CN100563734C - 吸附免疫抑制物质的材料、体外循环柱以及癌症的治疗方法 - Google Patents
吸附免疫抑制物质的材料、体外循环柱以及癌症的治疗方法 Download PDFInfo
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Abstract
本发明提供吸附免疫抑制物质的材料,所述吸附材料可从体液中直接、高效、选择性吸附被认为与癌细胞的增殖有关的过量的免疫抑制物质,且可安全地进行体外循环,进而可对癌症的治疗发挥作用。即本发明是以将亲水性氨基固定在水不溶性载体为特征的免疫抑制吸附材料。本发明还提供以填充了本发明的吸附材料为特征的体外循环柱。本发明又提供癌症的治疗方法,其特征在于使用本发明的体外循环柱进行体外循环。
Description
技术领域
本发明涉及吸附免疫抑制物质的材料、体外循环柱以及癌症的治疗方法。
背景技术
即使在医学发达的今日,癌症依然是人类主要的死亡原因之一.癌细胞不会因抗癌药的治疗或放射线治疗而完全除去,即使通过手术除去,在有转移灶的进行性癌症患者体内仍有癌细胞残留.
不能完全排除癌细胞的主要原因被认为是免疫抑制物质。本来,机体应该具有排除癌细胞的癌特异性杀伤细胞这样的免疫机能。而免疫抑制物质虽然其中也有存在于健康人的血液中,担负着调节免疫作用的功能的物质,但随着癌的进行,免疫抑制物质异常增加,阻碍癌特异性杀伤细胞的诱导或机能表达,抑制对癌细胞的免疫机能,结果助长了癌细胞的增殖.
已知免疫抑制物质有转化生长因子β(已知有1-5,以下总括简称为TGFβ.)、免疫抑制酸性蛋白、癌胚抗原、白细胞介素6、肿瘤坏死因子(TNF)等免疫抑制蛋白,前列腺素E2,B细胞、巨噬细胞等细胞(藤原大美著、肿瘤免疫学、89-112页、中外医学社、1998年)。
因此,如果除去了免疫抑制物质,则有望提高患者的免疫力,抑制癌细胞的增殖或使肿瘤消退。
有人尝试通过血浆置换来除去免疫抑制酸性蛋白、癌胚抗原等免疫抑制物质(例如参照非专利文献1)。另外,为减少置换液,也尝试了采用将双重过滤膜血浆分离装置与吸附低分子区域的免疫抑制因子的氨基玻璃珠制的吸附体组合起来的装置来除去免疫抑制物质(例如参照非专利文献2)。另外也尝试了血浆置换与抗癌药环磷酰胺的联合疗法(例如参照非专利文献3)。但是,治疗效果并不足够。其主要原因可能是吸附材料的吸附能力不足。另外血浆置换的除去效率低,还存在着由血浆供体感染疾病的风险。
有文献公开了具有疏水性配体的物质作为TGFβ吸附材料(参照专利文献1)。但是,正如该文献中记载的,该技术是以分子量约25,000的所谓活性型TGFβ为对象的吸附材料,对于分子量10万或30万的所谓潜在型TGFβ则毫无记载,另外通常同种化合物之间,分子量越高则越难以被吸附材料吸附。
还有文献公开了通过羟基磷灰石吸附或解吸血液中的TGFβ1,来分析活性型分子的技术(参照专利文献2-4),但这也涉及到活性型TGFβ。
免疫抑制酸性蛋白是分子量为5万左右的蛋白质,在临床上被用作癌的恶性程度的标志。曾尝试通过活性炭柱除去(参照非专利文献4),但由于吸附能力不足而未实现实际应用。另外,活性炭容易产生粉末,不适合作为体外循环这样直接与血液接触的用途.
还有尝试通过固定了内毒素——革兰阴性细菌的脂多糖的纤维进行体外循环,激活血液,治疗癌症(参照非专利文献5、专利文献5-9),但该纤维不是吸附材料,是细胞激活材料。并且并未言及免疫抑制物质的吸附。
专利文献10、11中公开了固定了亲水性胺的纤维,但这是涉及内毒素的吸附的材料,并未言及免疫抑制物质的吸附,另外并不是以治疗癌症为目的。
[非专利文献1]
峠等人、《癌症治疗中的血浆置换疗法的意义》、Biotherapy、2卷、1988年、1019-1028页
[非专利文献2]
[非专利文献3]
[非专利文献4]
O.Ishiko等人、癌症患者血清中的免疫抑制物质的除去、Jpn JCancer Res,81,564-566,(1990)
[非专利文献5]
T.Tani等人、新型的抗癌纤维在患癌兔血液灌注中的功效和生物适合性(Efficancy and Biocompatibility of a Nobel Anti-CancerFiber in Hemoperfusion on Cancer-Bearing Rabbits),Therapeutic Apheresis,6(2),167-172,(2000)
[专利文献1]
日本特开2001-218840号公报
[专利文献2]
日本特开平7-31875号公报
[专利文献3]
日本特开平8-193997号公报
[专利文献4]
日本特开平9-80042号公报
[专利文献5]
日本特开昭59-64053号公报
[专利文献6]
日本特开昭59-211458号公报
[专利文献7]
日本特开昭60-2258号公报
[专利文献8]
日本特开昭60-12071号公报
[专利文献9]
日本特开昭60-89425号公报
[专利文献10]
日本特开昭60-197703号公报
[专利文献11]
日本特开昭60-195455号公报
发明内容
本发明提供吸附免疫抑制物质的材料,所述材料可从体液中直接、高效、选择性吸附被认为与癌细胞的增殖有关的过量的免疫抑制物质,且可安全地进行体外循环;进而实现对癌症的治疗发挥作用的目的。
即,本发明提供吸附免疫抑制物质的材料,其特征在于将亲水性氨基固定在水不溶性载体上而制成.
本发明还提供体外循环柱,其特征在于填充了本发明的吸附材料。
本发明又提供癌症的治疗方法,其特征在于使用本发明的体外循环柱进行体外循环。
实施发明的最佳方式
本发明的吸附免疫抑制物质的材料是将亲水性氨基固定于水不溶性载体上而成。关于亲水性氨基吸附免疫抑制物质的机理尚不明确,但如后述实施例所示,本发明人证实了该吸附材料可吸附各种免疫抑制物质。
“亲水性”是指本身可溶解于水的胺与聚合物呈化学键合的状态。就碳原子数来讲,是指来自每个氮原子有18个或以下的碳原子的胺。
亲水性氨基优选季铵基,尤其是来自每个氮原子有3-18个、更优选有4-14个碳原子的叔胺,因其吸附性优异而优选。所述叔胺具有烷基的具体例子有:三甲胺、三乙胺、N,N-二甲基乙胺、N,N-二甲基丙胺、N,N-二甲基丁胺、N,N-二甲基己胺、N,N-二甲基辛胺、N,N-二甲基月桂胺、N-甲基-N-乙基-己胺等。另外,可优选使用烷基包含羟基或醚基的胺,例如N,N-二甲基-6-羟基己胺或N,N-二甲基-4-甲氧基丁胺等作为用于形成亲水性氨基的亲水性胺。
将亲水性氨基固定于水不溶性载体上的量优选每个水不溶性载体的重复单元固定0.01-2.0mol,更优选0.1-1.0mol。为0.01mol或以上、更优选0.1mol或以上,则可有效地表达吸附机能。为2.0mol或以下、更优选1.0mol或以下,则可保持作为载体的物理强度。亲水性氨基的固定量可通过离子交换树脂的离子交换容量测定方法来测定。具体的方法例如可如下进行。将1g固定了亲水性氨基的水不溶性载体装柱,通入50mL 1mol/L氢氧化钠水溶液,接着,通入水洗涤,直至洗脱液不被酚酞染红.向其中通入10mL 1mol/L盐酸,再通入300mL水,用0.5mol/L氢氧化钠水溶液中和滴定洗脱的酸量。由10mmol中减去中和所需的碱量,差则为亲水性氨基的量,将其用1g固定了素水性氨基的水不溶性载体中所含的重复单元除,则可以得出上述规定范围。
水不溶性载体要采用不溶于水、可固定亲水性胺作为亲水性氨基的物质.例如来自芳族系聚合物的物质容易导入官能团,因而优选.更具体地说,芳族系聚合物有聚苯乙烯所代表的聚(芳族乙烯化合物)。另外,来自聚(对苯醚砜)或-{(对-C6H4)-C(CH3)2-(对-C6H4)-O-(对-C5H4)-SO2-(对-C6H4)-O-}n-(以下简称为UDEL(ユ-デル)聚砜)等所代表的聚砜系聚合物的物质,其成型性优良,因而优选.另外也可以是来自聚醚酰亚胺、聚酰亚胺、聚酰胺、聚醚、聚苯硫醚等聚合物的物质。另外,采用可溶解于有机溶剂的物质作为水不溶性物质,其具有容易成型的优点。
另外,聚合物中可用于固定亲水性胺的反应性官能团有卤甲基、卤代乙酰基、卤代乙酰氨基甲基,卤代烷基等活性卤代基,环氧化物基、羧基、异氰酸基、硫代异氰酸基、酸酐基等,尤其是活性卤代基中的卤代乙酰基,其容易制备,且反应性高得适当,在温和的条件下即可实现亲水性胺的固定化反应,同时由固定化反应产生的共价键具化学稳定性,因而优选。具有卤代乙酰基的聚合物的具体例子有氯乙酰氨基甲基聚苯乙烯、氯乙酰氨基甲基化UDEL聚砜、氯乙酰氨基甲基化聚醚酰亚胺等。
将亲水性氨基固定于水不溶性载体的方法有:非均匀体系反应法,使亲水性胺的溶液与预先成型的水不溶性载体接触;均匀体系反应法,将水不溶性载体的溶液与亲水性胺的溶液混合并使其反应,然后成型.
作为溶解亲水性胺的溶剂,在非均匀体系反应法中,可优选使用水、甲醇、乙醇、异丙醇等不溶解水不溶性载体,而溶解亲水性胺的溶剂。在均匀体系反应法中,可优选使用溶解水不溶性载体和亲水性胺两者的溶剂,具体有四氢呋喃、二甲基亚砜、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺、N-甲基吡咯烷酮等。
非均匀体系反应法的一个例子如下:将氯乙酰氨基甲基化聚砜的中空丝等成型品浸渍于二甲基己胺、聚亚烷基亚胺等的异丙醇溶液中,在0-100℃的温度下进行反应。均匀体系反应法的一个例子如下:将氯乙酰氨基甲基化聚砜在有机溶剂中溶解,向该溶液中加入亲水性胺,在0-100℃的温度下进行反应。为了制成可溶解于有机溶剂的水不溶性载体,添加到溶液中的亲水性胺的量相对于用于固定的反应性官能团为摩尔比1倍或以上,尤其是当为多胺时,优选以极过量的量添加.
本发明的吸附免疫抑制物质的材料可以是将固定了亲水性氨基的水不溶性载体本身成型为后述的吸附材料的形状,也可以是将固定了亲水性氨基的水不溶性载体覆于其它基材的表面而形成。
覆于其它基材的表面的形式具有可简单且成本低地制成大表面积的吸附材料的优点。该其它基材优选采用与固定了亲水性氨基的水不溶性载体粘合性良好的材料,可以使用聚酰胺、聚氨酯、聚酰亚胺、聚砜、聚氯乙烯、聚酯、聚苯硫醚、聚烯烃、聚丙烯腈、纤维素类树脂等。尼龙、聚醚酰亚胺等聚酰胺类粘合性特别好,因而尤其优选使用。被覆方法例如有干涂法,将固定了亲水性氨基或具有亲水性胺的水不溶性载体溶解于二氨甲烷或四氢呋喃等低沸点溶剂中,将例如尼龙编结物或织造物等所述其它材料浸渍于其中,然后蒸发溶剂;或者湿涂法,将固定了亲水性氨基或带有亲水性胺的水不溶性载体溶解于N,N-二甲基甲酰胺等溶剂中,将所述其它材料浸渍于其中,再加入到水等贫溶剂中.
关于本发明的吸附免疫抑制物质的材料的比表面积,每1g吸附材料为0.1m2或以上时,吸附性和吸附容量得到提高,因而优选,更优选1m2或以上。不过由于不可无限大,因此实际上是有极限的,优选100m2或以下。该比表面积可通过氮气吸附法(BET法)测定。
本发明的吸附免疫抑制物质的材料优选具有膜、纤维、粒状物、海绵状物或它们组合的形状。通过制成所述形状,可实现大的比表面积和充分的体液等透过性两方面。纤维还可以制成单纤维、棉状、针织物、织物、毡等。另外,优选纤维中制成中空纤维。通过制成中空纤维,可以制成具备过滤机能的吸附材料,可以使体外循环柱起到人工透析仪或血浆分离器的作用,同时可以除去免疫抑制物质。
本发明的吸附免疫抑制物质的材料优选其吸附对象免疫抑制物质含有免疫抑制蛋白。
进一步优选免疫脂蛋白含有选自TGFβ、免疫抑制酸性蛋白、癌胚抗原中的至少一种。
还优选TGFβ为潜在型TGFβ。TGFβ本身为分子量25000左右的蛋白质,但在血液中与其它蛋白质结合,以10万(低分子量潜在型TGFβ)或30万(高分子量潜在型TGFβ)左右的分子量存在,因此希望将它们从癌症患者的血液中有效除去.
另外,优选吸附对象的免疫抑制物质含有前列腺素E2.
另外可认为可吸附多种作为吸附对象的免疫抑制物质,这对于癌症的治疗效果来讲优选。
如下所述,本发明的吸附免疫抑制物质的材料适合用作体外循环柱.另外也可以用作从输血用血液、血清、血浆中除去免疫抑制性蛋白的目的。
本发明的体外循环柱的特征是填充了本发明的吸附免疫抑制物质的材料。这样得到了适合于通过体外循环或者通过联合使用体外循环来治疗癌症的体外循环柱。
本发明的体外循环柱的形状可以采用圆筒状、矩形、圆盘状、环形等.
填充时,从减轻患者的经济负担角度考虑,优选空隙容积为200mL左右或以下。
本发明的体外循环柱中,关于本发明的吸附免疫抑制物质的材料的填充量,例如,血液中的大多为潜在型,但以包含潜在型和活性型的TGFβ为标准物质,其吸附能力为:假设以患癌哺乳动物作为治疗对象,优选每1kg体重填充250ng或以上吸附材料.这里,吸附能力等于每1g吸附材料对潜在型TGFβ的平衡吸附量乘以柱的填充量(克数)所得。
潜在型TGFβ平衡吸附量可如下求出:向1mL患癌大鼠的血清中加入50mg吸附材料,在37℃振荡4小时,测定上清中的TGFβ浓度,将吸附前后的浓度差除以吸附材料重量(0.05g),得到潜在型TGFβ的平衡吸附量。上清中的TGFβ浓度可如下求出:用酸对血清检体进行前处理,使潜在型TGFβ游离为活性型TGFβ,然后使用市售分析试剂盒中的抗TGFβ抗体,通过酶联免疫分析法求出。
“患癌哺乳动物”是指人、猴、牛、马、狗、猫、猪、羊等陆地哺乳动物产生了癌症导致的肿瘤。
本发明的癌症的治疗方法的特征是使用本发明的体外循环柱进行体外循环。这样,可从体外循环的血液中吸附除去免疫抑制物质,抑制癌细胞的增殖,有效地治疗癌症。“治疗”除治愈之外,也广义地包括抑制进行、预防转移、提高患者的QOL等。
体外循环的具体例子如下:将连接采血用穿刺管、用于连续给予肝素或萘莫司他甲磺酸等抗凝剂输液泵的滴灌腔、血泵、滴灌腔、本发明的体外循环柱、滴灌腔、返回用穿刺导管以上述顺序、用适当粗度的软管连接,制成体外循环回路,使血液流过其中.采血和回血可对股、腕动脉或静脉穿刺进行.对于大型哺乳动物,通常可使用用于血液透析仪或吸附型血液净化器的市售的体外循环装置和血液回路。体外循环的时间为10分钟至300分钟,通常优选进行30分钟至120分钟。
如前所述,本发明的癌症的治疗方法优选以患癌哺乳动物为治疗对象,体外循环柱对TGFβ的吸附能力为每1kg该患癌哺乳动物的体重填充250ng或以上。
另外,本发明的癌的治疗方法优选与抗恶性肿瘤药的给予联合使用进行体外循环.这样可以减轻抗恶性肿瘤药的副作用,治疗癌症。
抗恶性肿瘤药的例子有以吉西他滨、氟尿嘧啶、替加氟、阿糖胞苷、甲氨蝶呤等为代表的代谢拮抗性抗恶性肿瘤药;以环磷酰胺为代表的烷基化剂;以长春新碱、长春碱、长春地辛、依托泊苷、伊立替康、多西他赛、紫杉醇等为代表的生物碱类抗恶性肿瘤药;以多柔比星、表柔比星、吡柔比星、柔红霉素、丝裂霉素C、放线菌素D、培洛霉素、新制癌菌素、博来霉素等为代表的抗生素抗恶性肿瘤药;以吉非替尼等为代表的酶阻碍性抗恶性肿瘤药;顺铂、卡铂等。
其中代谢拮抗性抗恶性肿瘤药副作用、毒性等风险较低,因而优选。
代谢拮抗性抗恶性肿瘤药中,吉西他滨在肿瘤细胞内的代谢慢,因此抗肿瘤效果持久,对多数实体肿瘤显示抗肿瘤效果,因此特别优选。
抗恶性肿瘤药的给药方法有对肿瘤附近的组织注射的方法、静脉注射的方法、肌内注射的方法、经口给药的方法等,优选根据药物的特性适当采用。剂量优选通过与除去免疫抑制物质的柱联合使用的效果,使剂量为抗恶性肿瘤药所规定的正常剂量的百分之一或以上、二分之一或以下。关于给药时间,例如优选在体外循环的24-200小时前给药,更优选为24-100小时前。
本发明的癌症的治疗方法优选与癌的原发灶的切除联合使用进行体外循环。通常外科切除时,游离的癌细胞进入血管或淋巴管,发生转移,根据本发明的方法,可以抑制转移的癌细胞的增殖,因此可有效治疗,结果可以抑制癌的转移。
以下,通过实施例更具体地说明本发明,但本发明并不受此限定.
[受试体的制备]
(1)患癌大鼠1
8周龄的HOS:在Donryu大鼠(雄性)的背部皮下接种2×108个YS细胞(东北大学加龄研究所提供)。
(2)患癌大鼠2
12周龄的WKAH:在Hkm大鼠(雄性)的背部皮下接种2×106个4-二甲基氨基偶氮苯诱发肝癌细胞KDH-8{矢野谕、北海道医志、68卷5号、654-664(1993)}。该癌细胞通常在接种后1周时肿瘤开始变大,5.5周凋亡。
[测定方法]
(1)吸附材料的比表面积
使用日本ベル(株)制造的高精度全自动气体吸附装置“BELSORP36”,在100℃进行脱气处理后,在氮气氛围下求出77K下的吸附等温线。应用BET多分子层吸附理论,由该等温线求出比表面积。
(2)吸附材料的TGFβ平衡吸附能
收集5只患癌大鼠1的血清,制备30mL患癌大鼠血清。向1mL该血清中装入50mg吸附材料,在37℃下振荡4小时。按照下述(3)“TGFβ浓度”测定上清中的TGFβ浓度,将吸附前后的浓度差除以吸附材料重量(0.05g),以所得值作为TGFβ平衡吸附能.
(3)TGFβ浓度
使用ゼンザイム·ラク礻公司制造的人TGF-β1免疫分析试剂盒,按照使用说明书的要求进行测定。
(4)免疫抑制酸性蛋白的浓度
使用三光纯药制造的大鼠IAP免疫扩散板进行测定。
(5)清蛋白的浓度
用清蛋白分析试剂盒“清蛋白B-测试ワコ-”测定.
(6)PGE2的吸附率
PGE2浓度使用NEOGEN公司制造的PGE2分析试剂盒测定。吸附率的计算通过计算吸附后血清中的PGE2浓度/吸附前血清中的PGE2浓度来进行。
(7)肿瘤体积
用游标卡尺测量大鼠的肿瘤部分,以肿瘤最长的直径作为长径,以其中点与长径垂直相交方向的直径作为短径,长径×短径×短径×0.5为肿瘤体积。
[TGFβ·免疫抑制酸性蛋白的吸附材料]
(水不溶性载体)
为36岛的海岛复合纤维,由芯鞘复合形成的岛使用如下成分在纺丝速度800m/分钟,拉伸倍率3倍的制丝条件下获得。
岛的芯成分:聚丙烯
岛的鞘成分:90%聚苯乙烯、10%聚丙烯
海成分:共聚3%的5-钠磺基间苯二酸的聚对苯二甲酸乙二醇酯
复合比率:芯∶鞘∶海=40∶40∶20
将该海成分用热的氢氧化钠水溶液溶解,得到直径4μm的原丝1,作为芯鞘型聚丙烯补强聚苯乙烯纤维.
另外,将芯·鞘的复合比率固定,适当改变吐丝量、拉伸倍率,同样地制备,得到直径10μm的原丝2、直径50μm的原丝3。
(中间体)
在20℃,将3g多聚甲醛溶解于600mL硝基苯和390mL硫酸的混合液中,然后冷却到0℃,加入75.9gN-羟甲基-α-氨乙酰胺,在5℃或以下溶解。将10g上述原系1浸渍于其中,在室温下静置2小时。之后取出纤维,加入到极过量的冷甲醇中,洗涤。将纤维用甲醇充分洗涤后水洗、干燥,得到15.0gα-氯乙酰氨基甲基化聚苯乙烯纤维(中间体1)。中间体1作为比较例1使用。另外,将10g原丝2和10g原丝3同样进行处理,得到中间体2(收量14.4g)和中间体3(收量12.5g)。
(通过非均匀体系反应来固定亲水性胺)
将50g N,N-二甲基己胺和8g碘化钾溶解于360mL的DMF中,形成溶液,将5g中间体1浸渍于该溶液中,在85℃的浴中加热3小时。将纤维浸渍于1mol/L浓度的食盐水中,然后水洗,真空干燥,得到7.3g二甲基己基铵化纤维(实施例1).
将50g N,N-二甲基辛胺和8g碘化钾溶解于360mL的DMF中,形成溶液,将5g中间体1浸渍于该溶液中,在85℃的浴中加热3小时。将纤维用异丙醇洗涤,然后浸渍于1mo1/L浓度的食盐水中,然后水洗,真空干燥,得到8.3g二甲基辛基铵化纤维(实施例2)。
将50g N,N-二甲基月桂胺和8g碘化钾溶解于360mL的DMF中,形成溶液,将5g中间体1浸渍于该溶液中,在85℃的浴中加热3小时。将纤维用异丙醇洗涤,然后浸渍于1mol/L浓度的食盐水中,然后水洗,真空干燥,得到9.3g二甲基月桂基铵化纤维(实施例3).另外对中间体2和中间体3进行同样处理,分别得到实施例4(比表面积1.4m2/g)和参考例1(比表面积0.04m2/g)。
(通过非均匀体系的反应固定非亲水性胺)
非亲水性胺可如下固定:将50g硬脂酰胺溶解于360mL的乙醇中,形成溶液,将5g中间体1浸渍于该溶液中,在85℃的浴中加热3小时。将纤维用异丙醇洗涤,然后水洗,真空干燥,得到7.2g硬脂酰基氨基化纤维(比较例2)。
(磺化纤维)
将5g原丝1浸渍于溶解了500mg多聚甲醛的50mL硫酸中,在95℃加热1小时,然后依次进行水洗、1mol/L浓度食盐水的洗涤、水洗、干燥,得到7.3g磺化纤维(比较例3)。
(结合了亲水性胺的聚合物的合成和涂覆)
将16mL硝基苯和32mL硫酸的混合液冷却至0℃,全量加入4.2g N-羟甲基-α-氯乙酰胺,溶解,再一边充分搅拌一边将其全量加入到10℃的UDEL聚砜(帝人アモコ制造的P3500)的硝基苯溶液(300g/3L)中.再在室温下搅拌3小时。之后将反应混合物装入极过量的冷甲醇中,使聚合物沉淀.将沉淀用甲醇充分洗涤,然后干燥,再由二甲基甲酰胺/甲醇进行再沉淀,得到303gα-氯乙酰氨基甲基化聚砜(置换率0.05;聚合物A)。
另外,将60g聚乙烯亚胺(平均分子量10000:和光纯药)溶解于300mL的DMF形成的溶液和含有30g聚合物A的300mL DMF溶液全量混合,在室温下搅拌48小时。将反应混合物加入到极过量的饱和食盐水中,滤取沉淀的聚合物。用水洗涤聚合物,然后干燥,从二甲基甲酰胺/甲醇中再沉淀,制备27g由N-烷基化聚亚烷基亚胺固定的聚砜(聚合物B).
将20g单纤维直径为3.5μm的聚对苯二甲酸乙二醇酯纤维棉浸渍于250mL含有5g上述聚合物B的二氯甲烷溶液中,20小时后取出棉,倾去液体,风干,得到21g涂覆棉(实施例5).另外,以未涂覆的聚对苯二甲酸乙二醇酯纤维棉作为比较例5。
(非离子性官能团的吸附材料)
将5g乙酸纤维素溶解于250ml二氯甲烷,将20g单丝直径为3.5μm的聚对苯二甲酸乙二醇酯纤维棉浸渍其中,20小时后取出棉,倾去液体,风干,得到21g涂覆棉(比较例4).
(吸附能的评价)
对上述患癌大鼠1接种癌细胞后的第2-3周,由5只中采血,制备30mL患癌大鼠血清。各向1mL该血清中加入50mg各吸附材料,在37℃振荡4小时.测定上清中各蛋白质浓度,得到表1的结果。
表1
[前列腺素E2的吸附材料]
与前述同样地制备与实施例1、比较例1同样的纤维。
另外,对应中间体1(比较例1)的纤维收量为15.2g,对应实施例1的纤维的收量为7.4g,对应实施例1的纤维的比表面积为2.4m2/g。
另外,与前述同样地制备与实施例5同样的涂覆棉.
聚合物A的收量为305g,聚合物B的收量为28g,对应实施例5的涂覆棉的收量为21g,另外对应实施例5的涂覆棉的比表面积为1.2m2/g。
(吸附能的评价)
由上述患癌大鼠1采血,制备6mL血清(PGE2的浓度:1700ng/mL)。向1mL该血清中加入50mg纤维,在37℃振荡2小时.
对应实施例1的纤维对PGE2的吸附率为80%。
对应实施例5的涂覆棉对PGE2的吸附率为62%。
对应比较例1的纤维对PGE2的吸附率为33%。
[体外循环治疗]
(体外循环柱的制备)
将与实施例1同样的纤维(TGFβ平衡吸附能为500ng/g)制成无纺布,分别将0.46g(实施例6)、0.40g(实施例7)、0.38g(实施例8)、0.21g(实施例9)、0.16g(参考例2)填充到5支内径1cm、内容积2m1的聚丙烯制圆筒形柱内,制备体外循环柱。
另外,将与比较例3同样的纤维(TGFβ平衡吸附能为0ng/g)制成无纺布,将0.43g填充到同样的圆筒形柱内,制备体外循环柱(比较例6)。
将各0.43g单纤维直径3.5μm的聚对苯二甲酸乙二醇酯纤维的无纺布填充到2支同样的圆筒形柱内,制备体外循环柱(比较例7、8)。
进行体外循环前,预先用10mL含有1000单位肝素钠注射液(武田药品工业(株))的生理盐水洗涤这些体外循环柱,再用500mL生理盐水洗涤。
(体外循环治疗)
对于接种KDH细胞2周后的大鼠,以2mL/分钟的血流进行体外循环30分钟。由股动脉采血,流过吸附柱后返回股静脉。体外循环中以100U/小时的速度持续注入肝素钠注射液(武田药品工业(株))。
对体外循环前和后的大鼠采血,测定血清中的TGFβ1浓度,同时观察接种癌细胞后大鼠的存活天数,得到表2的结果。
表2
[抗癌药与体外循环联合使用]
(体外循环柱)
将实施例1的纤维制成无纺布,将0.4g该无纺布填充到内径1cm、内容积2m1的聚丙烯制圆筒形柱内,制备用于治疗癌症的体外循环柱。
(给予抗癌药)
接种癌细胞1周后(大鼠体重:400-430g),将0.6mg的盐酸吉西他滨(株式会社日本イ-ライリリ-制造、溶解于注射用生理盐水,使用20mg/mL浓度)注射到肿瘤附近。
(体外循环治疗)
在体外循环前,预先用含有1000单位肝素钠的生理盐水洗涤用于治疗癌症的体外循环柱,再用500mL生理盐水洗涤后使用。
给予抗癌药2天后进行体外循环治疗。制作如下回路:由股动脉采血,流过用于治疗癌症的体外循环柱后,返回到股静脉。以2mL/分钟的血流体外循环1小时。体外循环中以200U/小时的速度持续注入肝素钠注射液(武田药品工业(株))。
对6只进行治疗,测定接种癌细胞后的肿瘤体积,得到实施例10-15的结果(表3).未治疗组6只(比较例9-14)在表4中表示。对给予抗癌药但未进行体外循环治疗的比较例15-20表示在表5中.
表3
表4
表5
表3(实施例10-15)是给予盐酸吉西他滨后第2天进行DHP治疗,其中实施例10和11中肿瘤完全消失。即使实施例12-15与未治疗的比较例11-16(表4)比较,可知肿瘤增殖速度受到强烈抑制。比较例(表5)是给予盐酸吉西他滨后未进行体外循环治疗的情况,虽然在1周内(第14天)得到抑制效果,但由表4和表5的比较可知,之后与未治疗组并无差别。与此相对,实施例中,肿瘤的增殖受到强烈抑制,三分之一治愈。
(肿瘤转移的目视观察)
虽然作为大鼠个体各有不同,但与前述实施例10-15、比较例11-22同样地用各三只大鼠进行实验(实施例16-18、比较例21-26),目视观察肿瘤向除接种了肿瘤的背部皮下以外的部位转移的情况(表6)。体外循环后第35天,解剖大鼠,观察肿瘤块的存在,可知给予盐酸吉西他滨后第2天进行了体外循环治疗的大鼠几乎未观察到转移。
表6
转移情况观察结果(目视观察) | 备注(治疗方法) | |
实施例16 | 无 | 抗癌药+体外循环 |
实施例17 | 无 | 抗癌药+体外循环 |
实施例18 | 转移至前肢右肋附近微小(直径2mm)皮肤 | 抗癌药+体外循环 |
比较例21 | 转移至胸骨附近的皮肤 | 未治疗 |
比较例22 | 转移至前肢右肋的皮肤、转移至肺 | 未治疗 |
比较例23 | 转移至前肢右肋附近、胸骨附近的皮肤 | 未治疗 |
比较例24 | 转移至胸骨附近的皮肤 | 只给予抗癌药 |
比较例25 | 转移至前肢右肋附近微小(直径2mm)皮肤 | 只给予抗癌药 |
比较例26 | 转移至前肢右肋附近微小(直径2mm)皮肤 | 只给予抗癌药 |
产业实用性
本发明提供吸附免疫抑制物质的材料,所述吸附材料可从体液中直接、高效、选择性吸附被认为与癌细胞的增殖有关的过量的免疫抑制物质,且可安全地进行体外循环,进而可对癌症的治疗发挥作用。
Claims (9)
1.比表面积为每克0.1m2或以上,并且通过将来自每个氮原子有3-18个碳原子的叔胺的季铵基固定在水不溶性载体上而成的材料在制造潜在型转化生长因子β的吸附材料中的应用。
2.权利要求1的应用,其中水不溶性载体来自聚砜系聚合物。
3.权利要求1的应用,其中水不溶性载体来自聚(芳族乙烯化合物)。
4.权利要求1-3任一项的应用,所述材料具有膜、纤维、粒状或它们组合的形状。
5.填充了比表面积为每克0.1m2或以上,并且通过将来自每个氮原子有3-18个碳原子的叔胺的季铵基固定在水不溶性载体上而成的材料的柱在制造体外循环柱中的应用。
6.权利要求5的应用,其中体外循环柱是癌症治疗用体外循环柱。
7.权利要求5的应用,其中水不溶性载体来自聚砜系聚合物。
8.权利要求5的应用,其中水不溶性载体来自聚(芳族乙烯化合物)。
9.权利要求5-8任一项的应用,所述材料具有膜、纤维、粒状或它们组合的形状。
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JP240246/2002 | 2002-08-21 | ||
JP2002240246A JP2004073618A (ja) | 2002-08-21 | 2002-08-21 | 吸着材および該吸着材を充填した体外循環用カラム |
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WO2017189899A1 (en) * | 2016-04-27 | 2017-11-02 | Immunicom, Inc. | METHOD TO TREAT CANCER USING THERAPEUTIC APHERESIS TO REMOVE TGF-β VIA ITS COMPLEXES |
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US11633716B2 (en) | 2017-09-08 | 2023-04-25 | Toray Industries, Inc. | Immunosuppressive protein adsorption material and adsorption column |
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