浆蛋白结合,已经将聚乙二醇(PEG)(一种亲水大分子)用来修饰脂质体等的表面,并将修饰过的脂质体用作例如,抗癌药物的载体(例如,专利文献(PTL)1)。然而,已经揭示PEG为抗原性的。在其表面上展现PEG的载体对细胞的亲和力低,因此不大可能会被细胞摄取;因而很难将药物递送到肿瘤细胞内。由于N末端区域存在碱性氨基酸(赖氨酸或精氨酸),PTL2中公开的肽-脂质体复合物保留着正电荷,凭借pH不会发生电荷改变;因此无法预期足够的血液循环性能。
非专利文献(NPL)1使用His片段作为pH响应区域。根据NPL1中公开的技术,外部环境pH从7.4到5.0的急剧降低造成中性His带正电,因此而增加的静电排斥造成胶束的破坏。然而,在6.5的弱酸性pH下,His不会单独被质子化;因此,在pH6.5下很难引起电荷反转。
NPL2公开了pH响应胶束,其中当由于pH降低化学结合至位于嵌段聚合物末端的赖氨酸部分上的二甲基顺丁烯二酸被离解时,pH响应胶束的表面电荷会从负电荷变为正电荷。在NPL2中公开的肽中,二甲基顺丁烯二酸的离解会造成带正电荷赖氨酸残基的暴露;即使pH被升高,这种状态也不会恢复到初始状态。同样,在它们于血液循环中流动的同时穿过炎症位点或其他的低pH组织的情形下,二甲基顺丁烯二酸会被离解而暴露赖氨酸,造成与血液成分的相互作用;因此很难到达目标肿瘤。
引用文献列表
专利文献
PTL1:JP2004-10481A
PTL2:JP2004-523531A
非专利文献
NPL1:AIChE Journal Vol.56,No.7,2010,pp.1922-1931
NPL2:International Journal of Pharmaceutics376,2009,pp.134-140
发明概述
技术问题
本发明的目的是提供能在诸如癌症组织的弱酸性pH环境中释放目标物质的药物递送载体。
技术方案
本发明提供了涉及纳米颗粒或物质导入剂的以下项目(1)至(16)。
(1)包含肽和颗粒成型组分的纳米颗粒,其中
所述颗粒成型组分形成脂质体或胶束,且
所述肽具有含有2至8个单位的序列,其中每个单位以His(组氨酸)起始并以酸性氨基酸终止,且其中每个单位为相同的或不同的。
(2)如项目(1)所述的纳米颗粒,其中每个单位在His和酸性氨基酸之间具有2至5个氨基酸。
(3)如项目(1)或(2)所述的纳米颗粒,其中每个单位在His和酸性氨基酸之间具有3个氨基酸。
(4)如项目(2)或(3)所述的纳米颗粒,其中His和酸性氨基酸之间的氨基酸为选自以下的任意氨基酸:Gly、Ala、His、Leu、Ile、Val、Phe、Tyr、Trp、Cys、Met、Ser、Thr、Gln和Asn。
(5)如项目(4)所述的纳米颗粒,其中His和酸性氨基酸之间的氨基酸为选自以下的任意氨基酸:Gly、Ala、His、Cys和Ser。
(6)如项目(1)至(5)中任一项所述的纳米颗粒,
其中肽包含2至8个由以下式(I)表示的单位:
His-(AA1)(AA2)(AA3)-Glu/Asp (I),
其中His为组氨酸;Glu/Asp为谷氨酸或天冬氨酸;且AA1、AA2和AA3为相同的或不同的,各自表示Gly、Ala、His、Leu、Ile、Val、Phe、Tyr、Trp、Cys、Met、Ser、Thr、Gln或Asn,以及
其中每个单位的氨基酸序列为相同的或不同的。
(7)如项目(6)所述的纳米颗粒,其中所述肽具有SEQ ID Nos:1至3中任一个的序列。
(8)如项目(1)至(7)中任一项所述的纳米颗粒,其中所述肽在末端具有疏水基团以便被所述脂质体或胶束保留。
(9)如项目(8)所述的纳米颗粒,其中所述疏水基团为C12-24烃基或C12-24酰基。
(10)如项目(1)至(9)中任一项所述的纳米颗粒,其中所述颗粒成型组分含有磷脂。
(11)如项目(1)至(10)中任一项所述的纳米颗粒,其中所述颗粒成型组分形成脂质体。
(12)如项目(1)至(11)中任一项所述的纳米颗粒,其中所述纳米颗粒用选自以下目标物质中至少一种来装载:药物、核酸、肽、蛋白质、糖和它们的复合物。
(13)包含项目(1)至(12)中任一项的纳米颗粒的物质导入剂。
(14)由以下式(II)表示的肽化合物:
R1-(Z1)l-[His-(AA1)(AA2)(AA3)-Glu/Asp]n-(Z2)m-R2 (II),
其中His为组氨酸;Glu/Asp为谷氨酸或天冬氨酸;AA1、AA2和AA3为相同的或不同的,且各自表示Gly、Ala、His、Leu、Ile、Val、Phe、Tyr、Trp、Cys、Met、Ser、Thr、Gln或Asn;n表示2至8的整数;l和m为相同的或不同的,且各自表示0或1;R1为C12-24烃基或C12-24酰基;R2为OH或C末端保护基团;且Z1或Z2表示由选自以下氨基酸中1至8个氨基酸组成的连接臂:Gly、Ala、Leu、Ile、Val、Phe、Tyr、Trp、Cys、Met、Ser、Thr、Gln和Asn,
所述肽化合物总共含有10至60个氨基酸。
(15)如项目(14)所述的肽化合物,其中式(II)表示的肽化合物中的肽具有SEQ ID Nos:1至3中任一个的序列。
(16)如项目(14)或(15)所述的肽化合物,其中R1为C12-24酰基。
有益效果
本发明可提供能在具有pH约6.5的弱酸性细胞环境中释放封装的目标物质的纳米颗粒或物质导入剂。
本发明的纳米颗粒可在上述弱酸性区域释放目标物质来使所述物质在那里起作用,从而可提供优异的药物递送系统。
由于酸性氨基酸的负电荷,本发明的纳米颗粒可避免在生理条件,即pH7.4下与血液血浆组分等相互作用,同时具有长的血液循环性能。在本发明的纳米颗粒中,邻近His的酸性氨基酸的存在控制着His的pH响应性,使得本发明的纳米颗粒即使对弱酸性pH也能够显示敏感的响应性。为此,在由于EPR效应(增强的渗透和滞留效应)到达肿瘤后,本发明的纳米颗粒在肿瘤环境中的弱酸性条件下将被质子化,引起电荷反转;从而本发明的纳米颗粒被癌症细胞摄取。鉴于此,本发明的纳米颗粒是非常有用的。
附图说明
图1显示了生产性实施例1中获得的硬脂酰化的肽(SEQ ID NO:1;C端:CONH2)的HPLC和MALDI-TOF-MS结果。
图2显示了生产性实施例2中获得的硬脂酰化的肽(SEQ ID NO:2;C端:CONH2)的HPLC和MALDI-TOF-MS结果。
图3显示了生产性实施例3中获得的硬脂酰化的肽(SEQ ID NO:3;C端:CONH2)的HPLC和MALDI-TOF-MS结果。
图4显示了生产性实施例4中获得的硬脂酰化的肽(SEQ ID NO:4;C端:CONH2)的HPLC和MALDI-TOF-MS结果。
图5显示了通过使用流式细胞仪测量细胞内荧光染料的量获得的结果。
图6显示了通过使用共聚焦激光扫描显微镜(Zeiss LSM510META)观察细胞获得的结果。
图7显示了通过使用共聚焦激光扫描显微镜(Zeiss LSM510META)观察用Hoechst33342(蓝色)染色的核和用LysoTracker Green(绿色)染色的内含体/溶酶体获得的结果。
图8显示了实施例4的患有癌症小鼠的瘤内动力学评估结果。
图9显示了仅有肽和肽修饰的纳米颗粒的CD光谱,以及二级结构组成的预期结果。
图10显示了生产性实施例4中获得的杂乱顺序肽修饰的脂质体的细胞摄入结果,使用FACS评估。
图11显示了生产性实施例2中获得的肽修饰的脂质体的细胞摄入结果,使用FACS评估。
发明详述
本发明的纳米颗粒包含颗粒成型组分和肽作为构成要素。
本发明的肽总共包含10至60个,优选12至40个,且更优选14至30个氨基酸。
本发明的肽含有His(组氨酸,H)和酸性氨基酸(谷氨酸(Glu,E)或天冬氨酸(Asp,D)作为必需构成要素,并具有包含各自以His起始并以酸性氨基酸终止的单位的序列。这些单位中每一个都在His和酸性氨基酸之间含有2至5个,且优选3个氨基酸。这些单位中每一个在His和酸性氨基酸之间都具有相同数目的氨基酸。例如,当最初的单位具有3个氨基酸时,随后的单位中每一个也具有3个氨基酸。这些氨基酸选自:Gly、Ala、His、Leu、Ile、Val、Phe、Tyr、Trp、Cys、Met、Ser、Thr、Gln和Asn。这些氨基酸中,优选Gly、Ala、His、Cys和Ser。所述肽总共具有2至8个,优选2至6个,且更优选2至4个单位,且邻近的单位直接彼此结合。具体来说,His邻近其中单位直接彼此结合的部分(moieties)上的酸性氨基酸。
在一个优选的实施方案中,本发明的肽具有2至8个,优选2至6个,且更优选2至4个由以下式(I)表示的单位:
His-(AA1)(AA2)(AA3)-Glu/Asp (I),
其中His为组氨酸;Glu/Asp为谷氨酸或天冬氨酸;且AA1、AA2和AA3各自表示Gly、Ala、His、Leu、Ile、Val、Phe、Tyr、Trp、Cys、Met、Ser、Thr、Gln或Asn。
AA1、AA2和AA3中的每个优选为Gly、Ala、Ser、Cys或His,且更优选为Gly、Ala或His。在所述肽序列中,His残基的总数大于酸性氨基酸的总数。例如,当存在2个酸性氨基酸时,就存在3至7个His残基。当存在3个酸性氨基酸时,就存在4至10个His残基。当存在4个酸性氨基酸时,就存在5至13个His残基。当存在5个酸性氨基酸时,就存在6至16个His残基。当存在6个酸性氨基酸时,就存在7至19个His残基。当存在8个酸性氨基酸时,就存在9至25个His残基。本发明的肽含有2至8个,优选2至6个,更优选2至4个酸性氨基酸。本发明的肽含有3至25个,优选3至19个,且更优选3至13个His残基。
具体来说,本发明的单位优选为His-Gly-Ala-His-Glu、His-Ala-Gly-His-Glu、His-Ala-Ala-Gly-Glu或His-His-Ala-His-Glu。除了这些单位,本发明的肽可在N端或C端具有包含Gly、Ala、His等的氨基酸序列(Z1或Z2;连接臂)。构成所述连接臂(Z1或Z2)的氨基酸实例包括:Gly、Ala、Leu、Ile、Val、Phe、Tyr、Trp、Cys、Met、Ser、Thr、Gln和Asn。这些氨基酸中,优选Gly、Ala、Ser和Cys;更优选Gly、Ala和His。每个连接臂(Z1或Z2)总共含有1至8个,优选2至6个氨基酸。
本发明的肽可在C端具有C末端保护基团。C末端保护基团包括可与C末端羧基的碳原子形成酰胺的基团,或可与该羧基的氧原子形成酯的基团。可形成酯的基团实例包括烷基,尤其是C1-5直链或支链烷基(C1-5烷基),如甲基、乙基和丙基。可形成酰胺的基团实例包括胺官能团,如氨基;和烷基氨基官能团,如甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、甲基乙基氨基和其他的单或二-C1-5烷基氨基基团。优选可形成酰胺的基团;更优选氨基。
用疏水基团修饰本发明的肽。在肽的N端或C端,优选N端引入疏水基团。所述疏水基团具有12个或更多个,优选12至24个,更优选14至22个,还更优选16至20个碳原子。其实例包括烃基和酰基。尤其优选酰基。疏水基团可以具有直链或支链。烃基的实例包括具有12个或更多个碳原子的直链或支链烷基,如十二烷基、十四烷基、十六烷基、十八烷基和二十烷基。优选硬脂酰。优选的酰基实例包括月桂酰基、十四烷酰基、棕榈酰基、硬脂酰基、山崙酰氧基、异硬脂酰基、二十烷酰基、二十四烷酰基、异棕榈酰基、油酰基、亚油酰基等。更优选的酰基选自月桂酰基、十四烷酰基、棕榈酰基、硬脂酰基、异硬脂酰基和油酰基。
本发明的肽的优选实例包括具有氨基酸序列SEQ ID Nos:1至3中任何一个序列的肽。在一个优选的实施方案中,该肽的N端被结合到疏水基团上以便被所述脂质体或胶束保留。另一优选的实施方案为以由下式(II)表示的肽化合物:
R1-(Z1)l-[His-(AA1)(AA2)(AA3)-Glu/Asp]n-(Z2)m-R2 (II)
其中His为组氨酸;Glu/Asp为谷氨酸或天冬氨酸;AA1、AA2和AA3为相同的或不同的,且各自表示:Gly、Ala、His、Leu、Ile、Val、Phe、Tyr、Trp、Cys、Met、Ser、Thr、Gln或Asn;n为2至8的整数;l和m为相同的或不同的,且表示0或1;R1为C12-24烃类或C12-24酰基;R2为OH或C末端保护基团;Z1或Z2表示由选自以下氨基酸中1至8个氨基酸组成的连接臂:Gly、Ala、Leu、Ile、Val、Phe、Tyr、Trp、Cys、Met、Ser、Thr、Gln和Asn,所述肽化合物总共含有10至60个氨基酸。烃基、酰基和C末端保护基团的实例如上所述。
可以通过已知的肽合成方法制造本发明的肽,尤其是液相合成法或固相合成法。还可通过这样的方法合成本发明的肽,其包括:使用基因重组技术将编码本发明的肽的DNA引入到宿主细胞内,并表达DNA。例如,在固相合成法中,可以按如下获得本发明的肽:将N端受保护的氨基酸羧基结合到具有氨基的不溶性树脂上,其中对应于C端的氨基酸氨基被用尿烷保护基如9-芴基甲氧基羰基(Fmoc)保护;随后将氨基的保护基去除,以依次在N末端方向上缩合受保护的氨基酸;并去除不溶性树脂和氨基酸的保护基团从而获得本发明的肽。上述具有氨基的不溶性树脂不具体受限,但优选为Fmoc-NH-SAL树脂(4-(2',4'-二甲氧基苯基-Fmoc-氨基乙基)苯氧基连接臂树脂);可以通过树脂切割将目标物质直接给予到其处。使用已知的方法通过用已知的保护基团保护官能团,可以获得在本发明的肽的合成中使用的受保护氨基酸。还可能使用可商购的受保护氨基酸。关于保护基团,可以使用已知的保护基团。其实例包括:甲氧基羰基、乙氧基羰基、叔-丁氧基羰基、9-芴基甲氧基羰基、苄氧基羰基、4-甲氧基苄氧基羰基、2,2,2-三氯乙氧基羰基、甲酰基、乙酰基、丙酰基、丁酰基等。为了制备受保护的氨基酸,例如,可以使用已知的方法,如DIPCDI-HOBt(二异丙基碳化二亚胺-1-羟基苯并三唑)法。可以在已知的溶剂中进行该缩合反应,例如,诸如二甲基甲酰胺的有机溶剂。氨基保护基团的去保护试剂不受限,且可以将诸如哌啶/二甲基甲酰胺的已知试剂用来切割诸如Fmoc的保护基团。可以进行尿烷保护基团的去保护,例如,通过催化还原或使用三氟乙酸。还可以通过已知的方法进行其他保护基团的去保护。可以通过诸如茚三酮反应法的已知方法确认每个合成步骤中的缩合反应的进展程度。鉴于此,可以获得具有期望氨基酸序列的受保护的肽。使用Fmoc-NH-SAL树脂作为不溶性树脂,通过用TMSBr(三甲基甲硅烷基溴化物)、TFA(三氟乙酸)或诸如此类等处理,可以同时去除树脂和保护基团。根据所用树脂的类型,可以用COOH(R2=OH)或CONH2(R2=NH2)的C端获得肽。
当将R2定义为OH时,本发明的肽的C末端氨基酸的羧酸未被替换。同样地,当将R2定义为NH2时等,本发明的肽的C末端氨基酸的羧酸为酰胺(CONH2)。
可以通过已知的方法完成将疏水基团引入到本发明的肽内。例如,可以通过使具有游离N端的肽与对应于待引入酰基的羧酸,连同缩合剂(例如,HBTU/HOBt)和反应加速剂(例如,DIEA)进行反应,以引入期望的酰基。可以通过与对应于待引入烃基的卤化烃进行反应,在碱存在下实现烃基的引入。
可以通过已知方法分离和纯化本发明的由此获得的肽,如萃取、再结晶、各种色谱法(凝胶过滤、离子交换、分配和吸附)、电泳和逆流分配。优选反相高压液相色谱法。
在约中性的pH(例如,pH7或7.4),本发明的纳米颗粒具有约-100至50mV的ζ-电势,优选约-50至30mV,更优选约-30至10mV,且尤其是-30至0mV。可以通过使用ζ-电势分析仪(Zetasizer)测量ζ-电势。
尽管其并不限于此,本发明的纳米颗粒具有,例如,30至1000nm,优选50至500nm,更优选60至400nm,且尤其是70至300nm的平均粒径。例如,可通过动态光散射法、静态光散射法、电子显微镜观察、原子力显微镜观察或诸如此类等测量平均粒径。
可在体外或体内使用本发明的物质导入剂来将目标物质递送到低pH位点。
低pH位点的实例包括炎症位点、肿瘤位点、感染位点等。尤其优选肿瘤位点。
可装载在纳米颗粒内的目标物质实例包括,但不具体限于,选自以下的一个或多个成员:药物、核酸、肽(例如,催产素、缓激肽、促甲状腺激素释放因子、脑啡肽和可能的生物活性肽和肽激素)、蛋白质(例如,酶、白介素和各种可能的细胞因子、细胞转移因子、细胞生长因子和抗体)、糖以及它们的组合。可以根据目的如诊断或治疗目的挑选这些物质。核酸包括DNA和RNA,以及DNA和RNA的类似物和衍生物(例如,siRNA、肽核酸(PNA)和硫代膦酸DNA)。核酸可以为单链的或双链的,且可以为直链的或环状核酸。
可用作目标物质的药物实例包括:抗癌药物、血管舒张药、抗微生物剂等。抗癌药物的具体实例包括:喃氟啶、阿霉素、道诺霉素、顺铂、奥沙利铂、卡铂、紫杉醇、伊立替康、SN-38、放线菌素D、长春新碱、长春花碱、氨甲蝶呤、硫唑嘌呤、氟尿嘧啶、丝裂霉素C、多西他赛、环磷酰胺、卡培他滨、表柔比星、吉西他滨、米托蒽醌、亚叶酸、长春瑞滨、曲妥珠单抗、依托泊苷、雌二醇氮芥、强的松、干扰素α、白介素-2、博来霉素、异环磷酰胺、美司钠、六甲蜜胺、拓扑替康、阿糖胞苷、甲基泼尼松龙、地塞米松、巯嘌呤、硫鸟嘌呤、氟达拉滨、吉妥珠单抗、伊达比星、米托蒽醌、维甲酸、阿仑单抗、瘤可宁、克拉屈滨、伊马替尼、表柔比星、达卡巴嗪、甲基苄肼、氮芥、利妥昔单抗、地尼白介素(denileukin diftitox)、甲氧苄氨嘧啶/磺胺甲恶唑、别嘌呤醇、卡莫司汀、三苯氧胺、非格司亭、替莫唑胺、美法仑、长春瑞滨、阿扎胞苷、沙利度胺(Thalidomide)、丝裂霉素等。血管舒张药的实例包括:波生坦、安倍生坦、贝前列腺素钠等。抗微生物剂的实例包括:两性霉素B、青霉素G、氨苄青霉素、头孢唑啉、亚胺培南、氨曲南、庆大霉素、四环素、氯霉素、红霉素、阿奇霉素、罗他霉素、泰利霉素、奎奴普丁、磷米多辛(phosmidosine)、萘啶酸、诺氟沙星、司帕沙星、利奈唑胺等。
可用作目标物质的核酸的优选实例包括选自以下的任何双链RNAs(dsRNAs):meroduplex RNA(mdRNA)、带切口的dsRNA(ndsRNA)、有间隙的dsRNA(gdsRNA)、短干扰核酸(siNA)、siRNA、小RNA(miRNA)、短发卡RNA(shRNA)、短干扰寡核苷酸、短干扰替换的寡核苷酸、短干扰修饰的寡核苷酸、化学修饰的dsRNA和转录后基因沉默RNA(ptgsRNA)。可以单独或以两个或更多个组合的方式使用目标物质。例如,可以组合使用两种或更多种类型的siRNAs。
在替换和修饰(包括化学修饰)方面的一个实施方案中,双链RNA可以在双链RNA的一个或两个3'端包含1个至4个核苷酸的突出部分,如包含一个脱氧核苷酸或两个脱氧核苷酸(例如,胸苷、腺嘌呤)的突出部分。双链RNA可以在双链RNA的一端或两端具有平末端。在一个实施方案中,第一或第二链的5'端被磷酸化。在双链RNA的任何实施方案中,3’端的核苷酸突出部分可以包含在核酸的糖、碱基或骨架上化学修饰过的核糖核苷酸或脱氧核糖核苷酸。在双链RNA的任何实施方案,3’端的核苷酸突出部分可以包含一个或多个通用碱性核苷酸。在双链RNA的任何实施方案中,3’端的核苷酸突出部分可以包含一个或多个无环核苷酸。在双链RNA的任何实施方案中,dsRNA可以进一步包含末端磷酸基,如5'-磷酸(见Martinez et al.,Cell.110:563-574,2002和Schwarz et al.,Molec.Cell.10:537-568,2002)或5',3'-二磷酸。
双链RNA可以进一步包含2'-糖替换,如2'-脱氧、2'-O-甲基、2'-O-甲氧基乙基、2'-O-2-甲氧基乙基、卤素、2'-氟代、2'-O-烯丙基或诸如此类,或者它们的组合。在其他的实施方案中,双链RNA进一步在第一链的一端或两端或者在一条或多条第二链上包含末端帽替换,如烷基、脱碱基、脱氧脱碱基、丙三基、二核苷酸、无环核苷酸、反向脱氧核苷酸部分或它们的组合。
在其他的实施方案中,双链RNA可以进一步包含至少一个修饰的核苷酸间连接,如独立地,硫代磷酸酯、手性硫代磷酸酯、二硫代磷酸酯、磷酸三酯、氨基烷基磷酸三酯、甲基膦酸酯、烷基膦酸酯、3'-亚烷基膦酸酯、5'-亚烷基膦酸酯、手性膦酸酯、膦酰基乙酸酯、硫代膦酰基乙酸酯、次磷酸酯、磷酸酰胺酯、3'-氨基磷酸酰胺酯、氨基烷基磷酸酰胺酯、硫羰基磷酸酰胺酯、硫羰基烷基膦酸酯、硫羰基烷基磷酸三酯、硒磷酸酯、硼烷磷酸酯连接,或它们的组合。
可以通过使用以下物质替换或修饰(包括化学修饰)双链RNA:5-甲基胞嘧啶;5-羟甲基胞嘧啶;黄嘌呤;次黄嘌呤;2-氨基腺嘌呤;腺嘌呤和鸟嘌呤的6-甲基、2-丙基或其他的烷基衍生物;8-替换的腺嘌呤和鸟嘌呤(例如,8-氮杂、8-卤代、8-氨基、8-硫醇、8-硫代烷基、8-羟基);7-甲基、7-去氮杂和3-去氮杂腺嘌呤和鸟嘌呤;2-硫尿嘧啶;2-硫代胸腺嘧啶;2-硫代胞嘧啶;5-甲基、5-丙炔基、5-卤代(例如,5-溴代或5-氟代)、5-三氟代甲基或其他5-替换的尿嘧啶和胞嘧啶;以及核苷酸类似物,如6-氮杂尿嘧啶。
可以化学修饰RNAs,如双链RNAs(dsRNAs)。此类化学修饰的实例包括,但不限于:硫代磷酸核苷酸间连接、2'-脱氧核糖核苷酸、2'-O-甲基核糖核苷酸、2'-脱氧-2'-氟代核糖核苷酸、“无环”核苷酸、5'-C-甲基核苷酸和末端丙三基和/或反向的脱氧脱碱基残基并入。这些化学修饰可以保护细胞内的RNAi活性。
只要脂质体为具有脂质双层结构的闭合囊,其就可以为多层脂质体(MLV)或单层脂质体,如SUV(小单层囊)、LUV(大单层囊)或GUV(巨大单层囊)。
可在本发明的脂质体内形成脂质双层的脂质类型具体实例包括:卵磷脂(例如,二油酰基卵磷脂、二月桂酰卵磷脂、二肉豆蔻酰卵磷脂、二棕榈酰卵磷脂和二硬脂酰卵磷脂)、磷脂酰甘油(例如,二油酰基磷脂酰甘油、二月桂酰磷脂酰甘油、二肉豆蔻酰磷脂酰甘油、二棕榈酰磷脂酰甘油和二硬脂酰磷脂酰甘油)、磷脂酰乙醇胺(例如,二油酰基磷脂酰乙醇胺、二月桂酰磷脂酰乙醇胺、二肉豆蔻酰磷脂酰乙醇胺、二棕榈酰磷脂酰乙醇胺、二硬脂酰磷脂酰乙醇胺)、磷脂酰丝氨酸、磷脂酰肌糖、磷脂酸、心磷脂和可能的磷脂或它们的氢加成物;以及鞘磷脂、神经节苷脂和可能的糖脂。可以单独或以两种或多种的组合形式使用这些脂质。磷脂可以为合成的脂质、半合成的脂质或来源于蛋黄、大豆或其他的动物或植物的天然脂质(例如,蛋黄卵磷脂和大豆卵磷脂)。可以单独或以两种或多种的组合形式使用这些脂质。
为了获得脂质双层的物理或化学稳定性并调节其膜流动性,脂质双层可以包含选自以下的一个或多个成员,例如:胆固醇、胆固醇琥珀酸、羊毛甾醇、二氢羊毛甾醇、脱氢胆固醇、二氢胆固醇和可能的动物来源的甾醇类;豆甾醇、谷甾醇、菜油甾醇、菜籽甾醇和可能的植物来源的甾醇类(植物甾醇);酵母甾醇、麦角甾醇和可能的微生物来源的甾醇类;甘油、蔗糖和可能的糖类;三油酸甘油酯、三辛酸甘油酯和可能的甘油脂肪酸酯。它们的量不具体受限,但基于构成双层的脂质总量优选为5%至40%(摩尔比率),更优选为10%至30%(摩尔比率)。
脂质双层可以包含:生育酚、没食子酸丙酯、抗坏血酸棕榈酸酯、丁羟甲苯和可能的抗氧化剂;硬脂酰胺、油酰胺和可能的用于提供正电荷的带电材料;双十六烷基磷酸和可能的用于提供负电荷的带电材料;膜外在蛋白、膜内在蛋白和可能的膜蛋白。可以恰当地调节它们的量。
本发明的纳米颗粒在其表面上包含含有10至60个氨基酸的肽。当使用本发明的肽修饰所述纳米颗粒的表面时,优选修饰约1至10mol%构成纳米颗粒的总脂质。单层脂质体的脂质体表面为脂质双层的外表面,而多层脂质体的脂质体表面为最外面的脂质双层的外表面。本发明的纳米颗粒可以在除所述表面外的位置处(例如,脂质双层的内表面)包含前面提及的肽。
本发明的纳米颗粒优选包含辅助性脂质(辅助脂)。辅助性脂质的实例包括EPC(蛋卵磷脂)、DLPC(二亚油酰卵磷脂)、DMPC(二肉豆蔻酰卵磷脂)、DPPC(二棕榈酰卵磷脂)、DSPC(二硬脂酰卵磷脂)、POPC(棕榈酰油酰卵磷脂)、DOPC(二油酰卵磷脂)、DOPE(二油酰磷脂酰乙醇胺)、SOPE(硬脂酰油酰卵磷脂)等。这些脂质中,优选EPC、DOPC、DOPE和SOPE。
使用水合法的脂质体的生产性实例描述如下。
将作为脂质双层构成组分的脂质和前面提及的用疏水基团或疏水性化合物修饰的肽溶于有机溶剂中,随后通过蒸发去除有机溶剂,从而获得脂质膜。本文中使用的有机溶剂实例包括:烃类,如戊烷、己烷、庚烷和环己烷;卤代烃,如亚甲基氯和氯仿;芳香烃,如苯和甲苯;低级醇类,如甲醇和乙醇;酯类,如乙酸甲酯和乙酸乙酯;酮类,如丙酮;等等。可以单独或以两种或更多种的组合形式使用这些有机溶剂。随后,使脂质膜成水合物,并搅拌或超声处理,从而制备在它们的表面上具有前面提及的肽的纳米颗粒。
通过仅使用本发明的含有诸如硬脂酰基(优选酰基)的疏水基团的肽可以制备胶束。在这种情形下,肽还用作颗粒成型组分。通过使用本发明的肽结合诸如可形成胶束的磷脂或表面活性剂的其他组分也可以制备胶束。
关于磷脂,可以使用上面列出的可形成脂质体的磷脂和辅助性脂质。关于表面活性剂(阴离子、非离子和阳离子),可以使用以下物质。
阴离子型表面活性剂的实例包括:磺酸盐,如烷基磺酸盐、链烷烃磺酸盐、烷基苯磺酸盐、α-烯烃磺酸盐、磺基琥珀酸盐和磺基琥珀酸酯(例如,二辛基钠和月桂醇聚醚磺基琥珀酸酯二钠)、羟乙磺酸盐、酰基羟乙磺酸盐(例如,2-月桂酰氧乙烷磺酸钠)和脂肪酸的磺烷基酰胺,尤其是N-酰基甲基牛磺酸;硫酸盐,如烷基硫酸盐、乙氧基烷基硫酸盐、硫酸化单甘油酯、硫酸化烷醇酰胺及硫酸化脂和油;羧化物,如具有12个或更多个碳原子碳链长度的烷基羧化物、酰基肌氨酸盐、肌氨酸盐(例如,十二烷基肌氨酸钠)、乙氧基钠羧酸盐、羧酸和盐(例如,油酸钾和月桂酸钾)、醚羧酸;乙氧基羧酸和盐,如羧甲基烷基乙氧化钠;磷酸酯和盐(例如,卵磷脂);酰基谷氨酸盐(例如,正月桂酰谷氨酸二钠)以及它们的混合物。
非离子型表面活性剂的实例包括:聚氧乙烯,如乙氧基脂肪醇、乙氧基醇类(例如,辛氧乙烯乙二醇单十六烷基醚、C16E8和C12E8)、乙氧基脂肪酸、乙氧基脂肪胺、乙氧基酰胺、乙氧基烷醇酰胺和乙氧基烷基酚类;磷酸三酯类(例如,二油烯基磷酸钠);烷基酰胺二乙胺;烷基酰胺丙基甜菜碱(例如,椰油酰胺丙基甜菜碱);胺氧化物衍生物,如烷基二甲基胺氧化物、烷基二羟基乙胺氧化物、烷基酰胺二甲胺氧化物和烷基酰胺二羟基乙胺氧化物;聚羟基衍生物,如多元醇酯和醚类(例如,蔗糖一油酸、十六十八酰葡萄糖苷、β-辛基呋喃葡萄糖苷酯、具有10至16个碳原子碳链长度的烷基葡萄糖苷)、单、二和聚甘油醚及聚甘油酯(例如,四甘油单月硅酸酯和四甘油单甘油酯及三甘油一油酸酯(如Grinsted生产的TS-T122)、二甘油一油酸酯(如Grinsted生产的TST-T101))和乙氧基甘油酯;单甘油酯,如油酸单甘油酯和亚油酸单甘油酯;以及二甘油酯脂肪酸,如二甘油单异硬脂酸盐。
阳离子型表面活性剂的实例包括:脂肪族-芳香族季铵卤化物;季铵烷基酰胺衍生物;烷基酰胺丙基二甲基乳酸铵;烷基酰胺丙基二羟基乙基乳酸铵;烷基酰胺丙基吗啉乳酸盐等。
可以按如下方法制备本发明的脂质体形式的纳米颗粒。
将作为脂质双层构成组分的脂质溶于有机溶剂中,随后通过蒸发去除有机溶剂,从而得到脂质膜。使该脂质膜成水合物,并搅拌或超声处理来制造纳米颗粒。随后,将前面提及的用疏水基团或疏水化合物修饰的肽加入到纳米颗粒的外部液体中。从而可以将肽引入到每个纳米颗粒的表面上。
在制备纳米颗粒中,可以恰当地改变阳离子脂质(EtOH溶液)/辅助性脂质(EtOH溶液)/Chol(EtOH溶液)的比率。当将PEG用于修饰时,恰当地调整了PEG的比率。例如,可基于脂质的总量按0.1至15mol%的量加入PEG。
本发明的纳米颗粒可以封装待递送至细胞内的目标物质。
当目标物质为水溶性时,将其加入到制备纳米颗粒期间使脂质膜成水合物时使用的水溶剂中;从而可以将目标物质封装在纳米颗粒的水相中。当为脂溶性时,将目标物质加入到制备纳米颗粒时间使用的有机溶剂中;从而可以将目标物质封装在纳米颗粒的脂质双层中。如本文中所用,术语“封装”指以下两种情形:将目标物质包含到诸如纳米颗粒的中空颗粒内,和将目标物质携带于表面作为载体,如脂质双层。只要其为脊椎动物,目标物质被递送到的生物物种是不受限的。优选哺乳动物。哺乳动物的实例包括:人、猿、牛、绵羊、山羊、马、猪、兔、狗、猫、大鼠、小鼠、豚鼠等。
可以以分散态使用本发明的纳米颗粒。作为分散溶剂,可以使用缓冲溶液,如生理盐水溶液、磷酸盐缓冲溶液、柠檬酸盐缓冲溶液或醋酸缓冲溶液。为了分散,可以加入添加剂,如糖类、多元醇、水溶性聚合物、非离子型表面活性剂、抗氧化剂、pH调节物和水合促进剂。
还可以以干燥的分散态(例如,冷冻干燥的或喷雾干燥的)使用本发明的纳米颗粒。可以将干燥的纳米颗粒加入到诸如生理盐水溶液、磷酸盐缓冲溶液、柠檬酸盐缓冲溶液或醋酸缓冲溶液的缓冲溶液中,来制备分散态。
可在体外和体内使用纳米颗粒。当体内使用纳米颗粒时,给予途径可以为,例如,静脉内注射、静脉内滴注等。可以根据封装在本发明每个纳米颗粒内的目标物质类型和量恰当地调整剂量和给予频率。
本发明的纳米颗粒既不会引起体重减轻也不会引起肝病,因此可以安全地给予。
实施例
以下参考生产性实施例和实施例更为详尽地描述本发明。然而,本发明的范围不限于这些实施例。
生产性实施例1
硬脂酰化肽(化合物1)的合成
化合物1:C17H35-C(O)-GGGGHGAHEHAGHEHAAGEHHAHE-NH2
使用Rink酰胺树脂(0.67mMol/g)作为起始材料,以0.1mM或0.03mM的规模,通过Fmoc固相合成法,使用氨基酸、缩合剂(HBTU/HOBt)和反应加速物(DIEA)(相对于树脂各自为4当量)合成SEQ ID NO:1(C端:CONH2)的肽。将硬脂酸(M.W.284.48)、缩合剂(HBTU/HOBt)和反应促进剂(DIEA)(相对于树脂各自为4当量)加入到树脂中来引起活化,且随后以这样的状态将所得产物加入到树脂中并在室温下反应过夜:其中氨基酸的延伸已经完成,仅留下N端游离。(HBTU:M.W.379.2;HOBt:无水的,M.W.135.1,DIEA:M.W.129.2)。反应完成后,将TFA(三氟乙酸)混合物溶液(TFA:125mL;H2O:0.25mL;苯酚:0.375g;乙二硫醇:0.125mL;及茴香硫醚:0.25mL)加入到树脂中,并在冰冷却下反应15min,在室温下反应2h,来获得粗肽。通过HPLC进行纯化,随后冻干。通过HPLC和MALDI-TOF-MS测量纯度。在以下的HPLC条件下进行分析,获得的目标产物为单峰(保留时间15.1min)。
A缓冲液:0.1%TFA/H2O;B缓冲液:0.1%TFA/乙腈;柱:SunFire C18柱,5μm,4.6x150mm;流速:1mL/min;波长:220nm。
将应用生物系统(Applied Biosystems)公司的Voyager系统用于MALDI-TOF-MS。计算的分子量:2651.8;发现的分子量:2651.73。图1显示了HPLC和MALDI-TOF-MS的结果合成规模:0.1-mM规模(分子量:2651.8);所用树脂的量:159.8mg;通过使用该树脂所得肽的理论值:283.9mg;实际获得的粗产量:183.1mg(产率:64.5%)。
生产性实施例2
减少4个AA的肽(化合物2)的合成
化合物2:C17H35-C(O)-GGGGHGAHEHAGHEHAAGEH-NH2
按生产性实施例1中所述进行合成来获得目标肽。目标肽在N端含有硬脂酰基(硬脂酸酰胺),并在C端含有CONH2。该肽具有SEQ ID NO:2的氨基酸序列。
目标硬脂酰化肽的计算的分子量:2177.3;发现的分子量:2177.9。图2显示了HPLC和MALDI-TOF-MS的结果。
合成规模:0.03-mM规模(分子量:2177.3);所用树脂的量:61.2mg;通过使用该树脂所得肽的理论值:89.3mg;实际获得的粗产量:28.3mg(31.7%的产率)。
生产性实施例3
减少8个AA的肽(化合物3)的合成
化合物3:C17H35-C(O)-GGGGHGAHEHAGHEHA-NH2
按生产性实施例1中所述进行合成来获得目标肽。目标肽在N端含有硬脂酰基(硬脂酸酰胺),并在C端含有CONH2。该肽具有SEQ ID NO:3的氨基酸序列。
目标硬脂酰化肽的计算的分子量:1782.9;发现的分子量:1782.4。图3显示了HPLC和MALDI-TOF-MS的结果。
合成规模:0.03-mM规模(分子量:1782.9);所用树脂的量:67.0mg;通过使用该树脂所得肽的理论值:80.0mg;实际获得的粗产量:51.4mg(产率:64.3%)。
生产性实施例4
杂乱肽(比较化合物)的合成
化合物4:C17H35-C(O)-GGGGHGEAHHAEGHHAEAHHGEAH-NH2
按生产性实施例1中所述进行合成来获得目标肽。目标肽在N端含有硬脂酰基(硬脂酸酰胺),并在C端含有CONH2。该肽具有SEQ ID NO:4的氨基酸序列。
目标硬脂酰化肽的计算的分子量:2651.8;发现的分子量:2651.0。图4显示了HPLC和MALDI-TOF-MS的结果。
合成规模:0.03-mM规模(分子量:2651.8);所用树脂的量:45.3mg;通过使用该树脂所得肽的理论值:80.5mg;实际获得的粗产量:31.0mg(产率:38.5%)。
实施例1:不同pH条件下的粒径和表面电势(ζ-电势)的测量结果(展示pH响应性)
(1)按如下制备脂质体。具体来说,将以8:1比率(mol比率)混合蛋黄卵磷脂(EPC)和二油酰四铵丙烷(DOTAP)制得的混合物脂质乙醇溶液分配在测试管中,并用等量的氯仿与其混合,随后在氮气流下蒸发干燥,以获得薄的脂质膜。将pH7.4的缓冲溶液加入其中,并在室温下使混合物充分水合10min。在水合完成后,使用水箱型超声装置超声处理测试管来制备脂质体(脂质浓度:10mM)。向所得脂质体悬液中以5mol%总脂质含量的量加入从生产性实施例1中获得的肽(化合物1),并孵育该混合液。静电相互作用导致所述肽接合到脂质膜表面上,并将所述肽的硬脂酰基移到(插入)膜脂质的疏水部分上。从而制备出表面被肽修饰的脂质体1。
(2)通过Malvern Instruments Ltd.制造的Zetasizer Nano电势分析仪测量了具有不同pH的稀释并悬浮在缓冲溶液中的脂质体1的粒径(大小)和表面电势(ζ电势)。表1显示了结果。
表1
当pH为7.4时,粒径稍小于200nm。即使当pH值减小时,也没有观察到粒径的大变化。当pH为7.4时,表面电势约为-15mV;然而,当pH为6.5时,表面电势增加到7mV。这表明由于pH的轻微变化,表面电荷从负电荷变为正电荷。
实施例2:不同pH条件下细胞摄入的测量结果(展示pH响应性)
按实施例1中的制备方法制备了脂质体,除了预先以1mol%脂质含量的量将荧光染料标记的脂质(若丹明标记的二油酰磷脂酰乙醇胺)加入到脂质溶液中。将所制备的相关脂质体加入到具有不同pH(5.5、6.0、6.5和7.4)的培养基中培养的小鼠黑色素瘤细胞(B16-F1)中,并在37°C下培养1小时。此后,从其中去除培养上层清液,并通过胰蛋白酶化收获细胞。通过流式细胞仪(FACS Caliber流式细胞仪)测量细胞中荧光染料的量(细胞摄入脂质体的量)。图5显示了结果。
当pH为7.4时,细胞摄入相关脂质体的量与未处理的细胞(未加入脂质体)的量几乎相同。相反,当pH为5.5或6.5时,大量相关脂质体被细胞摄取。具体来说,通过轻微地改变pH值(从7.4到6.5),细胞摄入相关脂质体的量得到显著增加。
此处使用共聚焦激光扫描显微镜(Zeiss LSM510META)观察细胞。图6显示了结果。当pH为7.4时,在细胞内几乎没有观察到相关脂质体的荧光(红色)。相反,当pH为6.5或5.5时,在细胞质内观察到了相关脂质体的大量荧光(蓝色为用Hoechst33342染色的核)。这还表明,通过轻微地改变pH(从7.4到6.5),细胞摄入相关脂质体的量得到明显增加。
实施例3:培养的细胞系统中的细胞内动力学观察结果(展示内含体中的pH响应性)
如实施例2中所述,将荧光标记的相关脂质体(红色)加入到具有不同pH(5.5、6.0、6.5和7.4)的培养基中培养的小鼠黑色素瘤细胞(B16-F1)中,并在37°C下培养1小时。此后,用Hoechst33342(蓝色)染色核,同时用LysoTracker Green(绿色)染色内含体和溶酶体。随后使用共聚焦激光扫描显微镜(Zeiss LSM510META)进行观察。图7显示了结果。
结果与实施例2的结果相似;具体来说,当pH为7.4时,在细胞内几乎没有观察到红色着色,表明相关脂质体没有被细胞摄取。相反,当pH为6.5或5.5时,在细胞内观察到大量的红色着色,表明许多相关脂质体被细胞摄取。红色着色没有与绿色着色重叠;几乎所有的红色着色仅为红色。这意味着相关脂质体没有保留在内含体或溶酶体内,而是逸入细胞质内。内含体和溶酶体在其内具有低pH环境。考虑到这一点,表明存在可能性即相关脂质体被改变而与例如内含体膜或溶酶体膜融合,从而从内含体或溶酶体中逸出。这证实相关脂质体具有响应内含体和溶酶体内pH变化而从内含体和溶酶体中逸出的能力。
实施例4:患癌小鼠肿瘤的动力学(展示肿瘤内的pH响应性)
将0.2mL含有荧光染料(CellTracker CM-DiI(红色))的相关脂质体以0.5%脂质含量(脂质浓度:10mM)的浓度,或作为对照将0.2mL含有与以上类似的CellTracker CM-DiI的聚乙二醇(PEG)修饰的脂质体以0.5%脂质含量(脂质组成:EPC:胆固醇:PEG2000修饰的二硬脂酰磷脂酰乙醇胺=1.85:1:0.15;脂质浓度:10mM)的浓度,经尾静脉进行静脉内注射到患有通过B16-F1细胞皮下移植形成的生长至100mm3大小肿瘤的患癌无毛小鼠体内。此后,切除并冷冻分割肿瘤。用4%多聚甲醛处理冷冻切片来固定组织,随后使用抗-CD31抗体(抗内皮细胞标记蛋白的抗体)作为第一抗体进行处理。随后,使用荧光染料(Alexa488(绿色))标记的抗体作为第二抗体进行另外的处理来免疫标记固定的组织。此外,将相同的固定的组织包埋于(embedded)含有细胞核染料(DAPI)的Vectashield封片剂中。用共聚焦激光扫描显微镜观察由此获得的包埋并固定的组织。表8显示了结果。
在肿瘤组织中等量地观察到了两种脂质体(红色)。这表明相关脂质体与PEG具有大体上相同的长血液循环性能,尽管相关脂质体没有被PEG包覆。此外,观察到了许多PEG脂质体(红色)与绿色(黄色)在一起;这表明PEG脂质体被置于血管内和血管周围。从而假设PEG脂质体可能被从肿瘤组织漏出。相反,关于相关脂质体,观察到红色远离绿色单独存在,这表明相关脂质体位于远离血管的地方,即,深入肿瘤组织内。这表明相关脂质体可能保留在肿瘤内(具有优异的寻靶效果)。
实施例5:不同pH条件下单独的肽或肽修饰的纳米颗粒的CD光谱(展示pH响应性和膜结构基质的必要性)
将单独的生产性实施例1中获得的肽和实施例1中获得的脂质体1(各自具有20μM的肽浓度)悬浮在具有不同pH的PBS(-)中,并将CD(圆二色性)光谱记录在J-720WI分光偏振计(JASCO公司制造)上。随后,用分析软件(见JWSSE-480;Molecular Membrane Biology,July,August2007;24(4):282-293)预测广谱中二级结构的组成。图9显示了结果。
在以下的图9中,“α螺旋”表示α螺旋结构;“卷曲”表示无规则卷曲结构(不形成清晰的二级结构);且“转角”表示弯曲结构。
根据单独使用肽得到的结果,pH值为7.4和6.5时得到的CD光谱几乎相同,且pH为6.0时的光谱改变很大。这证实当单独使用肽时,结构改变不会发生,除非pH被降低到6.0。
考虑到脂质体1的CD光谱,pH为7.4时脂质体1的光谱与单独使用肽得到的光谱不同。因此表明由于肽位于脂质膜上,二级结构的状态与单独使用肽时的状态不同。此外,pH从7.4到6.5的改变造成了CD光谱的巨大变化,其结果几乎与pH值为6.0和5.5时得到的结果相同。这澄清了由于小的pH改变,位于脂质体1上的肽经历了大的结构变化这一事实。从而证实诸如脂质体或胶束的颗粒或膜结构对于确保肽对小pH改变的敏感性是必需的。
实施例6:关于具有杂乱序列的肽和关于不同长度的肽的pH响应性评估结果(粒径、ζ-电势、细胞摄取等)
(1)如实施例1的制备方法中所述,将生产性实施例2至4的硬脂酰化肽加入到分别的各自以8:1比率(摩尔比率)含有EPC和DOTAP的脂质体悬浮液中,并孵育该混合物,从而制备肽修饰的脂质体2至4,它们各自的表面被用分别的肽进行了修饰。
(2)通过Malvern Instruments Ltd.制造的Zetasizer Nano电势分析仪测量稀释并悬浮在不同pH的缓冲溶液中的每个肽修饰的脂质体的粒径(大小)和表面电势(ζ电势)。
表2显示了使用生产性实施例4的肽得到的肽修饰的脂质体4的结果。
表2
不具有以His起始并以酸性氨基酸终止的单元重复的脂质体4在所有pH下具有正表面电势。因此,脂质体4在它们的性能方面与本发明的脂质体完全不同。
通过FACS评估了脂质体4的细胞摄入。当pH为7.4时,大量的脂质体4被细胞摄取;甚至当pH被降低到6.5时,几乎相同的量被细胞摄取(图10)。这些结果符合获得的关于上述表面电势的结果,表明即使具有相同的组成氨基酸,不具有以His起始并以酸性氨基酸终止的单元重复的脂质体4不对小的pH改变作出响应。
(3)如实施例1的方法所述,使用生产性实施例2的具有比生产性实施例1中得到的肽短4个残基的肽,分别以5、6和7mol%用于修饰的脂质含量的量,制备了脂质体2a、2b和2c,并测量了表面电势。结果,所有的脂质体都显示与脂质体1类似的倾向(表3)。
表3
肽(缩短4个残基的)修饰的脂质体
(肽修饰:5mol%脂质含量)
肽(缩短4个残基的)修饰的脂质体
(肽修饰:6mol%脂质含量)
此外,通过FACS评估了细胞摄入。结果,当pH为7.4时,所有这些脂质体的细胞摄入的量几乎与涉及未处理细胞的情形下的量相同,即,几乎没有脂质体被细胞摄取;然而,当pH为6.5时,细胞摄入的量增加。
这证实即使当用缩短4个残基的肽修饰脂质体时,它们也会响应小的pH改变,从而显著地增加它们对细胞的亲和力。
(4)此外,如实施例1的方法中所述,使用生产性实施例3的具有比生产性实施例1的肽短8个残基的肽,分别以5、7.5和10mol%用于修饰的脂质含量的量,制备脂质体3a、3b和3c,并测量了每个脂质体的表面电势(表4)。
表4
肽(缩短8个残基的)修饰的脂质体
(肽修饰:5mol%脂质含量)
肽(缩短8个残基的)修饰的脂质体
(肽修饰:7.5mol%脂质含量)
肽(缩短8个残基的)修饰的脂质体
(肽修饰:10mol%脂质含量)
结果,所有这些脂质体在7.4和6.5的pH值之间都显示表面电势的大差异。具体来说,其中10mol%脂质含量被修饰的脂质体3c具有巨大的表面电势。
Claims (15)
1.包含肽和颗粒成型组分的纳米颗粒,其中
所述颗粒成型组分形成脂质体或胶束,且
所述肽具有含有2至8个单位的序列,其中每个所述单位以His(组氨酸)起始并以酸性氨基酸终止,且其中每个所述单位为相同的或不同的。
2.如权利要求1所述的纳米颗粒,其中每个所述单位在所述His和所述酸性氨基酸之间具有2至5个氨基酸。
3.如权利要求1或2所述的纳米颗粒,其中每个所述单位在所述His和所述酸性氨基酸之间具有3个氨基酸。
4.如权利要求2或3所述的纳米颗粒,其中所述His和所述酸性氨基酸之间的氨基酸为选自以下的任意氨基酸:Gly、Ala、His、Leu、Ile、Val、Phe、Tyr、Trp、Cys、Met、Ser、Thr、Gln和Asn。
5.如权利要求4所述的纳米颗粒,其中在所述His和所述酸性氨基酸之间的氨基酸为选自以下的任意氨基酸:Gly、Ala、His、Cys、和Ser。
6.如权利要求1至5中任一项所述的纳米颗粒,其中所述肽包含2至8个由以下式(I)表示的单位:
His-(AA1)(AA2)(AA3)-Glu/Asp (I),
其中His为组氨酸;Glu/Asp为谷氨酸或天冬氨酸;且AA1、AA2和AA3为相同的或不同的,各自表示Gly、Ala、His、Leu、Ile、Val、Phe、Tyr、Trp、Cys、Met、Ser、Thr、Gln或Asn,以及
其中每个单位的氨基酸序列为相同的或不同的。
7.如权利要求6所述的纳米颗粒,其中所述肽具有SEQ ID Nos:1至3中任一个的序列。
8.如权利要求1至7中任一项所述的纳米颗粒,其中所述肽在末端具有疏水基团以便被所述脂质体或胶束保留。
9.如权利要求8所述的纳米颗粒,其中所述疏水基团为C12-24烃基或C12-24酰基。
10.如权利要求1至9中任一项所述的纳米颗粒,其中所述颗粒成型组分含有磷脂。
11.如权利要求1至10中任一项所述的纳米颗粒,其中所述颗粒成型组分形成脂质体。
12.物质导入剂,其包含权利要求1至11中任一项所述的纳米颗粒。
13.由以下式(II)表示的肽化合物:
R1-(Z1)l-[His-(AA1)(AA2)(AA3)-Glu/Asp]n-(Z2)m-R2 (II),
其中His为组氨酸;Glu/Asp为谷氨酸或天冬氨酸;AA1、AA2和AA3为相同的或不同的,且各自表示Gly、Ala、His、Leu、Ile、Val、Phe、Tyr、Trp、Cys、Met、Ser、Thr、Gln或Asn;n表示2至8的整数;l和m为相同的或不同的,且各自表示0或1;R1为C12-24烃基或C12-24酰基;R2为OH或C末端保护基团;且Z1或Z2表示由选自以下氨基酸中1至8个氨基酸组成的连接臂:Gly、Ala、Leu、Ile、Val、Phe、Tyr、Trp、Cys、Met、Ser、Thr、Gln和Asn,
所述肽化合物总共含有10至60个氨基酸。
14.如权利要求13所述的肽化合物,其中式(II)表示的肽化合物中的肽具有SEQ ID Nos:1至3中任一个的序列。
15.如权利要求13或14所述的肽化合物,其中R1为C12-24酰基。
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