CN106459259B - 含n-乙酰葡糖胺糖链基化合物、药剂输送用载体化合物、制剂、及药剂输送系统 - Google Patents

含n-乙酰葡糖胺糖链基化合物、药剂输送用载体化合物、制剂、及药剂输送系统 Download PDF

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CN106459259B
CN106459259B CN201580026100.4A CN201580026100A CN106459259B CN 106459259 B CN106459259 B CN 106459259B CN 201580026100 A CN201580026100 A CN 201580026100A CN 106459259 B CN106459259 B CN 106459259B
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acetylglucosamine
drug delivery
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glycosyl
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伊势裕彦
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Abstract

本发明提供容易到达波形蛋白、结蛋白系的蛋白质露出的细胞·部位，并且，与N‑乙酰葡糖胺糖链识别蛋白的结合性优异的含N‑乙酰葡糖胺糖链基化合物、包含该化合物的药剂输送用载体化合物及使用了该药剂输送用载体化合物的制剂、及药剂输送系统。特征是重均分子量为15000～100000的范围的含N‑乙酰葡糖胺糖链基化合物、包含该化合物的药剂输送用载体化合物、使用了该药剂输送用载体化合物的制剂、及药剂输送系统。

Description

含N-乙酰葡糖胺糖链基化合物、药剂输送用载体化合物、制 剂、及药剂输送系统
技术领域
本发明涉及含N-乙酰葡糖胺糖链基化合物、药剂输送用载体化合物、制剂、及药剂输送系统，详细而言，涉及容易到达波形蛋白、结蛋白系的蛋白质露出的细胞·部位、并且与N-乙酰葡糖胺糖链识别蛋白的结合性优异的含N-乙酰葡糖胺糖链基化合物、包含该化合物的药剂输送用载体化合物、使用了该载体化合物的制剂、及药剂输送系统。
背景技术
以往，对由动脉硬化、血栓形成导致的冠状动脉血管狭窄的缺血性心脏病的患者实施向血管插入球囊、支架而使狭窄部位扩张的介入治疗。
此时，球囊、支架在狭窄部分摩擦而使血管内皮细胞剥离，从而带来伤害。其结果，在血管中引起炎症，或者引起由位于该伤害部位的内皮下的平滑肌细胞、心肌细胞的异常增生导致的内膜肥厚、新的血栓形成而再次使血管狭窄。因此，必须实施如下的繁杂且患者负担大的处理：将涂布有用于抗炎症、防止肥厚、防止血栓等的药物的缓释制剂的线圈插入到该部位来防止再狭窄等。
另外，过度纤维化引起病理性疾病及组织的功能障碍的纤维性疾病等各种纤维性疾病，是由于纤维性组织在组织内以异常的形态蓄积而发生的。该纤维性组织也会由于外科手术、外伤或者除创伤以外的疾病过程而产生，例如也可以举出肝硬化、肝脏纤维化、肾小球肾炎、肺纤维化、硬皮症、心肌纤维化、心肌梗塞后的纤维化、发作后或神经退行性疾病(阿尔茨海默病等)后的中枢神经系统纤维化、增生性玻璃体视网膜病变(PVR)、再狭窄(血管成形术后等)及关节炎等慢性病症。
在前述症状等的治疗(抑制、防止或者恢复)时，期望能够向心脏、血管或者纤维化的伤害部位特异性地输送它们的药物的简便的系统。作为药物输送系统，非专利文献1中记载了作为糖链导入药物传输材料的拟糖蛋白(Neoglycoprotein)与脂质体的复合体，另外，非专利文献2中记载了作为对肝细胞特异的基因输送剂的聚乙烯亚胺与阿拉伯半乳聚糖的复合体。但是，它们没有与心脏、血管的伤害部位的特异结合性。
提出了在如下的药品的制造中使用转化酶抑制剂(convertase inhibitor)：所述药品为局部应用于创伤或纤维性疾病的部位且用于减少创伤治愈中的斑痕形成、或减少纤维性情况的治疗中的纤维化的药物(参照专利文献1)。进而，关于药物输送剂等，提出了具有与存在于因缺血等而产生疾病的心肌细胞、血管平滑肌细胞、骨格肌成肌细胞等中的波形蛋白、结蛋白等特定蛋白质的特异性相互作用的化合物，例如N-乙酰葡糖胺类露出、或者借助包覆在胶体颗粒表面的抗生素蛋白(avidin)类而结合有N-乙酰葡糖胺类的药物输送剂(参照专利文献2及3)。另外，提出了使用如下的药剂输送用载体化合物的药剂输送系统等：所述药剂输送用载体化合物具有对内部具有药物的脂质膜有亲和性的第1区域、和与前述第1区域结合而且包含自带磁性有机分子的第2区域(参照专利文献4)。
现有技术文献
专利文献
专利文献1：日本特开2005-535674号公报(权利要求书及其它)
专利文献2：日本特开2007-1923号公报(权利要求书及其它)
专利文献3：日本特开2009-46413号公报(权利要求书及其它)
专利文献4：日本特开2013-63926号公报(权利要求书及其它)
非专利文献
非专利文献1：Noboru Yamazaki,Yoshifumi Jigami,Hans-Joachim Gabius,andShujiKojima,Trends in Glycoscience and Glycotechnology,Vol.13,No.71,pp.319-329(May 2001)
非专利文献2：M.Nogawa,T.Ishihara,T.Akaike,and A.Maruyama,S.T.P.PharmaSciences,Vol.11,No.1,pp97-102(2001)
发明内容
发明要解决的问题
在前述专利文献1中记载的发明中，没有将转化酶抑制剂输送到预定部位的方法，使用了向部位直接应用、或者在可能的范围内直接送达的方法(例如肺的创伤治愈的情况下，作为吸入剂使用)。但是，该方法中，由于转化酶抑制剂不是局部应用的物质，因此成为全身给药，但转化酶抑制剂的全身给药是有害的，因此不优选。另外，在前述专利文献2及3中，作为药物输送剂，使用了N-乙酰葡糖胺类，但难以到达波形蛋白、结蛋白系的N-乙酰葡糖胺识别蛋白露出的细胞·部位，另外，即使药剂到达，也不与N-乙酰葡糖胺糖链识别蛋白结合、或者难以结合等，在性能方面尚未得到满足。
因此，本发明的目的在于，提供容易到达波形蛋白、结蛋白系的蛋白质露出的细胞·部位、并且与N-乙酰葡糖胺糖链识别蛋白的结合性优异的含N-乙酰葡糖胺糖链基化合物、包含该化合物的药剂输送用载体化合物、使用了该药剂输送用载体化合物的制剂、及药剂输送系统。
用于解决问题的方案
本发明人为了解决上述问题进行了深入研究，结果发现，通过将具有N-乙酰葡糖胺糖链基的化合物的重均分子量调整至特定的范围，能够解决上述问题，完成了本发明。
即，本发明的含N-乙酰葡糖胺糖链基化合物的特征在于，重均分子量在15000～100000的范围。
本发明的含N-乙酰葡糖胺糖链基化合物优选为聚合物。
本发明的含N-乙酰葡糖胺糖链基化合物优选每1分子中具有27～175个前述N-乙酰葡糖胺糖链基。
本发明的含N-乙酰葡糖胺糖链基化合物优选为生物素化合物。
本发明的含N-乙酰葡糖胺糖链基化合物优选在末端结合有3-巯基丙酸。
本发明的药剂输送用载体化合物的特征在于，包含前述含N-乙酰葡糖胺糖链基化合物。
本发明的制剂的特征在于，前述药剂输送用载体化合物负载治疗剂、荧光剂及造影剂中的至少1种药剂，并且前述N-乙酰葡糖胺糖链基在表面露出。
本发明的药剂输送用载体化合物的特征在于，是前述N-乙酰葡糖胺糖链基在表面露出的胶体状颗粒。
本发明的制剂的特征在于，在前述药剂输送用载体化合物的前述胶体状颗粒中含有治疗剂、荧光剂及造影剂中的至少1种药剂。
本发明的药剂输送系统的特征在于，使前述含N-乙酰葡糖胺糖链基化合物结合在治疗剂、荧光剂及造影剂中的至少1种药剂的表面，通过露出在表面的N-乙酰葡糖胺糖链基将前述药剂诱导到目标患部区域。
本发明的药剂输送系统的特征在于，使表面结合有前述含N-乙酰葡糖胺糖链基化合物的胶体状颗粒中含有治疗剂、荧光剂及造影剂中的至少1种药剂，通过露出在表面的N-乙酰葡糖胺糖链基将前述胶体状颗粒中的前述药剂诱导到目标患部区域。
发明的效果
根据本发明，能够提供容易到达波形蛋白、结蛋白系的蛋白质露出的细胞·部位、并且与N-乙酰葡糖胺糖链识别蛋白的结合性优异的含N-乙酰葡糖胺糖链基化合物、包含该化合物的药剂输送用载体化合物、使用了该药剂输送用载体化合物的制剂、及药剂输送系统。
附图说明
图1为评价比较例2的含N-乙酰葡糖胺糖链基化合物与固定于金表面的波形蛋白的结合的传感图。
图2为评价比较例3的含N-乙酰葡糖胺糖链基化合物与固定于金表面的波形蛋白的结合的传感图。
图3为评价实施例1的含N-乙酰葡糖胺糖链基化合物与固定于金表面的波形蛋白的结合的传感图。
图4为评价比较例4的含N-乙酰葡糖胺糖链基化合物与固定于金表面的波形蛋白的结合的传感图。
图5为示出基于FITC标记了的比较例1的含N-乙酰葡糖胺糖链基化合物的HeLa细胞的染色度的图。
图6为示出基于FITC标记了的比较例2的含N-乙酰葡糖胺糖链基化合物的HeLa细胞的染色度的图。
图7为示出基于FITC标记了的比较例3的含N-乙酰葡糖胺糖链基化合物的HeLa细胞的染色度的图。
图8为示出基于FITC标记了的实施例1的含N-乙酰葡糖胺糖链基化合物的HeLa细胞的染色度的图。
图9为示出基于FITC标记了的比较例4的含N-乙酰葡糖胺糖链基化合物的HeLa细胞的染色度的图。
具体实施方式
本发明的含N-乙酰葡糖胺糖链基化合物是具有如下特征的化合物：重均分子量在15000～100000的范围，具有N-乙酰葡糖胺糖链基。若重均分子量小于15000，则对波形蛋白、结蛋白等N-乙酰葡糖胺识别蛋白结合性低。另外，若超过100000，则向期望的细胞·部位的药剂到达率降低。从合成性、收率及药剂到达率的方面出发，前述重均分子量优选在16000～50000的范围、更优选在16500～40000的范围、进一步优选在17000～30000的范围。需要说明的是，作为以往的含N-乙酰葡糖胺糖链基化合物，使用在N-乙酰葡糖胺末端结合有壳二糖的乙烯基系树脂(例如专利文献2的实施例1)，其重均分子量为120000左右。另外，还使用了将由壳二糖和生物素结合而得到的含N-乙酰葡糖胺糖链基化合物(分子量700左右)结合到载体上而得到的药物输送剂的胶体(例如专利文献3的实施例13)。
作为本发明的含N-乙酰葡糖胺糖链基化合物中的N-乙酰葡糖胺糖链基，例如可以举出N-乙酰葡糖胺基、结合有2～6个N-乙酰葡糖胺基的壳聚糖基、即壳二糖基、壳三糖基、壳四糖基、壳五糖基、壳六糖基。其中，优选N-乙酰葡糖胺基及壳二糖基、更优选壳二糖基。
作为N-乙酰葡糖胺糖链基的具体例，可举出壳二糖基的化学式，但本发明不限定于此。
Figure BDA0001157977030000061
本发明的含N-乙酰葡糖胺糖链基化合物优选每1分子中具有27～175个前述N-乙酰葡糖胺糖链基、更优选为29～88个、进一步优选为30～70个、特别优选为30～50个。
对于本发明的含N-乙酰葡糖胺糖链基化合物，为了与波形蛋白、结蛋白等N-乙酰葡糖胺识别蛋白作用而具有N-乙酰葡糖胺糖链基，可以通过对根据目的适宜选择的化合物导入N-乙酰葡糖胺糖链基而获得。本发明的化合物更优选为使具有N-乙酰葡糖胺糖链基的单体聚合而得到的聚合物、使N-乙酰葡糖胺与聚合物等高分子化合物结合而得到的化合物。本发明的化合物优选为聚合物。
本发明的含N-乙酰葡糖胺糖链基化合物从与载体的吸附性的观点出发，也可以具有疏水性基团。
对含N-乙酰葡糖胺糖链基化合物的制造方法不作特别限定。例如作为使前述具有N-乙酰葡糖胺糖链基的单体聚合而得到的聚合物的制造方法，可以举出使在N-乙酰葡糖胺糖链的还原末端结合苯乙烯化合物等具有疏水性基团的化合物而得到的单体聚合的方法等。作为更详细的制造方法，可以举出如下方法等：将作为具有疏水性基团的化合物的乙烯基苄胺的氨基用壳二糖还原性地氨基化，由此得到导入了N-乙酰葡糖胺基的苯乙烯系单体之后，使该单体聚合，从而制造。另外，作为在前述高分子化合物上结合有N-乙酰葡糖胺的化合物的制造方法，可以举出在N-乙酰葡糖胺糖链的还原末端与作为阳离子性聚合物的聚乙烯亚胺、聚-L-赖氨酸等具有疏水性基团的聚合物化合物结合的方法等。
此处，对使N-乙酰葡糖胺糖链与化合物结合的方法不作特别限定，例如可以通过还原氨基化法将具有氨基的化合物的氨基与N-乙酰葡糖胺糖链的还原末端结合。另外，也可以用羧基取代N-乙酰葡糖胺糖链的羟基，通过1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDC)偶联法等与具有氨基的化合物的氨基结合。
另外，对将前述单体聚合的方法没有特别限定，例如可以通过活性自由基聚合法、利用链转移剂的聚合法等来获得。作为具体例，可以将作为N-乙酰葡糖胺糖链的壳二糖和作为具有疏水性基团的化合物的乙烯基苄基邻苯二甲酰亚胺以摩尔比计1：1的比例混合而制造单体，在DMF、DMSO或水等溶液中进行自由基聚合来获得聚[N-对乙烯基苄基-O-2-乙酰胺-2-脱氧-β-D-吡喃葡萄糖基-(1→4)-2-乙酰胺-2-脱氧-β-D-葡糖酰胺](poly[N-p-vinylbenzyl-O-2-acetoamid-2-deoxy-β-D-glucopyranosyl-(1→4)-2-a cetoamide-2-deoxy-β-D-gluconamide])(PVGlcNAc)。使用了链转移剂的聚合法中，通过在聚合时改变巯基丙酸等链转移剂相对于单体的混合比进行聚合，能够制造分子量被控制的聚合物。
本发明的含N-乙酰葡糖胺糖链基化合物可以为含N-乙酰葡糖胺糖链基生物素化合物。含N-乙酰葡糖胺糖链基生物素化合物的制造可以如下进行：将含N-乙酰葡糖胺糖链基化合物用弱酸进行处理而制作醛基，使具有肼基的生物素反应。
〔药剂输送用载体化合物〕
本发明的药剂输送用载体化合物包含本发明的含N-乙酰葡糖胺糖链基化合物。本发明的药剂输送用载体化合物可以仅由前述含N-乙酰葡糖胺糖链基化合物构成，也可以使前述含N-乙酰葡糖胺糖链基化合物结合在药剂输送中使用的载体等其它材料例如胶体状颗粒的表面。作为胶体状颗粒，例如可以举出金、铂、银、磁体、陶瓷等金属或无机颗粒、源自聚乙二醇、聚苯乙烯、丙烯酸系树脂、聚乳酸、聚己内酯、聚羟基烷酸酯、聚乙醇酸、改性聚乙烯基醇、酪蛋白、改性淀粉及纤维素、蛋白质等合成物或天然物的树脂颗粒、脂质体等。对使含N-乙酰葡糖胺糖链基化合物结合在该胶体状颗粒的表面的方法不作特别限定。例如，在胶体状颗粒为金颗粒的情况下，可以通过将硫醇基导入到含N-乙酰葡糖胺糖链基化合物，共价键合至金胶体表面来结合。另外，将在聚乳酸的情况下，可以通过将使含N-乙酰葡糖胺糖链基化合物溶解而得到的溶液与聚乳酸混合，将含N-乙酰葡糖胺糖链基化合物包覆在聚乳酸颗粒的表面来结合。进而在脂质体的情况下，可以通过将在含N-乙酰葡糖胺糖链基化合物中导入有烷基的化合物包覆在脂质体表面来结合。
对于胶体状颗粒的粒径，质均粒径优选在5～800nm的范围。若该粒径小于5nm，则难以使含N-乙酰葡糖胺基化合物结合，未附加有N-乙酰葡糖胺基的颗粒在机体中会迅速被排出，因此不优选。另外，若粒径超过800nm，则会通过吞噬细胞等作为机体中的异物而排除，因此不优选。从N-乙酰葡糖胺基对颗粒表面的负荷性及药剂输送性的方面出发，优选在7～500nm、特别优选在10～300nm的范围。通过将粒径控制在该范围内，从而选择性地有效地仅到达在血管伤害部位的细胞间产生的间隙、在血管内露出的平滑肌细胞等细胞或部位，变得容易进入到细胞·部位。
〔制剂〕
本发明的制剂的特征在于，前述药剂输送用载体化合物负载治疗剂、荧光剂及造影剂中的至少1种药剂，并且，前述N-乙酰葡糖胺糖链基露出至表面。另外，本发明的又一制剂的特征在于，前述药剂输送用载体化合物为N-乙酰葡糖胺糖链基露出至表面的胶体状颗粒，在前述胶体状颗粒中含有治疗剂、荧光剂及造影剂中的至少1种药剂。若给药所述本发明的制剂，则通过血液循环到达露出有波形蛋白、结蛋白等N-乙酰葡糖胺糖链识别蛋白的细胞·部位。这样，药剂输送用载体化合物的N-乙酰葡糖胺糖链基与N-乙酰葡糖胺糖链识别蛋白相互作用从而吸引接近，附着于该细胞上或侵入至该细胞。之后，前述药剂从制剂中渗出而释放，被吸收到细胞中，产生发生荧光或造影而表现药效。
荧光剂例如可以举出异硫氰酸荧光素(FITC)、活细胞染色用色素Calcein-AM(株式会社同人化学研究所制；商品名)。造影剂例如可以举出核磁共振图像诊断用钆化合物。治疗剂例如可以举出血管内皮细胞增生促进剂、血管平滑肌细胞增生抑制剂、抗炎症剂、抗癌剂、抗风湿剂。
〔药剂输送系统〕
本发明的药剂输送系统的特征在于，使本发明的化合物结合在荧光剂、造影剂及治疗剂中的至少1种药剂的表面，通过露出至表面的N-乙酰葡糖胺糖链基将前述药剂诱导到患部区域。另外，本发明的又一药剂输送系统的特征在于，使表面结合有本发明的化合物的胶体状颗粒中含有治疗剂、荧光剂及造影剂中的至少1种药剂，通过露出至表面的N-乙酰葡糖胺糖链基将前述胶体状颗粒中的前述药剂诱导到目标患部区域。
本发明的含N-乙酰葡糖胺糖链基化合物、药剂输送用载体化合物、使用了该药剂输送用载体化合物的药剂、及药剂输送系统由于与以往的药剂输送系统相比能够使药剂有效地到达期望的细胞·部位(波形蛋白、结蛋白系的蛋白质露出的细胞·部位)，因此能够以比迄今为止的药剂输送系统中使用的药剂量少的量有效地使药剂到达期望部位，结果能够得到高的药剂效果。因此，本发明的含N-乙酰葡糖胺糖链基化合物、药剂输送用载体化合物、制剂、及药剂输送系统对医疗领域、特别是对检查·诊断·治疗是有效的。
实施例
以下，用实施例更详细地对本发明进行说明，但本发明不限定于这些实施例。
(单体的制作)
将壳二糖(0.5g)溶解于甲醇(20mL)，添加1.425g的碘。滴加4％KOH直至碘的褐色消失。然后，用二乙醚再结晶后，将结晶物溶解于水，通过离子交换树脂(Amberlite IR-120)对壳二糖酸(chitobionic acid，
Figure BDA0001157977030000101
)进行纯化。使用WSC(水溶性碳二亚胺)使壳二糖酸缩合于乙烯基苄胺中。用氯仿将所制作的单体沉淀纯化。然后，将沉淀物溶解于水，进行冻干。
[比较例1：含N-乙酰葡糖胺糖链基化合物(PV-GlcNAc；重均分子量9，300)的制作]
在上述得到的单体0.185mmol中混合0.00185mmol的3-巯基丙酸(MPA)、及最终浓度成为0.5％的量的偶氮二异丁腈(AIBN)，溶解于500μL的二甲基亚砜(DMSO)。将该溶液在65℃的油浴中进行18小时培养而进行聚合。18小时后，溶解于水中，进行一昼夜的透析。透析后，进行冻干。
[比较例2：含N-乙酰葡糖胺糖链基化合物(PV-GlcNAc；重均分子量11000)的制作]
在上述得到的单体0.185mmol中混合0.0009mmol的MPA、及最终浓度成为0.5％的量的AIBN，溶解于500μL的DMSO。将该溶液在65℃的油浴中进行18小时培养而进行聚合。18小时后，溶解于水中，进行一昼夜的透析。透析后，进行冻干。
[比较例3：含N-乙酰葡糖胺糖链基化合物(PV-GlcNAc；重均分子量14000)的制作]
在上述得到的单体0.185mmol中混合0.00037mmol的MPA、及最终浓度成为0.5％的量的AIBN，溶解于500μL的DMSO。将该溶液在65℃的油浴中进行18小时培养而进行聚合。18小时后，溶解于水中，进行一昼夜的透析。透析后，进行冻干。
[实施例1：含N-乙酰葡糖胺糖链基化合物(PV-GlcNAc；重均分子量17000)的制作]
在上述得到的单体0.185mmol中混合0.000185mmol的MPA、及最终浓度成为0.5％的量的AIBN，溶解于500μL的DMSO。将该溶液在65℃的油浴中进行18小时培养而进行聚合。18小时后，溶解于水中，进行一昼夜的透析。透析后，进行冻干。
[比较例4：含N-乙酰葡糖胺糖链基化合物(PV-GlcNAc；重均分子量120000)的制作]
在上述得到的单体0.185mmol中以最终浓度成为0.5％的量混合AIBN，溶解于500μL的DMSO。将该溶液在65℃的油浴中进行18小时培养而进行聚合。18小时后，溶解于水中，进行一昼夜的透析。透析后，进行冻干。
将各种物性值的测定方法及各特性的评价方法示于以下。将所得结果示于表1。
(1)与N-乙酰葡糖胺糖链识别蛋白(波形蛋白)的相互作用
将波形蛋白的N-乙酰葡糖胺结合域的重组蛋白固定在传感器芯片上，使用GEHealthcare公司制BIACORE-J，通过表面等离子共振分析研究含N-乙酰葡糖胺糖链基化合物对波形蛋白的相互作用。由所得到的传感图，观察传感图，通过目视比较传感图的最大的值，对相互作用的程度进行相对的判断。
(2)解离常数(KD(M))
准备含N-乙酰葡糖胺糖链基化合物的5种浓度系列(0.5μg/ml、1μg/ml、2.5μg/ml、5μg/ml、10μg/ml这5种)，用GE Healthcare公司制BIACORE-J对固定于金表面的波形蛋白与所准备的含N-乙酰葡糖胺糖链基化合物的结合(分子间相互作用)进行研究。由各浓度的传感图的结果算出含N-乙酰葡糖胺糖链基化合物的解离常数。将比较例2、比较例3、实施例1及比较例4的含N-乙酰葡糖胺糖链化合物的传感图的结果分别示于图1～4(关于比较例3，未测定0.5μg/ml)。纵轴表示共振单位，横轴表示时间(秒)。这些图示出各浓度的化合物对波形蛋白的反应性。随着变成高浓度，反应性上升。自使含N-乙酰葡糖胺糖链基化合物与波形蛋白反应起直至120秒(比较例为60秒)，表示与波形蛋白的结合，120秒(比较例为60秒)以后表示含N-乙酰葡糖胺糖链基化合物自波形蛋白的解离。由这些反应经过算出解离常数。需要说明的是，关于比较例2，0.5μg/ml几乎没有变化，自解离常数的计算排除。
(3)与FITC-PV-GlcNAc的相互作用
使进行了FITC标记的含N-乙酰葡糖胺糖链基化合物(FITC-PV-GlcNA c)以4μg/mL在5×105cells/mL的HeLa细胞悬浮液500μL中反应。反应在4℃下进行30分钟。然后，进行离心，再悬浮于PBS中，对其细胞染色，用流式细胞仪(GUAVAeasyCyte、Millipre公司制)进行流式细胞术，对基于FI TC-PV-GlcNAc的HeLa细胞的染色进行研究。将比较例1、比较例2、比较例3、实施例1及比较例4的含N-乙酰葡糖胺糖链化合物的流式细胞术的结果分别示于图5～9。纵轴表示细胞数，横轴表示荧光强度。涂满的直方图是作为阴性对照使FITC-PV-MA作用的情况，中空的直方图表示与FITC-PV-GlcNAc反应的HeLa细胞群。
(4)重均分子量
用高速GPC装置(TOSOH CORPORATION制、HLC-8220GPC)，在以下条件下测定各材料的重均分子量。在色谱柱使用TSKgelG6000PWxL-CP+G5000PWxL-CP+3000PWxL-CP、洗脱液为200mM硝酸钠/乙腈＝80/20下进行。在流量为1mL/分钟、检测器为RI检测器、柱温度为40℃下进行。分子量的标准曲线用普鲁兰多糖(Pullulan)来制作。
[表1]
Figure BDA0001157977030000141
表中的“-”表示无法测定。
由这些结果可知，实施例的含N-乙酰葡糖胺糖链基化合物与N-乙酰葡糖胺糖链识别蛋白的相互作用优异，另外，容易到达HeLa细胞中的N-乙酰葡糖胺糖链识别蛋白。由此可知，通过使用了本发明的含N-乙酰葡糖胺糖链基化合物的药剂输送剂载体，能使药剂选择性地到达期望的细胞及部位。另外可知，通过使用了本发明的化合物的药剂输送系统，能使药剂有效地到达期望的细胞·部位。

Claims (9)

1.一种含N-乙酰葡糖胺糖链基化合物，其特征在于，重均分子量在15000～17000的范围，所述含N-乙酰葡糖胺糖链基化合物为生物素化合物，每1分子所述含N-乙酰葡糖胺糖链基化合物中具有27～70个所述N-乙酰葡糖胺糖链基。
2.根据权利要求1所述的含N-乙酰葡糖胺糖链基化合物，其特征在于，为聚合物。
3.根据权利要求2所述的含N-乙酰葡糖胺糖链基化合物，其特征在于，在末端结合有3-巯基丙酸。
4.一种药剂输送用载体化合物，其特征在于，包含权利要求1～3中任一项所述的含N-乙酰葡糖胺糖链基化合物。
5.根据权利要求4所述的药剂输送用载体化合物，其特征在于，是所述N-乙酰葡糖胺糖链基在表面露出的胶体状颗粒。
6.一种制剂，其特征在于，权利要求4所述的药剂输送用载体化合物负载治疗剂、荧光剂及造影剂中的至少1种药剂，并且所述N-乙酰葡糖胺糖链基在表面露出。
7.一种制剂，其特征在于，在权利要求5所述的药剂输送用载体化合物的所述胶体状颗粒中含有治疗剂、荧光剂及造影剂中的至少1种药剂。
8.一种药剂输送系统，其特征在于，使权利要求1～3中任一项所述的含N-乙酰葡糖胺糖链基化合物结合在治疗剂、荧光剂及造影剂中的至少1种药剂的表面，通过露出至表面的N-乙酰葡糖胺糖链基将所述药剂诱导到目标患部区域。
9.一种药剂输送系统，其特征在于，使表面结合有权利要求1～3中任一项所述的含N-乙酰葡糖胺糖链基化合物的胶体状颗粒中含有治疗剂、荧光剂及造影剂中的至少1种药剂，通过露出至表面的N-乙酰葡糖胺糖链基将所述胶体状颗粒中的所述药剂诱导到目标患部区域。
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