TW201620552A - 含ｎ－乙醯葡萄胺糖鏈基之化合物、藥劑輸送用載體化合物、製劑及藥劑輸送系統 - Google Patents

含ｎ－乙醯葡萄胺糖鏈基之化合物、藥劑輸送用載體化合物、製劑及藥劑輸送系統 Download PDF

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TW201620552A
TW201620552A TW104116215A TW104116215A TW201620552A TW 201620552 A TW201620552 A TW 201620552A TW 104116215 A TW104116215 A TW 104116215A TW 104116215 A TW104116215 A TW 104116215A TW 201620552 A TW201620552 A TW 201620552A
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acetylglucosamine
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Hirohiko Ise
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Somar Corp
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Abstract

提供一種容易到達露出波形蛋白(vimentin)或韌帶素(desmin)系之蛋白質的細胞、部位，且與辨識N-乙醯葡萄胺糖鏈之蛋白質之結合性優異的含N-乙醯葡萄胺糖鏈基之化合物、由該化合物組成之藥劑輸送用載體化合物及使用該藥劑輸送用載體化合物之製劑，以及藥劑輸送系統。一種含N-乙醯葡萄胺糖鏈基之化合物、由該化合物組成之藥劑輸送用載體化合物、使用該藥劑輸送用載體化合物之製劑，以及藥劑輸送系統，該含N-乙醯葡萄胺糖鏈基之化合物之特徵在於重量平均分子量為15,000~100,000之範圍。

Description

含N-乙醯葡萄胺糖鏈基之化合物、藥劑輸送用載體化合物、製劑及藥劑輸送系統
本發明係關於一種含N-乙醯葡萄胺糖鏈基之化合物、藥劑輸送用載體化合物、製劑及藥劑輸送系統，詳細而言，係關於一種容易到達露出波形蛋白(vimentin)或韌帶素(desmin)系之蛋白質的細胞、部位，且與辨識N-乙醯葡萄胺糖鏈之蛋白質之結合性優異的含N-乙醯葡萄胺糖鏈基之化合物、由該化合物組成之藥劑輸送用載體化合物、使用該載體化合物之製劑，以及藥劑輸送系統。
一直以來，對於因動脈硬化或形成血栓而導致冠狀動脈血管狹窄之缺血性心臟病患者，實施向血管插入氣球或支架而擴張狹窄部位之介入性治療(intervention treatment)。
此時，氣球或支架於狹窄部分磨擦而使血管內皮細胞剝離，造成傷害。其結果為，於血管引起發炎，引發位於其傷害部位之內皮下的平滑肌細胞或心肌細胞之異常增生造成的內膜肥厚或新的血栓形成，而使血管再度狹窄。因此，必須實施如下之繁複而為患者負擔之大規模處理：將塗佈有用於抗發炎或防止肥厚或防止血栓等藥物之持續釋放性(sustained release)製劑的線圈插入至此部位，防止再度狹窄等。
又，過度纖維化引起病理性障礙及組織之功能不完整的纖維 化障礙等各種纖維性障礙(fibrotic disorders)，係因纖維性組織以異常之形式累積於組織內而發生。此纖維性組織亦會自外科手術或外傷或創傷以外之障礙過程而產生，例如肝硬化、肝臟纖維化、絲球體腎炎、肺纖維化、硬皮病、心肌纖維化、心肌梗塞後之纖維化、發作後或神經退化性障礙(阿茲海默症等)後之中樞神經系統纖維化、增生性玻璃體視網膜病變(PVR)、再狹窄(血管形成術後等)及關節炎等慢性之病症。
於上述症狀等之治療(抑制、預防或回復)時，期望有能夠對 心臟或血管或纖維化之傷害部位特別地輸送該等藥物之簡便的系統。作為藥物輸送系統，在非專利文獻1記載有作為導入糖鏈之藥物輸送(drug delivery)材料之新成醣蛋白(neoglycoprotein)與微脂體的複合體，又於非專利文獻2，記載有於肝細胞作為特異性之基因輸送劑的聚乙亞胺與阿拉伯半乳聚糖之複合體。然而，該等並無與心臟或血管之傷害部位的特異結合性。
提出有製造下述藥物時使用轉化酶抑制物，該藥物係用以局 部地應用於創傷或纖維化障礙之部位，用以減少創傷治癒中之疤痕形成，或減少纖維化情形之治療中的纖維化(參考專利文獻1)。進而，關於藥物輸送劑等，提出有如下化合物：具有與存在於受到因缺血等引起之障礙的心肌細胞或血管平滑肌細胞、骨骼肌母細胞(skeletal myoblast)等中之波形蛋白或韌帶素等之特定蛋白質的特異性相互作用之化合物，例如露出N-乙醯葡萄胺糖類，或經由塗布於膠體粒子表面之己二酸類及衍生物(adipic acid analogues and derivatives)而結合有N-乙醯葡萄胺糖類之藥物輸送劑。又，提出使用有如下藥劑輸送用載體化合物之藥劑輸送系統等，該藥劑輸送用載體化合物具有對在內部具有藥物之脂質膜具有親和性之第1區域，與和 上述第1區域結合而且含有自帶磁性有機分子之第2區域。
[專利文獻1]日本特開2005-535674號公報(專利申請範圍其他)
[專利文獻2]日本特開2007-1923號公報(專利申請範圍其他)
[專利文獻3]日本特開2009-46413號公報(專利申請範圍其他)
[專利文獻4]日本特開2013-63926號公報(專利申請範圍其他)
[非專利文獻1]Noboru Yamazaki, Yoshifumi Jigami, Hans-Joachim Gabius, and Shujikojima, Trends in Glycoscience and Glycotechnology, Vol. 13, No. 71, pp.319-329(May 2001)
[非專利文獻2]M. Nogawa, T. Ishihara, T. Akaike, and A. Maruyama, S.T.P.PharmaScience, Vol.11, No.1, pp97-102 (2001)
於上述專利文獻1記載之發明中，並無將轉化酶抑制物運送至特定部位之方法，而是使用對部位直接應用，或是盡可能直接送達部位之類的方法(例如於肺之創傷治癒之情形時，用作吸入劑)。然而，此方法中，由於轉化酶抑制物並非應用於局部者而成全身用藥(whole body dministration)，但轉化酶抑制物之全身用藥為有害，故欠佳。又，上述專利文獻2及3中，雖使用N-乙醯葡萄胺糖類作為藥劑輸送劑，但難以到達露出波形蛋白或韌帶素系之辨識N-乙醯葡萄胺糖的蛋白質之細胞、部位，又，即使藥劑到達亦不與辨識N-乙醯葡萄胺糖鏈的蛋白質結合，或難以 結合等，於功能方面尚未滿足。
因此，本發明之目的在於提供一種容易到達露出波形蛋白或 韌帶素系之蛋白質的細胞、部位，且與辨識N-乙醯葡萄胺糖鏈之蛋白質之結合性優異的含N-乙醯葡萄胺糖鏈基之化合物、由該化合物組成之藥劑輸送用載體化合物、使用該藥劑輸送用載體化合物之製劑及藥劑輸送系統。
本發明人為了解決上述課題努力進行研究，結果發現，藉由 將具有N-乙醯葡萄胺糖鏈基之化合物的重量平均分子量調整至特定之範圍，可解決上述課題，從而完成本發明。
即，本發明之含N-乙醯葡萄胺糖鏈基之化合物的特徵在於：重量平均分子量為15,000~100,000之範圍。
本發明之含N-乙醯葡萄胺糖鏈基之化合物較佳為聚合物。
本發明之含N-乙醯葡萄胺糖鏈基之化合物，較佳於每一分子具有27~175個該N-乙醯葡萄胺糖鏈基。
本發明之含N-乙醯葡萄胺糖鏈基之化合物較佳為生物素化合物。
本發明之含N-乙醯葡萄胺糖鏈基之化合物較佳於末端結合有3-巰基丙酸(3-mercaptopropionic acid)
本發明之藥劑輸送用載體化合物之特徵在於：由上述含N-乙醯葡萄胺糖鏈基之化合物構成。
本發明之製劑之特徵在於：上述藥劑輸送用載體化合物載持有治療劑、螢光劑及造影劑中之至少一種藥劑，且該N-乙醯葡萄胺糖鏈 基露出於表面。
本發明之藥劑輸送用載體化合物之特徵在於：為該N-乙醯葡萄胺糖鏈基露出於表面之膠體狀粒子
本發明之製劑之特徵在於：該藥劑輸送用載體化合物之該膠體狀粒子中，含有治療劑、螢光劑及造影劑中之至少一種藥劑。
本發明之藥劑輸送系統之特徵在於：使上述含N-乙醯葡萄胺糖鏈基之化合物結合於治療劑、螢光劑及造影劑中之至少一種藥劑的表面，藉由露出於表面之N-乙醯葡萄胺糖鏈基將該藥劑誘導至目標之患部區域。
本發明之藥劑輸送系統之特徵在於：使表面結合有上述含N-乙醯葡萄胺糖鏈基之化合物的膠體狀粒子中含有治療劑、螢光劑及造影劑中之至少一種藥劑，藉由露出於表面之N-乙醯葡萄胺糖鏈基將該該膠體狀粒子中的藥劑誘導至目標之患部區域。
根據本發明，可提供一種容易到達露出波形蛋白或韌帶素系之蛋白質的細胞、部位，且與辨識N-乙醯葡萄胺糖鏈之蛋白質之結合性優異的含N-乙醯葡萄胺糖鏈基之化合物、由該化合物組成之藥劑輸送用載體化合物、使用該藥劑輸送用載體化合物之製劑及藥劑輸送系統。
[圖1]係評價比較例2之含N-乙醯葡萄胺糖鏈基之化合物與固定化於金表面之波形蛋白的結合之感應圖譜(sensorgram)。
[圖2]係評價比較例3之含N-乙醯葡萄胺糖鏈基之化合物與固定化於金表面之波形蛋白的結合之感應圖譜。
[圖3]係評價實施例1之含N-乙醯葡萄胺糖鏈基之化合物與固定化於金表面之波形蛋白的結合之感應圖譜。
[圖4]係評價比較例4之含N-乙醯葡萄胺糖鏈基之化合物與固定化於金表面之波形蛋白的結合之感應圖譜。
[圖5]係表示經FITC標記之比較例1的含N-乙醯葡萄胺糖鏈基之化合物所產生之HeLa細胞的染色度之圖。
[圖6]係表示經FITC標記之比較例2的含N-乙醯葡萄胺糖鏈基之化合物所產生之HeLa細胞的染色度之圖。
[圖7]係表示經FITC標記之比較例3的含N-乙醯葡萄胺糖鏈基之化合物所產生之HeLa細胞的染色度之圖。
[圖8]係表示經FITC標記之實施例1的含N-乙醯葡萄胺糖鏈基之化合物所產生之HeLa細胞的染色度之圖。
[圖9]係表示經FITC標記之比較例4的含N-乙醯葡萄胺糖鏈基之化合物所產生之HeLa細胞的染色度之圖。
本發明之含N-乙醯葡萄胺糖鏈基之化合物之特徵在於：重量平均分子量為15,000~100,000之範圍，具有N-乙醯葡萄胺糖鏈基。若重量平均分子量未達15,000，則與波形蛋白及韌帶素等辨識N-乙醯葡萄胺糖的蛋白質之結合性低。又，若重量平均分子量超過100,000，則向所欲之細胞、部位之到達率降低。上述重量平均分子量就合成性或產率及藥劑到達率之方面而言，較佳為16,000~50,000之範圍，更佳為16,500~40,000之範圍，進而較佳為17,000~30,000之範圍。再者，作為習知之含N-乙醯葡 萄胺糖鏈基之化合物，使用有幾丁二糖於N-乙醯葡萄胺末端結合之乙烯系樹脂(例如專利文獻2之實施例1)，其重量平均分子量為120,000左右。又，亦使用有將幾丁二糖與生物素結合而得之含N-乙醯葡萄胺糖鏈基的化合物(分子量700左右)結合於載體而得之藥物輸送劑的膠體(例如專利文獻3之實施例13)。
作為本發明之含N-乙醯葡萄胺糖鏈基之化合物中的N-乙醯葡萄胺糖鏈基，例如可列舉N-乙醯葡萄糖胺基，或結合有2~6個N-乙醯葡萄糖胺基之幾丁聚糖基(chitopolyose group)，即，幾丁二糖基、幾丁三糖基、幾丁四糖基、幾丁五糖基、幾丁六糖基。其中，較佳為N-乙醯葡萄糖胺基及幾丁二糖基，更佳為幾丁二糖基。
作為N-乙醯葡萄胺糖鏈基之具體例，可舉幾丁二糖基之化學式，但本發明並非限定於此。
關於本發明之含N-乙醯葡萄胺糖鏈基之化合物，較佳於每一分子具有27~175個N-乙醯葡萄胺糖鏈基，更佳為29~88個，再更佳為30~70個，尤佳為30~50個。
本發明之含N-乙醯葡萄胺糖鏈基之化合物，為了與波型蛋白與韌帶素等之辨識N-乙醯葡萄胺的蛋白質作用而具有N-乙醯葡萄胺 糖鏈基，對於根據目的適當選擇之化合物，能夠導入N-乙醯葡萄胺糖鏈基而得。本發明之化合物更佳為如下化合物：將具有N-乙醯葡萄胺糖鏈基之單體聚合而得之聚合物，或使N-乙醯葡萄胺糖結合於聚合物等之高分子化合物而成之化合物。本發明之化合物較佳為聚合物。
本發明之含N-乙醯葡萄胺糖鏈基之化合物從與載體之吸附性之觀點而言，亦可具有疏水性基。
含N-乙醯葡萄胺糖鏈基之化合物之製造方法並無特別限定。例如作為將上述之具有N-乙醯葡萄胺糖鏈基之單體聚合而獲得之聚合物的製造方法，可舉於N-乙醯葡萄胺糖鏈之還原末端，將結合有具有苯乙烯化合物等疏水性基的化合物之聚合物聚合的方法。做為更詳細之製造方法，可舉將作為具有疏水性基的化合物之乙烯基苄胺的胺基藉幾丁二糖而還原性地胺化，藉此得到導入有N-乙醯葡萄糖胺基之苯乙烯系單體後，使該單體聚合而製造之方法等。又，作為上述高分子化合物結合有N-乙醯葡萄胺糖之化合物之製造方法，可舉於N-乙醯葡萄胺糖鏈之還原末端將具有作為陽離子性聚合物之聚乙烯亞胺或具有poly-L-lysine等之疏水性基之聚合體化合物結合之方法等。
此處，使N-乙醯葡萄胺糖鏈與化合物結合之方法並無特別限定，例如可將具有胺基之化合物的胺基與N-乙醯葡萄胺糖鏈之還原末端利用還原胺化法進行結合。又，亦可使以羧基取代N-乙醯葡萄胺糖鏈之羥基，利用1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide，EDC)偶合法等，與具有胺基之化合物的胺基結合。
又，上述將聚合物聚合之方法並無特別限定，例如藉由活性 自由基聚合法或利用鍊轉移劑之聚合法等而可獲得。作為具體例，可將作為N-乙醯葡萄胺糖鏈之幾丁二糖，與作為具有疏水性基之化合物之乙烯基苄基鄰苯二甲醯亞胺(vinylbenzyl phthalimide)以莫耳比1：1之比例混合而製造單體，於DMF、DMSO或水等溶液中藉由自由基聚合獲得poly[N-p-vinylbenzyl-0-2-acetoamid-2-deoxy-β-D-glucopyranosyl-(1→4)-2-acetoamide-2-deoxy-β-D-gluconamide](PCGIcNAc)。使用鍊轉移劑之聚合法中，於聚合時改變巰基丙酸等之鍊轉移劑相對於單體的混合比，進行聚合，藉此可製造分子量受到控制之聚合物。
本發明之含N-乙醯葡萄胺糖鏈基之化合物，亦可為含有N -乙醯葡萄胺糖鏈基之生物素化合物。含有N-乙醯葡萄胺糖鏈基之生物素化合物之製造，可藉由下述方式進行：將含N-乙醯葡萄胺糖鏈基之化合物以弱酸處理而製造醛基，使具有肼基之生物素反應。
[藥劑輸送用載體化合物]
本發明之藥劑輸送用載體化合物係由本發明之含N-乙醯葡萄胺糖鏈基之化合物構成者。本發明之藥劑輸送用載體化合物可僅由上述含N-乙醯葡萄糖胺基之化合物構成，亦可為使用於藥劑輸送之載體等之其他材料，例如使含N-乙醯葡萄胺糖鏈基之化合物結合於膠體狀粒子之表面者。作為膠體狀粒子，例如可列舉金、鉑、銀、磁性物、陶瓷等之金屬或無機粒子，源自聚乙二醇、聚苯乙烯、丙烯酸系樹脂、聚乳酸、聚己內酯、聚羥基烷酯(polyhydroxyalkanoate)、聚乙醇酸(polyglycolic acid)、改質聚乙烯醇、酪蛋白、改質澱粉及纖維素、蛋白質等合成或天然物之樹脂粒子、脂質體 等。將含N-乙醯葡萄胺糖鏈基之化合物結合於膠體狀粒子之表面之方法並無特別限定。例如於膠體狀粒子為金粒子之情形時，可藉由將硫醇基導入至含N-乙醯葡萄胺糖鏈基之化合物，向金膠體之表面進行共價鍵結而結合。又，於聚乳酸之情形時，藉由混合溶解有含N-乙醯葡萄糖胺基之化合物之溶液與聚乳酸，將含N-乙醯葡萄胺糖鏈基之化合物塗佈於聚乳酸粒子之表面而結合。進而於脂質體之情形時，藉由將於含N-乙醯葡萄胺糖鏈基之化合物導入有烷基者塗佈於脂質體表面而結合。
關於膠體狀粒子之粒徑，其質量平均粒徑較佳為5~800nm 之範圍。若此粒徑未達5nm，則難以將含N-乙醯葡萄糖胺基之化合物結合，未附加有N-乙醯葡萄糖胺基之粒子於生物體內迅速被排泄，故欠佳。 又，若粒徑超過800nm，則會經由吞噬細胞等而作為生物體中的異物被排除，故欠佳。自向粒子表面之N-乙醯葡萄胺基之負荷性及藥劑輸送性之方面而言，較佳為7~500nm，尤佳為10~300nm之範圍。將粒徑控制於此範圍內，選擇性而有效率地僅到達血管傷害部位之產生於細胞間的間隙或於血管內露出之平滑肌細胞等之細胞或部位，變得容易被取入於細胞、部位。
[製劑]
本發明之製劑之特徵在於：上述藥劑輸送用載體化合物載持有治療劑、螢光劑及造影劑中之至少一種藥劑，且上述N-乙醯葡萄胺糖鏈基露出於表面。又，本發明之其他製劑之特徵在於：上述藥劑輸送用載體化合物係N-乙醯葡萄胺糖鏈基露出於表面之膠體狀粒子，於上述膠體狀粒子中含有治療劑、螢光劑及造影劑中之至少一種之藥劑。若投予該等之本發 明之製劑，則藉由血液循環到達露出波型蛋白或韌帶素等辨識N-乙醯葡萄胺糖鏈之蛋白質的細胞、部位。若如此則藥劑輸送用載體化合物之N-乙醯葡萄胺糖鏈基與辨識N-乙醯葡萄胺糖鏈之蛋白質互相作用而吸引接近，附著而侵入至此細胞。其後，上述藥劑自製劑中滲出而釋放，被細胞吸收，發出螢光或造影而表現藥效。
關於螢光劑，例如可列舉螢光異硫氰酸鹽(FITC)、活細胞染 色用色素Calcein-AM(同人化學研究所股份有限公司製造；商品名)。關於造影劑，例如可舉核磁共振影像診斷用釓化合物。關於治療劑，例如可列舉血管內皮細胞增生促進劑、血管平滑肌細胞增生抑制劑、抗發炎劑、抗癌劑、抗風濕劑等。
[藥劑輸送系統]
本發明之藥劑輸送系統之特徵在於：於螢光劑、造影劑及治療劑中之至少一種藥劑的表面結合有本發明之化合物，而藉由在表面露出之N-乙醯葡萄胺糖鏈基，將上述藥劑誘導至患部區域。又，本發明之其他藥劑輸送系統之特徵在於：使表面結合有本發明之化合物的膠體狀粒子中含有治療劑、螢光劑及造影劑中之至少一種藥劑，藉由露出於表面之N-乙醯葡萄胺糖鏈基將上述膠體狀粒子中之上述藥劑誘導至目標之患部區域。
本發明之含N-乙醯葡萄胺糖鏈基之化合物、藥劑輸送用載 體化合物、使用該藥劑輸送用載體化合物之藥劑以及藥劑輸送系統，由於相較於以往之藥劑輸送系統能夠有效率地到達所欲之細胞、部位(露出波型蛋白或韌帶素系之蛋白質的細胞、部位)，故能以較至今之藥劑輸送系統所使用的藥劑量更少量使藥劑效率佳地到達所欲之部位，其結果能夠獲得高 藥劑效果。因此，本發明之含N-乙醯葡萄胺糖鏈基之化合物、藥劑輸送用載體化合物、製劑及藥劑輸送系統對於醫療領域，尤其是檢查、診斷、治療有效。
實施例
以下使用實施例更詳細地說明本發明，但本發明並非限定於該等之實施例者。
(單體之製作)
將幾丁二糖(0.5g)溶解於甲醇(20mL)，添加1.425g之碘。滴加4%KOH直到碘之茶色消失。其後，藉乙醚再結晶化後，將結晶物溶解於水而藉離子交換樹脂(Amberlite IR-120)精製chitobionic acid。使用WSC(水溶性碳二亞胺)將chitobionic acid縮合於乙烯基苄胺。藉氯仿將所製作之單體沉澱精製。其後，將沉澱物溶解於水而進行冷凍乾燥。
[比較例1：含N-乙醯葡萄胺糖鏈基之化合物(PV-GlcNAc；重量平均分子量9,300)之製造]
於上述所獲得之單體0.185mmol混合3-巰基丙酸0.00185mmol，以及終濃度成為5%之量之偶氮二異丁腈(azobisisobutyronitrile，AIBN)，溶解於500μL之二甲基亞碸(DMSO)。將此溶液於65℃之油浴中進行18小時織培養而聚合。18小時後，溶解於水而進行一日一夜之透析。透析後，進行冷凍乾燥。
[比較例2：含N-乙醯葡萄胺糖鏈基之化合物(PV-GlcNAc；重量平均分子量11,000)之製造]
於上述所獲得之單體0.185mmol混合0.0009mmol MPA以及終濃度成為 5%之量之AIBN，溶解於500μL之二甲基亞碸(DMSO)。將此溶液於65℃之油浴中進行18小時織培養而聚合。18小時後，溶解於水而進行一日一夜之透析。透析後，進行冷凍乾燥。
[比較例3：含N-乙醯葡萄胺糖鏈基之化合物(PV-GlcNAc；重量平均分子量14,000)之製造]
於上述所獲得之單體0.185mmol混合0.00037mmol MPA以及終濃度成為5%之量之AIBN，溶解於500μL之二甲基亞碸(DMSO)。將此溶液於65℃之油浴中進行18小時織培養而聚合。18小時後，溶解於水而進行一日一夜之透析。透析後，進行冷凍乾燥。
[實施例1：含N-乙醯葡萄胺糖鏈基之化合物(PV-GlcNAc；重量平均分子量17,000)之製造]
於上述所獲得之單體0.185mmol混合0.000185mmol MPA以及終濃度成為5%之量之AIBN，溶解於500μL之二甲基亞碸(DMSO)。將此溶液於65℃之油浴中進行18小時織培養而聚合。18小時後，溶解於水而進行一日一夜之透析。透析後，進行冷凍乾燥。
[比較例4：含N-乙醯葡萄胺糖鏈基之化合物(PV-GlcNAc；重量平均分子量120,000)之製造]
於上述所獲得之單體0.185mmol混合終濃度成為5%之量之AIBN，溶解於500μL之二甲基亞碸(DMSO)。將此溶液於65℃之油浴中進行18小時織培養而聚合。18小時後，溶解於水而進行一日一夜之透析。透析後，進行冷凍乾燥。
各種物性值之測量方法及各特性之評價方法如下所示。將所 獲得之結果示於表1。
(1)與辨識N-乙醯葡萄胺糖鏈之蛋白質(波型蛋白)的相互作用
將波型蛋白之N-乙醯葡萄胺糖鏈結合域之重組蛋白質固定化於感應晶片(sensor chip)，使用奇異醫療公司製造之BIACORE-J，藉由表面電漿共振研究含N-乙醯葡萄胺糖鏈基之化合物向波型蛋白之相互作用。自所獲得之感應圖譜，觀察感應圖譜，藉由目視，比較感應圖譜之最大值而相對地判斷相互作用之程度。
(2)解離常數(KD(M))
準備含N-乙醯葡萄胺糖鏈基之化合物之5種濃度系列(concentration series)(0.5μg/ml、1μg/ml、2.5μg/ml、5μg/ml、10μg/ml 5種)，藉奇異醫療公司製造之BIACORE-J對固定於金表面之波型蛋白與所準備之含N-乙醯葡萄胺糖鏈基之化合物的結合(分子間相互作用)進行研究。自各濃度之感應圖譜的結果算出含N-乙醯葡萄胺糖鏈基之化合物之解離常數。將比較例2、比較例3、實施例1及比較例4之含N-乙醯葡萄胺糖鏈之化合物的感應圖譜之結果各自示於圖1~4(關於比較例3，未測量0.5μg/ml)。縱軸表示共振單元，橫軸表示時間(秒)，該等之圖顯示各濃度之化合物相對於波型蛋白的反應性。隨著成為高濃度，反應性上升。自使含N-乙醯葡萄胺糖鏈基之化合物於波型蛋白反應後120秒(比較例為60秒)為止表示與波型蛋白之結合，120秒(比較例為60秒)以後，表示來自波型蛋白之含N-乙醯葡萄胺糖鏈基之化合物的解離。自該等反應過程算出解離常數。再者，關於比較例2，0.5μg/ml幾乎沒有變化，自解離常數之計算加 以排除。
(3)與FITC-PV-GlcNAc之相互作用
使經FITC標記之含N-乙醯葡萄胺糖鏈基之化合物(FITC-PV-GlcNAc)以4μg/ml於5×105cells/ml之HeLa細胞懸浮液500μL進行反應。反應於4℃進行30分。其後，進行離心，再懸浮於PBS，將其細胞染色藉由流式細胞儀(GUAVA easyCyte，Millipre公司製)進行流式細胞測量，研究FITC-PV-GlcNAc引起的HeLa細胞之染色。將比較例1、比較例2、比較例3、實施例1及比較例4之含N-乙醯葡萄胺糖鏈基之化合物的流式細胞測量之結果各自示於圖5~9。縱軸表示細胞數，橫軸表示螢光強度。塗滿之直方圖係作為負控制組而使FITC-PV-A反應者，中空之直方圖係表示於FITC-PV-GlcNAc反應之HeLa細胞團。
(4)重量平均分子量
使用高速GPC(gel permeation chromatography)裝置(東曹公司製，HLC-8220GPC)以下述條件測量各材料之重量平均分子量。以管柱使用TSK gel G6000PWxL-CP+G5000PWxL-CP+3000PWxL-CP，溶液使用200mM硝酸鈉/乙腈=80/20進行。以流量為1mL/min，檢測器為RI檢測器，管柱溫度為40℃進行。分子量之標準曲線以聚三葡萄糖施行。
表中之「-」表示無法測量。
自該等結果，得知實施例的含N-乙醯葡萄胺糖鏈基之化合物與辨識N-乙醯葡萄胺糖鏈之蛋白質的相互作用優異，又，容易到達HeLa細胞中之辨識N-乙醯葡萄胺糖鏈之蛋白質。由該等情形，得知若藉由使用有本發明之含N-乙醯葡萄胺糖鏈基之化合物的藥劑輸送劑載體，能夠選擇性地使藥劑到達所欲之細胞及部位。又，得知若藉由使用有本發明之化合物之藥劑輸送系統，能夠效率佳地使藥劑到達所欲之細胞、部位以外的細胞、部位。

Claims (11)

  1. 一種含N-乙醯葡萄胺糖鏈基之化合物，其重量平均分子量為15,000~100,000之範圍。
  2. 如申請專利範圍第1項之含N-乙醯葡萄胺糖鏈基之化合物，其為聚合物。
  3. 如申請專利範圍第1項之含N-乙醯葡萄胺糖鏈基之化合物，其中，每一分子具有該N-乙醯葡萄胺糖鏈基27~175個。
  4. 如申請專利範圍第1項之含N-乙醯葡萄胺糖鏈基之化合物，其係生物素化合物。
  5. 如申請專利範圍第2項之含N-乙醯葡萄胺糖鏈基之化合物，其末端結合有3-巰基丙酸(3-mercaptopropionic acid)。
  6. 一種藥劑輸送用載體化合物，其由申請專利範圍第1~5項中任一項之含N-乙醯葡萄胺糖鏈基之化合物構成。
  7. 如申請專利範圍第6項之藥劑輸送用載體化合物，其為於表面露出有該N-乙醯葡萄胺糖鏈基之膠體狀粒子。
  8. 一種製劑，其中，申請專利範圍第6項之藥劑輸送用載體化合物載持有治療劑、螢光劑及造影劑中之至少一種藥劑，且該N-乙醯葡萄胺糖鏈基露出於表面。
  9. 一種製劑，其中，於申請專利範圍第7項之藥劑輸送用載體化合物之該膠體狀粒子中，含有治療劑、螢光劑及造影劑中之至少一種藥劑。
  10. 一種藥劑輸送系統，使申請專利範圍第1~5項中任一項之含N-乙醯葡萄胺糖鏈基之化合物結合於治療劑、螢光劑及造影劑中之至少一種藥 劑的表面，藉由露出於表面之N-乙醯葡萄胺糖鏈基將該藥劑誘導至目標之患部區域。
  11. 一種藥劑輸送系統，其使於表面結合有申請專利範圍第1~5項中任一項之含N-乙醯葡萄胺糖鏈基之化合物的膠體狀粒子中含有治療劑、螢光劑及造影劑中之至少一種藥劑，藉由露出於表面之N-乙醯葡萄胺糖鏈基將該該膠體狀粒子中的藥劑誘導至目標之患部區域。
TW104116215A 2014-05-21 2015-05-21 含ｎ－乙醯葡萄胺糖鏈基之化合物、藥劑輸送用載體化合物、製劑及藥劑輸送系統 TWI723951B (zh)

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