CN116059171A - 用于将生理活性成分递送至血管的组合物 - Google Patents
用于将生理活性成分递送至血管的组合物 Download PDFInfo
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- CN116059171A CN116059171A CN202211269946.9A CN202211269946A CN116059171A CN 116059171 A CN116059171 A CN 116059171A CN 202211269946 A CN202211269946 A CN 202211269946A CN 116059171 A CN116059171 A CN 116059171A
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Abstract
本发明涉及用于将生理活性成分递送至血管的组合物。根据本发明的包括多孔二氧化硅颗粒的组合物通过使颗粒表面修饰以抑制血液中的聚集和沉淀,可以有效地将生物活性物质递送至血流中的靶组织或细胞。除了上述优点之外,根据本发明的包括多孔二氧化硅颗粒的栓塞用组合物还有具有特定的物理性质如生物降解性和持续释放的优点,从而实现优异的栓塞效果和针对靶肿瘤组织或细胞的靶向性,从而减少副作用。
Description
本申请是申请日为2018年7月25日、申请号为2018800619732(国际申请号:PCT/KR2018/008445)的专利申请“用于将生理活性成分递送至血管的组合物”的分案申请。
技术领域
本发明涉及用于将生理活性成分递送至血管的组合物
背景技术
药物递送系统是指使以往医药品的副作用最小化且使效能和效果极大化来能够有效地递送所需量的药物,例如,蛋白质、核酸或其他小分子等的医药技术。最近,减少开发新药所需的费用和时间的这种技术与纳米技术相结合,以在医药界成为创造新的附加值的尖端技术之一。在20世纪80年代末,技术发达的国家,例如美国,日本等,都集中在药物输送系统的开发以及围绕制药公司等企业的新药的开发。
到目前为止,病毒基因、重组蛋白、脂质体、阳离子聚合物及各种形状的纳米颗粒和纳米物质已用于将药物递送到动物细胞中。然而,已发现许多阳离子脂质体和阳离子聚合物由于强细胞毒性而在临床应用方面不适合。并且,已经尝试了对核酸的主链进行化学修饰修饰的方法以使核酸向细胞膜内稳定地透过。但是,该方法成本高,花费很长时间,且需要劳动密集的工序,因此不适合临床应用。作为有意义的尝试,已经开发了利用包括量子点、磁性颗粒或金纳米颗粒的各种形式的纳米颗粒的药物递送系统(drug deliverysystem,DDS)。然而,这些颗粒具有细胞毒性和难以导入如核酸等生物聚合物的结构,且细胞内导入效率低。
为了细胞中生理活性物质(或生物活性物质)的功能研究或细胞内递送,需要有效的递送系统。然而,尚未开发出能够递送多种生物活性材料的普遍适用的递送系统,能够容纳和递送大量药物的系统以及用于以持续方式释放药物的系统。
发明内容
发明要解决的问题
本发明的一个目的是提供一种用于将生理活性物质(以下称为“生物活性物质”)递送到血管中的组合物,其包括在血液中具有稳定性的多孔二氧化硅颗粒。
本发明的另一个目的是提供一种用于栓塞的组合物(通常称为“栓塞用组合物”),其包括具有生物降解性和持续释放的多孔二氧化硅颗粒。
用于解决问题的方案
1.一种用于在血管中递送生物活性物质的组合物,其包括多孔二氧化硅颗粒,其中生物活性物质被负载在颗粒的表面上或颗粒的孔的内部,并且多孔二氧化硅颗粒的ζ电势为+3mV以上或-18mV以下,和
在颗粒的表面上或孔的内部对颗粒进行化学修饰。
2.根据上述1所述的组合物,
其中颗粒的表面上或颗粒的孔的内部的至少一部分硅烷醇基被选自由以下组成的组的至少一种官能团取代:醛、酮、氨基甲酸酯、硫酸酯、磺酸酯、氨基、胺、氨基烷基、甲硅烷基、羧基、磺酸、硫醇、铵、巯基、磷酸酯、酯、酰亚胺、硫代酰亚胺、醚、茚、磺酰基、甲基膦酸酯、聚乙二醇、取代或未取代的C1至C30烷基、取代或未取代的C3至C30环烷基、取代或未取代的C6至C30芳基和C1至C30酯基基团。
3.根据上述1所述的组合物,
其中颗粒的表面上或颗粒的孔的内部的至少一部分硅烷醇基被选自由以下组成的组的至少一种官能团取代:氨基、胺、PEG、丙基、辛基、羧基、硫醇、磺酸、甲基膦酸酯和醛基基团。
4.根据上述1所述的组合物
其中所述颗粒的直径为100至1000nm。
5.根据上述1所述的组合物
其中所述颗粒的ζ电势为+3mV至+100mV或-100mV至-18mV。
6.根据上述1所述的组合物
其中所述颗粒具有每克为0.7至2.2ml的体积。
7.根据权利要求1所述的组合物,
其中当下式1中的吸光度比达到1/2时,t为20以上:
[式1]
At/A0
(其中A0为通过将5ml的包括1mg/ml所述多孔二氧化硅颗粒的悬浮液置于具有50kDa直径的孔的圆筒状渗透膜中来测定的所述多孔二氧化硅颗粒的吸光度,
其中15ml的与所述悬浮液相同的溶剂存在于所述渗透膜的外部并与所述渗透膜接触,所述渗透膜的内部和外部在37℃和60rpm下水平搅拌,
At为在测定A0后t小时测定的所述多孔二氧化硅颗粒的吸光度)。
8.根据上述1所述的组合物,
其中负载在所述颗粒上的生物活性物质的最大释放量为99重量%以上。
9.根据上述1所述的组合物,
其中所述生物活性物质是选自由以下组成的组的至少一种:核酸、核苷酸、蛋白质、肽、氨基酸、糖、脂质、化合物、抗体、抗原、细胞因子、生长因子和组成它们的要素。
10.根据上述1所述的组合物,
其中所述生物活性物质是选自由以下组成的组的至少一种:多柔比星(doxorubicin)、伊立替康(irinotecan)、索拉非尼(sorafenib)、阿霉素(adriamycin)、道诺霉素(daunomycin)、丝裂霉素(mitomycin)、顺铂(cisplatin)、表阿霉素(epirubicin)、甲氨蝶呤(methotrexate)、5-氟尿嘧啶(5-fluorouracil)、阿克拉霉素(aclacinomycin)、氮芥(nitrogen mustard)、环磷酰胺(cyclophosphamide)、博来霉素(bleomycin)、柔红霉素(daunorubicin)、长春新碱(vincristine)、长春花碱(vinblastine)、长春地辛(vindesine)、他莫昔芬(tamoxifen)、戊柔比星(valrubisin)、吡喃阿霉素(pirarubicin)、米托蒽醌(mitoxantrone)、吉西他滨(gemcitabine)、去甲氧柔红霉素(idarubicin)、替莫唑胺(temozolomide)、紫杉醇(paclitaxel)、地塞米松(dexamethasone)、阿地白介素(aldesleukin)、阿伐单抗(avelumab)、贝伐单抗(bevacizumab)、卡铂(carboplatin)、瑞格非尼(regorafenib)、多西他赛(docetaxel)、多西尔(doxil)、吉非替尼(gefitinib)、甲磺酸伊马替尼(imatinib mesylate)、赫赛汀(herceptin)、伊马替尼(imatinib)、阿地白介素(aldesleukin)、可瑞达(keytruda)、欧狄沃(opdivo)、丝裂霉素C(mitomycin C)、纳武单抗(nivolumab)、奥拉帕尼(olaparib)、派姆单抗(pembrolizumab)、利妥昔单抗(rituximab)、舒尼替尼(sunitinib)、阿特珠单抗(atezolizumab)、拉帕替尼(lapatinib)和易普利单抗(ipilimumab)。
11.根据上述1所述的组合物,
其中所述组合物通过导管释放至靶组织中。
12.一种栓塞用组合物,其包括根据上述1至11中任一项所述的组合物。
13.根据上述12所述的组合物,
其进一步包括造影剂和栓塞物质中的至少一种。
14.根据上述12所述的组合物,
其进一步包括选自由以下组成的组的至少一种栓塞物质:碘油、右旋糖酐、聚乙烯醇、氰基丙烯酸正丁酯、凝胶泡沫、明胶、乙醇、右旋糖酐、二氧化硅、聚丙烯酸钠乙烯醇共聚物、玻璃颗粒、聚-L-古洛糖醛酸盐、聚乙醇酸-聚乳酸、聚二噁烷酮、聚乙醇酸-共-己内酯、聚丙烯和具有10μm以上直径的多孔二氧化硅颗粒。
15.根据上述12所述的组合物,其中所述组合物被释放至经由导管直接与肿瘤连接的血管中。
发明的效果
根据本发明的包括多孔二氧化硅颗粒的组合物通过颗粒表面修饰以抑制在血液中的聚集和沉淀,可以有效地将生物活性物质递送至血流中的靶组织或细胞。
除上述优点外,根据本发明的包括多孔二氧化硅颗粒的栓塞用组合物还有具有特定的物理性质如生物降解性和持续释放的优点,从而获得优异的栓塞效果和针对靶肿瘤组织或细胞的靶向性,从而减少副作用。
附图说明
图1为根据本发明的实施方案的多孔二氧化硅颗粒的显微图像。
图2为根据本发明的实施方案的多孔二氧化硅颗粒的显微图像。
图3为根据本发明的实施方案的用于制造多孔二氧化硅颗粒的工艺中的小孔颗粒的显微图像。
图4为根据本发明的实施方案的小孔颗粒的显微图像。
图5为根据本发明的实施方案的多孔二氧化硅颗粒的孔径的显微图像。
在图5中,可降解的递送载体(degradable delivery vehicle,DDV)是该实施方案中的颗粒,其中括号中的数字表示颗粒的直径,并且下标的数字表示孔径。例如,DDV20010在实施方案中是指具有200nm粒径和10nm孔径的颗粒。
图6为能够确认根据本发明的实施方案的多孔二氧化硅颗粒的生物降解性的显微图像。
图7为显示根据本发明的实施方案提供的具有圆筒状渗透(或可渗透)膜的管的视图。
图8为显示根据本发明的实施方案的多孔二氧化硅颗粒的吸光度随时间降低的结果的图。
图9为显示根据本发明的实施方案的多孔二氧化硅颗粒根据粒径的吸光度随时间降低的结果的图和表格。
图10为显示根据本发明的实施方案的多孔二氧化硅颗粒根据孔径的吸光度随时间降低的结果的图和表格。
图11是显示根据本发明的实施方案的多孔二氧化硅颗粒根据环境pH的吸光度随时间降低的结果的图。
图12为显示根据本发明的实施方案的多孔二氧化硅颗粒的吸光度降低的结果的图。
图13为显示在两种条件下从负载有多柔比星的多孔二氧化硅颗粒中释放多柔比星的量的图。
图14为显示从负载有伊立替康的多孔二氧化硅颗粒中释放伊立替康的量的图。
图15为显示从负载有索拉非尼的多孔二氧化硅颗粒中释放索拉非尼的量的图。
图16为显示从负载有视黄酸的多孔二氧化硅颗粒中释放视黄酸的量的图。
图17为显示从负载有p53蛋白的多孔二氧化硅颗粒中释放p53蛋白的量的图。
图18为显示用于识别负载的生物活性物质释放的管的视图。
图19为显示从负载有siRNA的多孔二氧化硅颗粒中释放siRNA的量的图。
图20和21为显示从负载有pDNA的多孔二氧化硅颗粒中释放pDNA的量的图。
图22为显示从负载有线性DNA的多孔二氧化硅颗粒中释放线性DNA的量的图。
图23为显示从负载有BSA的多孔二氧化硅颗粒中释放BSA的量的图。
图24为显示分别从负载有IgG(A)、抗体1(B)和抗体2(C)的多孔二氧化硅颗粒中释放IgG、抗体1和抗体2的量的图。
图25为显示从负载有RNase的多孔二氧化硅颗粒中释放RNase的量的图。
图26为显示Cas9蛋白被负载在多孔二氧化硅颗粒上并被递送至细胞中的图像。
图27为显示siRNA被负载在多孔二氧化硅颗粒上并在小鼠中释放的图像和图(A);包括负载有多柔比星、siRNA、RNase A和肽的多孔二氧化硅颗粒的组合物在小鼠中的递送和治疗效果(B);和通过导管递送本发明的组合物(C)。
图28为显示用阴离子官能团修饰的多孔二氧化硅颗粒的FT-IR光谱的图。
图29为显示血液模拟溶液中多孔二氧化硅颗粒的沉淀程度的图像和图。
图30为显示经修饰的多孔二氧化硅颗粒的红细胞溶血程度的视图。
图31为显示未经修饰的多孔二氧化硅颗粒的红细胞溶血程度的视图。
图32为显示多孔二氧化硅颗粒对多柔比星负载能力的视图。
图33为显示多孔二氧化硅颗粒的细胞毒性试验结果的图。
图34为显示将多孔二氧化硅颗粒与碘油混合以乳化时的颗粒稳定性的图像。
图35为显示使用包括多孔二氧化硅颗粒的用于栓塞的组合物在栓塞后切除的兔肝的目视观察结果的图像。
图36为显示包括多孔二氧化硅颗粒的栓塞用组合物分别对靶组织的靶向性的图(A);和对靶细胞的靶向性的图(B);上述组合物对周围正常细胞的毒性微小的图(C);和上述组合物对靶肿瘤的靶向性的图(D)。
图37为显示使用包括多孔二氧化硅颗粒的栓塞用组合物进行栓塞时兔肝癌细胞的低存活率(A和B)以及AST和ALT浓度的测定结果的视图和图,其表明没有肝毒性。
具体实施方式
如本文所用,多孔二氧化硅颗粒是包括尺寸范围从几纳米至几微米的细孔的细纳米多孔二氧化硅微结构,在孔排列方面有明确的规则性,并且可以在材料特性(孔尺寸、比表面积、表面特性等)方面进行适当控制以适应使用环境。多孔二氧化硅颗粒也称为介孔二氧化硅颗粒。
在下文中,将详细描述本发明。
本发明提供用于在血管中递送药物的组合物,其包括多孔二氧化硅颗粒,以将生理活性(“生物活性”)物质负载在颗粒表面或其孔的内部,同时具有+3mV以上或-18mV以下的ζ电势,其中颗粒在颗粒表面或孔的内部化学修饰。
在本发明的组合物中,生物活性物质是负载在多孔二氧化硅颗粒上并递送至个体以表现出活性的生理活性物质/生物功能调节剂,其可以包括例如选自由以下组成的组的至少一种:低分子量药物、基因药物、蛋白质药物、提取物、核酸、核苷酸、蛋白质、肽、抗体、抗原、RNA、DNA、PNA、适体、化学物质、酶、氨基酸、糖、脂质、化合物(天然和/或合成化合物)及其组成成分,例如可以是选自由以下组成的组的至少一种:多柔比星(doxorubicin)、伊立替康、索拉非尼、阿霉素(adriamycin)、道诺霉素、丝裂霉素、顺铂、表阿霉素、甲氨蝶呤、5-氟尿嘧啶、阿克拉霉素、氮芥、环磷酰胺、博来霉素、柔红霉素、长春新碱、长春花碱、长春地辛、他莫昔芬、戊柔比星、吡喃阿霉素、米托蒽醌、吉西他滨、去甲氧柔红霉素、替莫唑胺、紫杉醇、地塞米松、阿地白介素、阿伐单抗、贝伐单抗、卡铂、瑞格非尼、多西他赛、多西尔、吉非替尼、甲磺酸伊马替尼、赫赛汀、伊马替尼、阿地白介素、可瑞达、欧狄沃、丝裂霉素C、纳武单抗、奥拉帕尼、派姆单抗、利妥昔单抗、舒尼替尼、阿特珠单抗、拉帕替尼和易普利单抗,但不限于此。这些物质可以包括以下描述的具体实例。
在本发明的组合物中,生物活性物质可以是能够确保对人或动物有机体的直接或间接、治疗、生理和/或药理作用的治疗活性剂。
治疗活性剂可以是例如典型的药品(medicines)、药物(drugs)、前药或靶组(target groups),或包括靶组的药物或前药。
治疗活性剂可包括,例如:心血管药物,特别是抗高血压药(例如,钙通道阻滞剂或钙拮抗剂)和抗心律不齐药;充血性心力衰竭药物;肌肉收缩药(muscle contractors);血管舒张药;ACE抑制剂;利尿剂;脱氧脱水酶抑制剂;强心苷;磷酸二酯酶抑制剂;阻滞剂;β-受体阻滞剂;钠通道阻滞剂;钾通道阻滞剂;β-肾上腺素能激动剂;血小板抑制剂;血管紧张素II拮抗剂;抗凝血剂;溶栓剂;出血治疗剂(bleeding therapeutics);贫血治疗剂(anemia therapeutics);凝血酶抑制剂;抗寄生虫药;抗菌药;抗炎药;特别是非甾体抗炎剂(NSAID),更特别是COX-2抑制剂;甾体抗炎药;预防性消炎药;抗青光眼药(anti-glaucoma);肥大细胞稳定剂;散瞳药物;影响呼吸系统的药物;过敏性鼻炎药物;α-肾上腺素拮抗剂;皮质类固醇;慢性阻塞性肺疾病药物;黄嘌呤氧化酶抑制剂;抗关节炎药物;痛风疗法;有效药物和有效药物拮抗剂;抗结核药物;抗真菌药物;抗原生动物药物;驱虫剂(helminthics);抗病毒药物,特别是呼吸道抗病毒药物、抗疱疹、巨细胞病毒、人类免疫缺陷病毒和肝炎感染的抗病毒药物;白血病和卡波济肉瘤的治疗剂;疼痛控制剂,特别是包括麻醉剂和镇痛药的阿片类药物、阿片类药物受体激动剂、阿片类药物受体部分激动剂、阿片类药物拮抗剂、阿片类药物受体混合激动剂-拮抗剂;抗精神病药物(neuroleptics);拟交感神经药物;肾上腺素拮抗剂;影响神经递质吸收和释放的药物;抗胆碱药物;抗出血药物;放射或化疗的预防或治疗剂;成脂药物;减脂药物;如脂肪酶抑制剂的抗肥胖药物;交感神经兴奋剂;如质子泵抑制剂的胃溃疡和炎症治疗剂;前列腺素;VEGF抑制剂;降高血脂药物,特别是他汀类药物;影响中枢神经系统(CNS)的药物,例如抗精神病药物、抗癫痫病药物和抗咬合(antiseizure)药物(抗惊厥药物)、精神治疗剂(psychoactive agents)、兴奋剂、抗焦虑药物和催眠药物;抗抑郁药物;抗帕金森症药物;激素如性激素及其片段;生长激素拮抗剂;促性腺激素释放激素及其类似物;类固醇激素及其拮抗剂;选择性雌性激素调节剂;生长因子;如胰岛素、胰岛素片段、胰岛素类似物、胰高血糖素样肽和降血糖药物的抗糖尿病药物;H1、H2、H3和H4抗组胺药;肽、蛋白质、多肽、核酸和寡核苷酸药物;天然蛋白、多肽,寡核苷酸和核酸的类似物、片段和变体;用于治疗偏头痛的药物;哮喘药物;胆碱能拮抗剂;糖皮质激素;雄性激素;抗雄性激素;肾上腺皮质激素生物合成抑制剂;诸如双磷酸盐类药物的骨质疏松症治疗剂;抗甲状腺药物;UV阻断剂、UV保护剂和过滤剂(UV protectors andfilters);细胞因子拮抗剂;抗肿瘤药物;抗阿兹海默症药物;HMGCoA还原酶抑制剂;贝特类药物(fibrate);胆固醇吸收抑制剂;HDL胆固醇增强剂;甘油三酯还原剂;抗衰老或抗皱药物;激素发育的前体分子;如胶原蛋白和弹性蛋白等蛋白质、抗菌药物;抗痤疮药物;抗氧化剂;头发护理和皮肤增白剂;UV阻断剂、UV保护剂和过滤剂;人载脂蛋白的变体;激素发育的前体分子;蛋白质及其肽;氨基酸;如葡萄籽提取物的植物提取物;脱氢表雄酮(DHEA);异黄酮;包括维生素、植物甾醇和环烯醚萜苷(phytosterols and iridoid glycosides)、倍半萜烯内酯、萜烯、酚糖苷、三萜、对苯二酚衍生物、苯基链烷酮的营养素;如视黄醇和其他视黄酸的抗氧化剂,包括辅酶Q10的类视黄醇;ω-3-脂肪酸;氨基葡萄糖;核酸、寡核苷酸、反义药物;酶;辅酶;细胞因子类似物;细胞因子激动剂;细胞因子拮抗剂;免疫球蛋白;抗体;抗体药物;基因治疗药物;脂蛋白;促红细胞生成素;疫苗;和用于治疗或预防人类或动物疾病,例如过敏/哮喘、关节炎、癌症、糖尿病、生长障碍、心血管疾病、炎症、免疫病症、脱发、疼痛、眼病、癫痫、妇科病症、CNS疾病、病毒感染、细菌感染、寄生虫感染、G1疾病、肥胖和血液疾病的低分子量治疗剂,但不限于此。
治疗活性剂可以是另外的活性剂,包括例如促红细胞生成素(EPO)、促血小板生成素、如白介素(包括IL-1至IL-17)的细胞因子、胰岛素、胰岛素样生长因子(包括IGF-1和IGF-2)、表皮生长因子(EGF)、转化生长因子(包括TGF-α和TGF-β)、人生长激素、转铁蛋白、低密度脂蛋白、高密度脂蛋白、瘦素、VEGF、PDGF、睫状神经营养因子(ciliaryneurotrophic factor)、催乳素、促肾上腺皮质激素(ACTH)、降钙素、人绒毛膜促性腺激素、皮质醇、雌二醇、促卵泡激素(FSH)、促甲状腺激素(TSH)、促黄体激素(LH)、黄体酮、睾丸激素、包括蓖麻毒素的毒素等。
治疗活性剂可选自用于治疗肿瘤疾病或细胞或组织修饰的药物组。合适的治疗剂型可以是抗肿瘤剂,包括例如:烷化剂,特别是烷基磺酸盐,例如白消安(busulfan)、英丙舒凡(improsulfan)、哌泊舒凡(piposulfane)、苯佐替派(benzodepa)、卡波醌(carboquone)、美妥替哌(metredepa)、如乌瑞替派(uredepa)的氮丙啶,等;乙烯亚胺(ethyleneimine)和甲基三聚氰胺(methylmelamine),例如六甲蜜胺(altretamine)、三亚乙基蜜胺(triethylene melamine)、三亚乙基磷酰胺(triethylene phosphoramide)、三亚乙基硫代磷酰胺(triethylene thiophosphoramide)、三羟甲基三聚氰胺(trimethylolmelamine),等;苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、环磷酰胺(cyclophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、氮芥(mechlorethamine)、氧氮芥盐酸盐(mechlorethamine oxide hydrochloride)、美法仑(melphalan)、新恩比兴(nomobichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、所谓的氮芥(nitrogen mustard)如尿嘧啶芥(uracil mustard),等;亚硝基脲化合物如卡莫司汀(carmustine)、氯脲霉素(chlorozotocin)、福莫司汀(fotenmustine)、洛莫司汀(lomustine)、尼莫斯汀(nimustine)、雷莫司汀(ranimustine),等;达卡巴嗪(dacarbazine)、甘露醇氮芥(mannomustine)、二溴甘露醇(mitobranitol)、二溴卫矛醇(mitolactol),等;哌泊溴烷(pipobroman);索拉非尼;多柔比星和顺铂及其衍生物,等,以及上述化合物的任何组合和/或衍生物。
治疗活性剂可选自包括抗病毒剂和抗菌剂的组,例如阿克拉霉素(aclacinomycin)、放线菌素D(actinomycin)、安曲霉素(anthramycin)、偶氮丝胺酸(azaserin)、博莱霉素、放线菌素C(cuctinomycin)、卡柔比星(carubicin)、嗜癌素(carzinophilin)、色霉素(chromomycin)、更生霉素(ductinomycin)、柔红霉素(daunorbicin)、6-重氮-5-氧代-1-正亮氨酸(6-diazo-5-oxn-1-norleucin)、多柔比星、表阿霉素、丝裂霉素、mycophenolsaure、诺拉霉素(mogalumycin)、橄榄霉素(olivomycin)、匹来霉素(peplomycin)、光辉霉素(plicamycin)、泊非霉素(porfiromycin)、嘌呤霉素(puromycin)、链黑菌素(streptonigrin)、链脲菌素(streptozocin)、杀结核菌素(tubercidine)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin)、氨基糖苷类(aminoglycoside)或多烯类(polyene)、大环内酯类抗体(macrolid-antibiotics),和其任何组合和/或衍生物。
治疗活性剂可选自:内皮抑素,血管抑素,干扰素,血小板因子4(PF4),血小板反应素,转化生长因子β,金属蛋白酶-1、-2和-3(timp-1、-2和-3)的组织抑制剂,TNP-470,马立马司他(marimastat),新伐司他(neovastat),BMS-275291,COL-3,AG3340,沙利度胺(thalidomide),角鲨胺(squalamine),考布他汀(combrestastatin),SU5416,SU6668,IFN-[α],EMD121974,CAI,IL-12,如IM-862的放射增敏药物(radio-sensitizer drugs),甾体或非甾体抗炎药,或涉及血管新生的制剂,和其任何组合和/或衍生物。
治疗活性剂可选自包括核酸的组,其中术语“核酸”包括其中至少两个核苷酸彼此共价连接的寡核苷酸,以获得基因治疗或反义效果。核酸优选具有磷酸二酯键并包括具有不同骨架的类似物。类似物可具有骨架,包括例如磷酰胺硫代磷酸酯、二硫代磷酸酯、O-甲基亚磷酰胺化合物和肽-核酸-骨架及其化合物等。其它类似物是分别具有离子骨架、非离子骨架、或非核糖骨架的那些。含有一个或多个碳环糖的核酸可适合作为本发明使用的核酸。除了选择本领域已知的核酸和核酸类似物之外,还可使用天然产生的核酸及其类似物或核酸及其类似物的混合物的任何组合。
治疗活性剂可包括抗迁移、抗增殖或免疫抑制、抗炎或再内皮化剂(re-endotheliating agents),例如依维莫司(everolimus)、他克莫司(tacrolimus)、西罗莫司(sirolimus)、霉酚酸酯(mycofenolate-mofetil)、雷帕霉素(rapamycin)、紫杉醇、放线菌素D、安培丁(angiopeptin)、巴马司他(batimastate)、雌二醇、VEGF、他汀类药物(statins),和其衍生物和类似物。
治疗活性剂可包括阿片类受体激动剂和拮抗剂,显示激动/拮抗联合活性的化合物,和显示部分激动活性的化合物,例如:吗啡、长效吗啡(depotmorphine)、阿托品(etropin)、二乙酰吗啡、双氢吗啡、氢羟吗啡酮、左啡诺(levorpanol)、美沙酮(methadone)、左美沙酮(levomethadyl)、杜冷丁(meperidine)、芬太尼(fentanyl)、舒芬太尼(serpentanyl)、阿芬他尼(alpentanyl)、可待因(codeine)、二氢可待因酮(hydrocodone)、羟可待酮(oxycodone)、蒂巴因(thebaine)、地素吗啡(desormorphine)、尼可吗啡(nicomorphine)、二丙酰吗啡(dipropanoylmorphine)、苄吗啡(benzylmorphine)、乙基吗啡(ethylmorphine)、哌替啶(petidine)、美沙酮、曲马多(tramadol)、右旋达尔丰(dextropropoxyphene);纳洛酮(naloxone)和纳曲酮(naltrexone);和叔丁啡(buprenorphine)、纳布啡(buprenorphine)、布托啡诺(butorpanol)、喷他佐辛(pentazoxin)和乙基氯代环唑星(ethyl ketocyclazoxin)。
治疗活性剂及其组合可选自:肝素、合成的肝素类似物(例如,磺达肝癸钠)、水蛭素、抗凝血酶III、重组人活化蛋白α(drotrecogin alpha);纤维蛋白溶解剂如阿替普酶、纤维蛋白溶酶、溶解激酶、因子VIIa、前尿激酶、尿激酶、阿尼普酶、链激酶,等;血小板聚集抑制剂如乙酰水杨酸(阿司匹林)、噻氯匹定(ticlopidine)、氯吡格雷(clopidogrel)、阿昔单抗(abciximab)、葡聚糖,等;皮质类固醇如阿氯米松(alclometasone)、安西奈德(amcinonide)、增强的倍他米松(betamethasone)、倍氯米松(beclomethasone)、倍他米松(betamethasone)、布地奈德(budesonide)、可的松(cortisone)、氯倍他索(clobetasol)、氯可托龙(clocortolone)、地索奈德(desonide)、去羟米松(desoximetasone)、地塞米松、氟轻松(fluocinolone)、醋酸氟轻松(fluocinonide)、氟氢缩松(fluandrenolide)、氟尼缩松(flunisolide)、氟替卡松(fluticasone)、哈西奈德(halcinonide)、卤贝他索(halobetasol)、氢化可的松(hydrocortisone)、甲泼尼龙(methylprednisolone)、莫美他松(momethasone)、泼尼卡酯(prednicarbate)、泼尼松(prednisone)、泼尼松龙(prednisolone)、曲安西龙(triamcinolone),等;非甾体抗炎药(NSAID)如双氯芬酸(diclofenac)、二氟尼柳(diflunisal)、依托度酸(etodolac)、菲诺洛芬(fenoprofen)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、吲哚美辛(indomethacin)、酮基布洛芬(ketoprofen)、酮咯酸(ketorolac)、甲氯灭酸(meclofenamate)、甲灭酸(mefenamicacid)、美洛昔康(meloxicam)、萘丁美酮(nabumetone)、萘普生(naproxen)、奥沙普秦(oxaprozin)、吡罗昔康(piroxicam)、双水杨酸酯(salsalate)、舒林酸(sulindac)、托麦汀(tolmetin)、塞来昔布(celecoxib)、罗非昔布(rofecoxib),等;细胞抑制剂如生物碱类(alkaloide),如长春花碱、长春新碱,等和鬼臼毒素,等;细胞毒素抗生素如柔红霉素、阿霉素、其它蒽环类药物(anthracycline)和相关物质、博莱霉素、丝裂霉素,等;抗代谢物如叶酸类似物、嘌呤类似物或嘧啶类似物,等;紫杉醇、多西他赛、西罗莫司,等;铂化合物如卡铂、顺铂或奥沙利铂(oxaliplatin),等;安吖啶(amsacrin)、伊立替康、伊马替尼、拓扑替康(topotecan)、干扰素-α2a、干扰素-α2b、羟基脲(hydroxycarbide)、米替福新(miltefosine)、喷司他丁(pentostatin)、卟菲尔(porfimer)、阿地白介素、贝沙罗汀(bexaroten)、维A酸(tretinoin);抗雄激素和抗雌激素;抗心律不齐药如奎宁型抗心律不齐药,具体地,I型抗心律不齐药如奎尼丁型抗心律不齐药(quinidine typeantiarrhythmic)、奎尼丁(quinidine)、达舒平(disopyramid)、阿义吗啉(azmaline)、重酒石酸普拉马林(prajmalium bitartrate)、重酒石酸地他义铵(detajimium bitartrate),等;例如,利多卡因型抗心律不齐药如利多卡因(lidocaine)、美西律(mexiletin)、苯妥英(phenytoin)、妥卡尼(tocainid),等;例如,Ic型抗心律不齐药如普罗帕酮(propafenone)和氟卡尼(flecainide)(醋酸),等;II类抗心律不齐药β-受体阻滞剂如美托洛尔(metoprolol)、艾司洛尔(esmolol)、普萘洛尔(propranolol)、阿替洛尔(atenolol)、氧烯洛尔(oxprenolol),等;III型抗心律不齐药如胺碘酮(amiodarone)和索他洛尔(sotalol);IV型抗心律不齐药如地尔硫卓(diltiazem)、维拉帕米(verapamil)、戈洛帕米(gallopamil),等;其它抗心律不齐药如腺苷、奥西那林(orciprenaline)、异丙托溴铵(ipratropium)、溴化物(bromide),等;用于促进心肌中血管新生的制剂,例如血管内皮生长因子(VEGF)、碱性成纤维生长因子(bFGF)、非病毒DNA、病毒DNA、内皮生长因子,等;FGF-1、FGF-2、VEGF和TGF;抗生素、单克隆抗体、抗运载蛋白;干细胞、内皮祖细胞(EPCs);洋地黄糖苷类如乙酰地高辛(acetyl digoxin)/甲基地高辛(methyldigoxin)、洋地黄毒甙(digitoxin)、地高辛,等;强心苷类(cardiac glycosides)如哇吧因(ouabain)、海葱次苷(proscillaridin),等;抗高血压剂如甲基多巴(methyldopa),咪唑啉受体激动剂如CNS活性抗肾上腺素能物质,等;钙通道阻滞剂如硝苯地平(nifedipine)、尼群地平(nitrendipine),等;ACE抑制剂;喹普利拉(quinaprilate)、西拉普利(cilazapril)、莫西普利(moexipril)、群多普利(trandolapril)、螺普利(spirapril)、咪达普利(imidapril);血管紧张素II拮抗剂;坎地沙坦酯(candesartancilexetil)、缬沙坦(valsartan)、替米沙坦(telmisartan)、奥美沙坦酯(olmesartanmedoxomil)、依普罗沙坦(eprosartan);外周活化α-受体阻滞剂如哌唑嗪(prazosin)、乌拉地尔(urapidil)、多沙唑嗪(doxazosin)、布纳唑嗪(bunazosin)、特拉唑嗪(terazosin)、吲哚拉明(indoramin),等;血管扩张药如双肼酞嗪(dihydralazine)、二氯醋酸二异丙胺(diisopropylamine dichloraetate)、米诺地尔(minoxidil)、硝普酸钠(nitroprusside sodium),等;其它抗高血压剂如吲达帕胺(indapamide)、甲磺酸双氢麦角碱(co-dergocrine mesylate)、甲磺酸二氢麦角碱(dihydroergotoxin methanesulfonate)、西氯他宁(cicletanin)、波生坦(bosetan)、氟氢可的松(fludrocortisones),等;抗高血压药如磷酸二酯酶抑制剂如米力农(milrinon)和依诺昔酮(enoximon),具体地,肾上腺素能和多巴胺能物质,例如多巴酚丁胺(dobutamine)、肾上腺素(ephinephrine)、依替福林(etilefrine)、去甲苯福林(norfenefrine)、去甲肾上腺素(norepinephrine)、奥洛福林(oxilofrine)、多巴胺(dopamine)、米多君(midodrine)、福来君(pholedrine)、methyl ameziniumm,等;部分肾上腺素能受体激动剂如双氢麦角胺(dihydroergotamine);炎性细胞因子如纤连蛋白、聚赖氨酸、乙烯醋酸乙烯酯、TGFβ、PDGF、VEGF、bFGF、TNFα、NGF、GM-CSF、IGF-a、IL-1、IL-8、IL-6、生长激素,等;此外,粘合物质如氰基丙烯酸酯、铍、二氧化硅,等;此外,如促血红细胞生长素的生长因子,激素如促肾上腺皮质激素、促性腺激素、生长激素、促甲状腺激素、去氨加压素、特利加压素、pxytocin、西曲瑞克(cetrorelix)、可的瑞林(corticorelin)、亮丙瑞林(leuprorelin)、曲普瑞林(triptorelin)、戈那瑞林(gonadorelin)、加尼瑞克(ganirelix)、布舍瑞林(buserelin)、那法瑞林(naarelin)、戈舍瑞林(goserelin),等,和调节肽如生长抑素、奥曲肽(octreotid),等;骨和软骨刺激肽,重组人BMP-2(rhBMP-2),重组BMP如磷酸双盐(例如利塞膦酸(risedronate)、帕米膦酸(pamidronate)、伊班膦酸(ibandronate)、唑来膦酸(zoledronic acid)、氯屈瞵酸(clodronic acid)、羟基乙叉二膦酸(etidronic acid)、阿仑膦酸(alendronic acid)、替鲁膦酸(tiludronic acid),等),骨形态发生蛋白(BMP),其是氟化物如单氟磷酸钠、氟化钠,等;降钙素、双氢速甾醇(dihydrotachystyrol);表皮生长因子(EGF)、血小板源性生长因子(PDGF)、成纤维细胞生长因子(FGF)、转化生长因子-b(TGF-b)、转化生长因子-a(TGF-a)、红细胞生成素(EPO)、胰岛素样生长因子-I(IGF-I)、胰岛素样生长因子-II(IGF-II)、白细胞介素-1(IL-1)、白细胞介素-2(IL 2)、白细胞介素-6(IL-6)、白细胞介素-8(IL-8)、肿瘤坏死因子-a(TNF-a)、肿瘤坏死因子-b(TNF-b)、干扰素-g(INF-g)、集落刺激因子(CSF);单核细胞趋化蛋白、成纤维细胞刺激因子1、组胺、纤维蛋白或纤维蛋白原、内皮素-1、血管紧张素II、胶原、溴隐亭(bromocriptine)、美西麦角(metysergide)、甲氨蝶呤、四氯化碳、硫代乙酰胺和乙醇;此外,银(离子)、二氧化钛,具体地,例如,β-内酰胺酶敏感青霉素如苄青霉素(benzylpenicillin)(青霉素G)、苯氧甲基青霉素(phenoxymethyl phenicillin)(青霉素V),等;例如,β-内酰胺酶抗性青霉素如阿莫西林(amoxicillin)、氨苄青霉素(ampicillin)、巴氨西林(bacampicillin),等;酰氨基青霉素如美洛西林(mezlocillin)和哌拉西林(piperacillin);羧基青霉素如头孢唑啉(cefazoline)、头孢呋肟(cefuroxim)、头孢西丁(cefoxitin)、头孢替安(cefotiam)、头孢克洛(cefaclor)、头孢羟氨苄(cefadroxil)、头孢氨苄(cefalexin)、氯碳头孢(loracarbef)、头孢克肟(cefixim)、头孢呋辛酯(cefuroximaxetil)、头孢布烯(ceftibuten)、头孢泊肟酯(cefpodoximproxetil),等;氨曲南(aztreonam)、厄他培南(ertapenem)、美罗培南(meropenem);β-内酰胺抑制剂如舒巴坦(sulbactam)和对甲苯磺酸舒他西林(sulfamicillintosylate);四环素如强力霉素(doxycycline)、米诺环素(minocycline)、四环素、金霉素(chlorotetracycline)、土霉素(oxytetracycline),等;氨基糖苷类如庆大霉素(gentamicin)、新霉素(neomycin)、链霉素(streptomycin)、妥布霉素(tobramycin)、阿米卡星(amikacin)、奈替米星(netilmicin)、巴龙霉素(paromomycin)、framyceetin、大观霉素(spectinomycin),等;大环内酯类抗生素如阿奇霉素(azithromycin)、克拉霉素(clarithromycin)、红霉素(erythromycin)、罗红霉素(roxithromycin)、螺旋霉素(spiramycin)、交沙霉素(josamycin),等;林可胺类如克林霉素(clindamycin)和林可霉素(ciprofloxacin);旋转酶抑制剂如氟喹诺酮类(fluoroquinolone),例如,环丙沙星(ciprofloxacin)、氧氟沙星(ofloxacin)、莫西沙星(moxifloxacin)、诺氟沙星(norfloxacin)、加替沙星(gatifloxacin)、依诺沙星(enoxacin)、氟罗沙星(fleroxacin)、左氧氟沙星(levofloxacin),等;喹诺酮类如吡哌酸(pipemidic acid);磺胺(sulfonamide)、甲氧苄啶(trimethoprim)、磺胺嘧啶(sulfadiazine)、sulffalene;糖肽类抗生素如万古霉素(vancomycin)和替考拉宁(teicoplanin);多肽类抗生素如多粘菌素(polymyxin),例如,抗敌素(colistin)和多粘菌素-b(polymyxin-b),硝基咪唑类衍生物,例如,甲硝唑(metronidazole)和替硝唑(tinidazole);氨基喹诺酮如氯喹(chloroquine)、甲氟喹(mefloquine)、硫酸羟基氯喹(hydroxychloroquine),等;双胍类如氯胍(proguanil);奎宁生物碱类如乙胺嘧啶(pyrimethamine)和二氨基嘧啶(diaminopyrimidine);酰胺醇类如氯霉素(chloramphenicol);利福布汀(rifabutin)、氨苯砜(dapson)、夫西地酸(fusidic acid)、磷霉素(fosfomycin)、硝呋太尔(nifuratel)、泰利霉素(telithromycin)、夫沙芬净(fusafungin)、喷他脒羟乙磺酸盐(pentamidine diisethionate)、利福平(rifampicin)、牛磺罗定(taurolidine)、阿托伐醌(atovaquone)、利奈唑胺(linezolid);病毒静力学药如阿昔洛韦(aciclovir)、更昔洛韦(ganciclovir)、泛昔洛韦(famciclovir)、膦甲酸(foscarnet)、肌苷-(二甲氨丙醇-4-乙酰氨基苯甲酸酯)(inosine-(dimefranol-4-acetamidobenzoate))、缬更昔洛韦(valganciclovir)、伐昔洛韦(valaciclovir)、西多福韦(cidofovir)、溴夫定(brivudin),等;抗逆转录病毒活性成分(核苷类似物逆转录酶抑制剂和衍生物)如拉米夫定(lamivudine)、扎西他滨(zalcitabine)、地达诺辛(didanosine)、齐多夫定(zidovudin)、泰诺福韦(tenofovir)、司他夫定(stavudin)、阿巴卡韦(avacavir),等;非核苷类似物逆转录酶抑制剂;安普那韦(amprenavir)、茚地那韦(indinavir)、沙奎那韦(saquinavir)、洛匹那韦(lopinavir)、利托那韦(ritonavir)、萘非那韦(nelfinavir);和金刚烷胺(amantadine)、利巴韦林(amantadine)、扎那米韦(zanamivir)、奥司他韦(oseltamivir)或拉米夫定(lamivudine),和其任何组合和混合物。
治疗活性剂可以是抗抑郁、抗精神病或抗焦虑剂,包括例如:阿普唑仑(alprazolam)、阿莫沙平(amoxapine)、苯他西泮(bentazepam)、溴西泮(bromazepam)、氯拉卓酸(clolazepine)、氯巴占(clobazam)、氯噻西泮(clotiazepam)、地西泮(diazepam)、劳拉西泮(lorazepam)、氟硝西泮(flunitrazepam)、氟西泮(flulazepam)、氯甲西泮(lormetazepam)、美达西泮(medazepam)、硝西泮(nitrazepam)、奥沙西泮(oxazepam)、替马西泮(temazepam)、马普替林(maprotiline)、米安舍林(myanserine)、去甲替林(nortriptyline)、利培酮(risperidone)、舍曲林(sertraline)、曲唑酮(trazodone)、氟哌啶醇(valoperidol)、马来酸曲米帕明氟西汀(trimipramine maleate fluoxetine)、恩丹西酮(ondansetron)、咪达唑仑(midazolam)、氯丙嗪(chlorpromazine)、氟哌啶醇(haloperidol)、三唑仑(triazolam)、氯氮平(clozapine)、氯丙嗪(fluoropromazine)、癸氟奋乃静(fluphenazine decanoate)、氟阿尼酮(fluanisone)、奋乃静(perfenazine)、匹莫奇特(pimozide)、丙氯拉嗪(prochlorperazine)、舒必利(sulpiride)、硫利达嗪(thioridazine)、帕罗西汀(paroxetine)、西酞普兰(citalopram)、安非他酮(bupropion)、苯乙肼(phenelzine)、奥氮平(olanzapine)、双丙戊酸钠(divalproex sodium)和文拉法辛(venlafaxine)。
治疗活性剂可包括阿片受体激动剂和拮抗剂,和表现激动/拮抗联合活性的化合物,和表现部分激动活性的化合物,例如:吗啡、长效吗啡、乙烯啡、二乙酰吗啡、双氢吗啡、氢羟吗啡酮、左啡诺、美沙酮、左美沙酮、杜冷丁、芬太尼、舒芬太尼、阿芬他尼、可待因、二氢可待因酮、羟可待酮、蒂巴因、地素吗啡、尼可吗啡、二丙酰吗啡、苄吗啡、乙基吗啡、哌替啶、美沙酮、曲马多、右旋达尔丰;纳洛酮和纳曲酮;和叔丁啡、纳布啡、布托啡诺、喷他佐辛和乙基氯代环佐辛。
治疗活性剂可以是三环化合物,包括例如偶氮噻吩(azothiophene)、阿米替林(amitriptyline)、法莫替丁(famotidine)、异丙嗪(promethazine)、帕罗西汀(paroxetine)、奥卡西平(oxcarbazepine)和米氮平(mirtazapine)。
治疗活性剂可以是抗糖尿病药,包括例如醋磺环已脲(acetohexamide)、氯磺丙脲(chlorpropamide)、格列本脲(glibenclamide)、格列齐特(gliclazide)、格列吡嗪(glipizide)、甲福明(metformin)、妥拉磺脲(tolazamide)、格列美脲(glimepiride)和甲苯磺丁脲(tolbutamide)。
治疗活性剂可以是抗癫痫剂,包括例如氯丙酰苄胺(beclamide)、卡马西平(carbamazepine)、加巴喷丁(gabapentin)、噻加宾(tiagabine)、氨己烯酸(vigabatrin)、托吡酯(topiramate)、氯安定(clonazepam)、乙苯妥英(ethotoin)、美芬妥因(metodine)、甲琥胺(methsuximide)、甲苯比妥(methyl phenobarbitone)、奧卡西平(oxycarbazepine)、甲乙双酮(paramethadione)、苯乙酰脲(phenacemide)、苯巴比妥(phenobarbitone)、苯妥英(phenyltoin)、密朗丁(phensuximide)、扑米酮(primidone)、舒布硫胺(sulthiamine)、苯妥英钠(phenytoin sodium)、呋喃妥因一水合物(nitrofurantoin monohydrate)、加巴喷丁(gabapentin)、拉莫三嗪(lamotrigine)、唑尼沙胺(zonisamide)、乙琥胺(ethosuximide)和丙戊酸(valproic acid)。
治疗活性剂可以是催眠/镇静药和/或肌肉松弛剂,包括例如酒石酸唑吡坦(zolpidem tartrate)、异戊巴比妥(amylobarbitone)、巴比妥(barbitone)、丁巴比妥(butobarbitone)、戊巴比妥(pentobarbitone)、溴替唑仑(brotizolam)、乙溴酰脲(carbromal)、氯氮卓(chlordiazepoxide)、氯美噻唑(chlormethiazole)、瓦尔米(ethinamate)、甲丙氨酯(meprobamate)、美他沙酮(methaqualone)、环苯扎林(cyclobenzaprene)、环苯扎林(cyclobenzaprine)、替扎尼定(tizanidine)、巴氯芬(baclofen)、异丁烯丙巴比妥(butalbital)、佐匹克隆(zopiclone)、阿曲库铵(atracurium)、筒箭毒碱(tubocurarine)和苯巴比妥(phenobarbital)。
治疗活性剂可以是抗真菌药、抗原虫药或抗寄生虫药,包括例如:两性霉素(amphotericin)、硝酸布康唑(butoconazole nitrate)、克霉唑(clotrimazole)、硝酸益康唑(econazole nitrate)、氟康唑(fluconazole)、氟胞嘧啶(flucytosine)、灰黄霉素(griseofulvin)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、咪康唑(miconazole)、纳他霉素(natamycin)、制霉菌素(nystatin)、硝酸硫康唑(sulconazolenitrate)、曲康唑(terconazole)、噻康唑(thioconazole)和十一烯酸(undecenoic acid);苄硝唑(benznidazole)、氯碘羟喹(clioquinol)、癸氧喹酯(decoquinate)、双碘喹啉(diiodohydroxyquinoline)、糠酸二氯尼特(diloxanide furoate)、二硝托胺(dinitolmide)、呋喃唑酮(furazolidone)、甲硝唑(metronidazole)、尼莫拉唑(nimorazole)、呋喃西林(nitrofurazone)、奥硝唑(ornidazole)、特比奈芬(terbinafine)、克霉唑、氯喹、甲氟喹、依曲康唑、乙胺嘧啶、吡喹酮(praziquantel)、疟疾平(quinacrine)、甲苯达唑(mebendazole)和替硝唑。
治疗活性剂可以试是抗高血压剂或心脏病药,包括例如坎地沙坦(candesartan)、肼屈嗪(hydralazine)、可乐定(clonidine)、氨苯蝶啶(triamterene)、非洛地平(felodipine)、吉非罗齐(gemfibrozil)、非诺贝特(fenofibrate)、硝苯地平、哌唑嗪、美加明(mecamylamine)、多沙唑嗪(doxazosin)、多巴酚丁胺和坎地沙坦(cilexetil)。
治疗活性剂可以是抗偏头痛药,包括例如甲磺酸二氢麦角胺(dihydroergotaminemesylate)、酒石酸麦角胺(ergotamine tartrate)、马来酸美西麦角(methisergidemaleate)、马来酸苯噻啶(pizotifen maleate)和琥珀酸舒马曲坦(sumatriptansuccinate)。
治疗活性剂可以是抗毒蕈碱剂,包括例如阿托品(atropine)、苯海索(benzhexol)、比哌立登(biferdene)、普罗吩胺(ethopropazine)、莨菪碱(hyoscyamine)、溴美喷酯(mepenzolate bromide)、奥昔布宁(oxybutynin)、盐酸奥西克利平(oxyphencyclimine)和托吡卡胺(tropicamide)。
治疗活性剂可以是抗肿瘤剂(或免疫抑制剂),包括例如氨鲁米特(aminoglutethimide)、安吖啶(amsacrine)、硫唑嘌呤(azathioprine)、白消安、苯丁酸氮芥、环孢素(cyclosporin)、达卡巴嗪、雌莫司汀、依托泊苷(etoposide)、洛莫司汀、美法仑、巯嘌呤(mercaptopurine)、甲氨蝶呤、丝裂霉素、米托坦(mitotane)、米托蒽醌(mitoxanthrone)、甲基苄肼(procarbazine)、枸橼酸他莫昔芬(tamoxifen citrate)、睾内酯(testolactone)、他克莫司和西罗莫司。
治疗活性剂可以是抗帕金森剂,包括例如甲磺酸溴隐亭(bromocriptinemesylate)、左旋多巴(levodopa)、托卡朋(tolcapone)、罗匹尼罗(ropinitrol)、溴隐亭,降血糖剂,例如磺酰脲类双胍(sulfonylurea biguanide)、α-葡糖苷酶抑制剂、噻唑烷二酮(thiazolidinedione)、卡麦角林(cabergoline)、卡比多巴(carbidopa)和马来酸麦角乙脲(lisuride maleate)。
治疗活性剂可以是抗甲状腺剂,包括例如卡比马唑(carbimazole)和丙硫氧嘧啶(propylthiouracil)。
治疗活性剂可以是心肌收缩剂,包括例如氨力农(amrinone)、米力农(milrinone)、洋地黄毒甙、依诺昔酮(enoximone)、毛花苷C(lanatoside C)和甲地高辛(medigoxin)。
治疗活化剂可以是低血脂症或高血脂症治疗剂,包括例如非诺贝特、安妥明(clofibrate)、普罗布考(probucol)、依折麦布(ezetimibe)和托彻普(torcetrapib)。
治疗活性剂可以是抗炎剂,包括例如美洛昔康(meloxycam)、曲安西龙、色甘酸(cromolyn)、奈多罗米(nedocromil)、硫酸羟基氯喹、孟鲁司特(montelukast)、齐留通(zileuton)、扎鲁司特(zafirlukast)和美络昔康(meloxicamp)。
治疗活性剂可以是抗组胺药,包括例如非索非那定(fexofenadine)、水合氯醛(chloral hydrate)、羟嗪(hydroxyzine)、异丙嗪、西替利嗪(cetirizine)、西咪替丁(cimetidine)、赛克利嗪(cyclizine)、美克洛嗪(meclizine)、茶苯海明(dimenhydrinate)、氯雷他定(loratadine)、尼扎替丁(nizatadine)和异丙嗪。
治疗活性剂可以是抗溃疡药,包括例如奧美拉唑(omeprazole)、兰索拉唑(lansoprazole)、潘妥拉唑(pantoprazole)和雷尼替丁(ranitidine)。
治疗活化剂可以是利尿剂,包括例如氢氯噻嗪(hydrochlorothiazide)、阿米洛利(amyloride)、乙酰唑胺(acetazolamide)、呋塞米(furosemide)和托拉塞米(torsemide)。
治疗活性剂可以是类视黄醇,包括例如:第一代类视黄醇如视黄醇、视黄醛、维A酸(视黄酸,retin-A)、异维A酸和阿利维A酸;第二代类视黄醇如依曲替酯(etretinate)和其代谢产物,即阿利维A酸;第三代类视黄醇如他扎罗汀(tazarotene)、贝沙罗汀(bexarotene)和阿达帕林(adapalene)。
治疗活性剂可以是他汀类药物及其衍生物,包括例如阿托伐他汀(atorvastatin)、氟伐他汀(fluvastatin)、洛伐他汀(lovastatin)、制霉菌素、瑞舒伐他汀(rosuvastatin)、普伐他汀(pravastatin)、奧利司他(orlistat)和辛伐他汀(simvastatin)。
治疗活性剂可以是刺激剂,包括例如安非他命(amfetamine)、芬特明(pentamine)、酪胺(tyramine)、麻黄碱(ephedrine)、间羟胺(metaraminol)、去氧肾上腺素(phenylephrine)、右旋安非他命(dexamfetamine)、右芬氟拉明(dexfenfluramine)、氟苯丙胺(fenfluramine)、尼古丁(nicotine)、咖啡因(caffeine)和马吲哚(marginol)。
治疗活性剂可以是血管舒张药,包括例如卡维地洛(carvedilol)、特拉唑嗪(terazosin)、酚妥拉明(phentolamine)和薄荷醇(menthol)。
治疗活性剂可以是抗阿尔茨海默病药,包括例如左乙拉西坦(levetiracetam)、左乙拉西坦和多奈哌齐(donepezil)。
治疗活性剂可以是ACE抑制剂,包括例如贝那普利(benzapril)、依那普利(enalapril)、雷米普利(ramipril)、福辛普利钠(fosinopril sodium)、赖诺普利(lisinopril)、米诺地尔、异山梨酯(isosorbide)、雷米普利和喹那普利(quinapril)。
治疗活性剂可以是β-肾上腺素受体拮抗剂,包括例如阿替洛尔、噻吗洛尔(timolol)、吲哚洛尔(pindolol)、盐酸普萘洛尔(pronanolol hydrochloride)、比索洛尔(bisoprolol)、艾司洛尔(esmolol)、琥珀酸美托洛尔(metoprolol succinate)、美托洛尔(metoprolol)和酒石酸美托洛尔(metoprolol tartrate)。
治疗活性剂可以是血管紧张素II拮抗剂,其包括氯沙坦(losartan)。
治疗活性剂可以是血小板抑制剂,包括例如阿昔单抗、氯吡格雷、替罗非班(tirofiban)和阿司匹林。
治疗活性剂可以是醇类或酚类,包括例如曲马多、盐酸曲马多(tramadolhydrochloride)、别嘌醇(allopurinol)、骨化三醇(calcitriol)、西洛他唑(cilostazol)、索他洛尔、熊去氧胆酸(ursodiol)、溴哌醇(bromperidol)、氟哌利多(droperidol)、氟哌噻吨癸酸酯(flupenthixol decanoate)、沙丁胺醇(albuterol)、硫酸沙丁胺醇(albuterolsulfate)、卡利普多(carisoprodol)、氯倍他索、罗匹尼罗(ropinirol)、拉贝洛尔(labetalol)和美索巴莫(methocarbamol)。
治疗活性剂可以是酮类或酯类,包括例如胺碘酮、氟替卡松、螺内酯(spironolactone)、泼尼松、曲唑酮、去羟米松(desoxymethason)、甲基泼尼松(methylprednisolone)、苯佐那酯萘丁美酮(benzonatate nabumetone)和丁螺环酮(buspirone)。
治疗活性剂可以是抗呕吐药,包括例如甲氧氯普胺(metoclopramide)。
治疗活性剂可以是眼科治疗剂,包括例如多佐胺(dorzolamide)、溴莫尼定(brimonidine)、奥洛他定(olopatadine)、环喷托酯(cyclopentolate)、匹罗卡品(pilocarpine)和碘依可酯(ecothiopate)。
治疗活性剂可以是抗凝血剂或抗血栓剂,包括例如华法林(warfarin)、依诺肝素(enoxaparin)和来匹卢定(lepirudin)。
治疗活性剂可以是痛风治疗剂,包括例如丙磺舒(probenesin)和磺吡酮(sulfinpyrazone)。
治疗活性剂可以是COPD或哮喘治疗剂,包括例如异丙托溴铵。
治疗活性剂可以是骨质疏松症治疗剂,包括例如雷洛昔芬(raloxifene)、帕米膦酸(pamidronate)和利塞膦酸。
治疗活性剂可以是用于化妆品的肽包括,包括例如乙酰基六肽-3、乙酰基六肽-8、乙酰基八肽和1-肌肽。
治疗活性剂可包括,例如:包括类毒素(灭活的有毒化合物)的疫苗;蛋白质、蛋白质亚基和多肽;聚核苷酸如DNA和RNA;缀合物;包含皂苷、病毒体、无机和有机佐剂的疫苗,例如zostavax。
治疗活性剂可以是营养医学或美容医学活性物质,包括例如:辅酶Q10(或泛醌)、泛醇或白藜芦醇;类胡萝卜素类如α、β或γ-胡萝卜素、番茄红素、叶黄素、玉米黄质和虾青素;植物营养素类如番茄红素、叶黄素、和硫代黄嘌呤(thioxanthin);ω-3-脂肪酸,包括亚油酸、缀合的亚油酸、二十二碳六烯酸(DHA)和二十碳五烯酸(EPA)和它们的甘油酯;油溶性维生素,包括维生素D(D2、D3及其衍生物)、维生素E(α、β、γ、δ-生育酚或α、β、γ、δ-生育三稀酚)、维生素A(视黄醇、视黄醛、视黄酸及其衍生物)、维生素K(K1、K2、K3及其衍生物)、三癸酸/辛酸甘油酯、叶酸、铁、烟酸、单亚油酸甘油酯、ω-6脂肪酸、维生素F、硒、氰钴胺、芦荟、β-葡聚糖、红没药醇、山茶茶(绿茶)提取物、崩大碗(雷公根)提取物、橄榄油鲸蜡醇酯、叶绿素、甜橙油、椰油酰基脯氨酸、二辛基醚、月桂亚氨基二丙酸生育酚磷酸酯盐二钠(维生素E磷酸盐)、甘油、甘油单油酸酯、甘草提取物、榛子(金缕梅)提取物、乳酸、卵磷脂、叶黄素、澳洲坚果籽油、洋甘菊提取物、月见草油、橄榄叶提取物、米糠油、鳄梨油、马利筋提取物(milkweed extract)、石榴固醇类、白藜芦醇、玫瑰油、檀香油、二氧化钛、叶酸、甘油、亚油酸甘油酯(ω-6(脂肪酸维生素F))、维生素A棕榈酸酯、葡萄籽油、卤贝他索、腺苷、三磷酸腺苷、α羟基酸、尿囊素、透明质酸及衍生物、isolutrol、传明酸、甘醇酸、精氨酸、抗坏血酸葡糖胺、抗坏血酸棕榈酸酯、水杨酸、鼠尾草酸、α-硫辛酸、γ-亚麻酸(GLA)、泛醇、维生素A丙酸酯、维生素A棕榈酸酯、呋喃甲基腺嘌呤、视黄醛、醣肽、艾地苯醌、二甲基乙醇胺(DMAE)、烟酰胺、β-葡聚糖、棕榈酰五肽-4、棕榈酰寡肽/四肽-7、依托考昔、神经酰胺、苯丙氨酸、葡醛内酯、左旋肉碱、羟磷灰石、棕榈酰三肽-3、磷胆碱(phoscholine)、氧化锌、α-红没药醇、丁香酚、水飞蓟宾、大豆异黄酮、梓醇、卡密松山金车源伪愈创木内酯、迷迭香酸、迷迭香酚、水杨酸类,例如,水杨甙、水杨醇和水杨酸,蒲公英甾醇、α-山莴苣醇、异山莴苣醇、蒲公英苷(taraxacoside)、神经酰胺、熊果苷、姜酚、姜烯酚、金丝桃素、弹力素、胶原及其肽。
在本发明的组合物中,可以将多孔二氧化硅颗粒(介孔二氧化硅颗粒,MSP)的表面和/或孔的内部修饰。
修饰是指用其他官能团取代二氧化硅颗粒中的硅烷醇基(Si-OH)的-OH官能团。更具体地,修饰可通过血管内注射根据本发明的组合物而用于减少副作用如由于硅烷醇基团与红细胞表面上的季铵基团之间的相互作用所引起的溶血。此外,取决于要被修饰的官能团的类型和修饰的程度,适合于负载的上述生物活性物质的类型可以不同。另外,由于ζ电势可能变化并且ζ电势的强度也可能引起大小的差异,因此可以通过颗粒之间的电荷排斥来防止血流中颗粒间的沉淀或聚集,从而确保血流中的流动顺畅。此外,控制多孔二氧化硅颗粒与释放生物活性物质的环境之间的相互作用,以便调节颗粒的降解速率以控制生物活性物质的释放速率。另外,可以调节生物活性物质与纳米颗粒的结合力以控制通过从颗粒的扩散的生物活性物质的释放。
可以选择化学或生物学修饰用于上述修饰,但不限于此。实际上,可以通过本领域公知的方法来进行修饰。然而,考虑到通过与二氧化硅颗粒的共价结合的官能团的取代,优选采用化学修饰(chemical modification)。此外,颗粒表面和孔的内部可以以相同的方式修饰或可以不同的方式修饰。
可以通过使要引入的具有亲水性的、疏水性的、阳离子性的或阴离子性的取代基的化合物与颗粒反应来实施修饰,但不限于此。实际上,可以通过使任何具有取代基的化合物与颗粒反应实施修饰,所述化合物负载生物活性物质,将生物活性物质转移至靶细胞,负载用于其他目的材料或结合其他附加的取代基,其中取代基可进一步包括抗体、配体、细胞可渗透肽或适体,等。
该化合物可以是例如具有C1至C10烷氧基的烷氧基硅烷,但不限于此。烷氧基硅烷具有一个或多个烷氧基,例如1至3个烷氧基,并且可以包括要引入到其中烷氧基没有键合的位点的取代基或由上述取代基取代的另一取代基。
当烷氧基硅烷与多孔二氧化硅颗粒反应时,在硅原子和氧原子之间形成共价键,使得烷氧基硅烷可以键合至多孔二氧化硅颗粒表面和/或孔的内部。此外,由于烷氧基硅烷具有要引入的取代基,所以可以将相应的取代基引入多孔二氧化硅颗粒表面和/或孔的内部。
反应可以通过使分散在溶剂中的多孔二氧化硅颗粒与烷氧基硅烷反应来进行。可以使用水和/或有机溶剂作为溶剂,并且有机溶剂可以是例如:醚类,例如1,4-二噁烷(特别是环状醚);卤代烃类,例如氯仿、二氯甲烷、四氯化碳、1,2-二氯乙烷、二氯乙烯、三氯乙烯、四氯乙烯、二氯丙烷、戊基氯、1,2-二溴乙烷,等;酮类,例如丙酮、甲基异丁基酮、γ-丁内酯、1,3-二甲基咪唑啉酮、甲基乙基酮、环己酮、环戊酮、4-羟基-4-甲基-2-戊酮,等;碳基芳族化合物,例如苯、甲苯、二甲苯、四甲基苯,等;烷基酰胺,例如N,N-二甲基甲酰胺、N,N-二丁基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮,等;醇类,例如甲醇、乙醇、丙醇、丁醇,等;二醇醚类(溶纤剂类),例如乙二醇单乙醚、乙二醇单甲醚、乙二醇单丁醚、二甘醇单乙醚、二甘醇单甲醚、二甘醇单丁醚、丙二醇单甲醚、丙二醇单乙醚、二丙二醇二乙醚、三甘醇单乙醚,等;和其他二甲基乙酰胺(DMAc)、N,N-二乙基乙酰胺、二甲基甲酰胺(DMF)、二乙基甲酰胺(DEF)、N,N-二甲基乙酰胺(DMAc)、N-甲基吡咯烷酮(NMP)、N-乙基吡咯烷酮(NEP)、1,3-二甲基-2-咪唑啉酮、N,N-二甲基甲氧基乙酰胺、二甲基亚砜、吡啶、二甲基砜、六甲基膦酰胺、四甲基脲、N-甲基己内酰胺、四氢呋喃、间二噁烷、对二噁烷、1,2-二甲氧基乙烷等。具体地,可以使用甲苯,但不限于此。
颗粒与烷氧基硅烷的反应可以例如在加热下实施,其中加热可以在80至180℃下,例如,在80至160℃、80至150℃、100至160℃、100至150℃、110至150℃的范围内等进行,但不限于此。
此外,颗粒与烷氧基硅烷的反应可以实施4至20小时,例如,在4至18小时、4至16小时、6至18小时、6至16小时、8至18小时、8至6小时、8至14小时、10至14小时的范围内等,但不限于此。
在上述修饰中,可以进行用阳离子性取代基的修饰以使颗粒带正电或负载带负电荷的生物活性物质,并且可以通过使颗粒与例如具有碱性基团的烷氧基硅烷反应来进行,所述碱性基团即为含氮基团,例如氨基、氨基烷基等。具体地,可以使用N-[3-(三甲氧基甲硅烷基)丙基]乙二胺、N1-(3-三甲氧基甲硅烷基丙基)二乙烯三胺、(3-氨基丙基)三甲氧基硅烷、N-[3-(三甲氧基甲硅烷基)丙基]苯胺、三甲氧基[3-(甲基氨基)丙基]硅烷、3-(2-氨基乙基氨基)丙基二甲氧基甲基硅烷,等,但不限于此。
在上述修饰中,可以进行用阴离子性取代基的修饰以使颗粒带负电或负载带正电的生物活性物质,并且可以通过使颗粒与例如具有酸性基团的烷氧基硅烷反应而进行,所述酸性基团如羧基、磺酸基、硫醇基等。具体地,可以使用(3-巯基丙基)三甲氧基硅烷,但不限于此。
在上述修饰中,用亲水性取代基的修饰在使用和配制根据本发明的组合物的容易性方面具有优势。实际上,可以通过使颗粒与例如具有羧基、氨基、羰基、巯基、磷酸基、硫醇基、铵基、酯基、硫代酰亚胺基,甲酰亚胺基、酮基、醚基、茚基、磺酰基、聚乙二醇基等的烷氧基硅烷反应来获得这些优势。具体地,可以使用N-[3-(三甲氧基甲硅烷基)丙基]乙二胺、N1-(3-三甲氧基甲硅烷基丙基)二亚乙基三胺、(3-氨基丙基)三甲氧基硅烷、(3-巯基丙基)三甲氧基硅烷、三甲氧基[3-(甲基氨基)丙基]硅烷、3-(2-氨基乙基氨基)丙基二甲氧基甲基硅烷,但不限于此。
在上述修饰中,用疏水性取代基的修饰具有增强与水溶性差的(疏水性的)生物活性物质的结合力的优势。实际上,可以通过使颗粒与例如具有取代或未取代的C1至C30烷基、取代或未取代的C3至C30环烷基、取代或未取代的C6至C30芳基、取代或未取代的C2至C30杂芳基、卤素、C1至C30酯基、含卤素基团或等的烷氧基硅烷反应来进行修饰。具体地,可以使用三甲氧基(十八烷基)硅烷、三甲氧基-正辛基硅烷、三甲氧基(丙基)硅烷、异丁基(三甲氧基)硅烷、三甲氧基(7-辛烯-1-基)硅烷、三甲氧基(3,3,3-三氟丙基)硅烷、三甲氧基(2-苯基乙基)硅烷、乙烯基三甲氧基硅烷、氰基甲基,3-[(三甲氧基甲硅烷基)丙基]三硫代碳酸酯、(3-溴丙基)三甲氧基硅烷,等,但不限于此。
修饰可以组合进行,例如,可以在外表面或孔的内部进行两种以上的表面修饰。作为更具体的实例,可以通过将具有羧基的化合物通过酰胺键结合到引入了氨基的二氧化硅颗粒上而使带正电荷的颗粒改变为具有不同的表面性质,但不限于此。
在修饰时,可以根据修饰的程度选择反应温度、时间和用于修饰的化合物的量。此外,取决于生物活性物质的亲水性、疏水性和电荷水平而变化反应条件可以调节二氧化硅颗粒的亲水性、疏水性和电荷水平,从而控制生物活性物质的释放速率。例如,如果生物活性物质在中性pH下具有强的负电荷,则可以提高反应温度、可以延长反应时间、或者也可以增加要处理的化合物的量,从而使多孔二氧化硅颗粒具有强的正电荷,但不限于此。
在本发明的组合物中,多孔二氧化硅颗粒(介孔二氧化硅颗粒,MSP)是可生物降解的颗粒。当可生物降解的颗粒负载生物活性物质然后在体内施用时,这些颗粒在体内可生物降解,同时释放生物活性物质,由此颗粒在体内缓慢降解,同时使负载的生物活性物质能够具有持续释放特性。例如,当下式1中的吸光度比达到1/2时,t为20以上。
[式1]
At/A0
(其中A0为通过将5ml的包括1mg/ml所述多孔二氧化硅颗粒的悬浮液置于具有50kDa直径的孔的圆筒状渗透膜中来测定的所述多孔二氧化硅颗粒的吸光度,
其中15ml的与所述悬浮液相同的溶剂存在于所述渗透膜的外部并与所述渗透膜接触,所述渗透膜的内部和外部在37℃和60rpm下水平搅拌,悬浮液的pH为7.4,和
At为在测定A0后t小时测定的多孔二氧化硅颗粒的吸光度)。
式1表示多孔二氧化硅颗粒在类似于体内的环境下降解的速率,其中吸光度A0和At可以例如在将多孔二氧化硅颗粒和悬浮液置于圆筒状渗透膜中之后,进一步将相同悬浮液注入渗透膜的外部测定。
悬浮液可以是缓冲溶液,和例如选自由磷酸盐缓冲盐水(PBS)和模拟体液(SBF)组成的组的至少一种,并且更具体地是PBS。
颗粒是可生物降解的并且可以在悬浮液中缓慢降解,其中50kDa的直径相当于约5nm,生物降解的颗粒可穿过50kDa的渗透膜,将该圆筒状渗透膜在60rpm下水平搅拌以使其均匀混合,并且降解的颗粒可以从渗透膜出来。
式1中的吸光度可以在,例如,用新的悬浮液替换渗透膜外部的悬浮液的环境下测定。悬浮液可以为定期替换的悬浮液,所述悬浮液以恒定周期替换。其中恒定周期可为周期性地或无规律的。例如,可在以下范围内进行替换:1小时至1周,特别地,以1小时、2小时、3小时、6小时、12小时、24小时间隔,或以2天、3天、4天、7天间隔等,但不限于此。
吸光度比达到1/2意味着t时间后的吸光度变为初始吸光度的一半,因此意味着已降解约一半的多孔二氧化硅颗粒。
当式1的吸光度比达到1/2时,t为20以上或24以上,例如,t可为20至120,具体地,在上述范围内的20至96、20至72、30至70、40至70、50至65等,但不限于此。
颗粒的特征在于,当式1中的吸光度比达到1/5时,t可为例如70至140,具体地,在上述范围内的80至140、80至120、80至110、70至140、70至120、70至110等,但不限于此。
颗粒的特征在于,当式1中的吸光度比达到1/20时,t可为例如130至220,具体地,在上述范围内的130至200、140至200、140至180、150至180等,但不限于此。
颗粒的特征在于,当测定的吸光度达到0.01以下时,t可为例如250以上,具体地,在上述范围内的300以上、350以上、400以上、500以上、1000以上等,上限为2000,但不限于此。
颗粒的特征在于,式1中的吸光度比与t具有高水平的正相关,具体地,皮尔森相关系数可以为0.8以上,例如0.9以上、0.95以上等。
式1中的t是指多孔二氧化硅颗粒在类似于体内的环境下降解的速率,例如可通过调节例如表面积、粒径、孔径、多孔二氧化硅颗粒表面上和/或孔的内部的取代基、表面的致密性等来控制。
更具体地,可以通过增加颗粒的表面积来减小t或通过减少其表面积来增加t。可以通过调节颗粒的直径和/或孔的直径来调节表面积。此外,使取代基位于颗粒表面上和/或孔的内部可减少多孔二氧化硅颗粒对环境(如溶剂)的直接暴露,从而增加t。此外,将生物活性材料负载在多孔二氧化硅颗粒上和增加生物活性材料与多孔二氧化硅颗粒之间的亲和性可减少多孔二氧化硅颗粒对环境的直接暴露,从而增加t。此外,在颗粒制备期间可更密集地制成表面从而增加t。在上文中,已描述了调节式1中t的各种实例,但不限于此。
在本发明的组合物中,多孔二氧化硅颗粒(介孔二氧化硅颗粒,MSP)是二氧化硅(SiO2)物质的颗粒,并且具有数纳米至数微米的直径。
颗粒的平均直径可为例如100至1000nm,具体地,在上述范围内的100至800nm、100至500nm、100至400nm、100至300nm、100至200nm等,但不限于此。
在本发明的组合物中,多孔二氧化硅颗粒(介孔二氧化硅颗粒,MSP)是包括纳米尺寸的孔的多孔颗粒,其中上述生物活性物质可以负载在孔中或颗粒表面上。
颗粒的平均孔径可为例如1至100nm,具体地,在上述范围内的5至100nm、7至100nm、7至50nm、10至50nm、10至30nm、7至30nm等,但不限于此。此外,考虑到要负载的生物活性物质的量和大小,优选选择和调节平均孔径。
在本发明的组合物中,多孔二氧化硅颗粒(介孔二氧化硅颗粒,MSP)的形状不特别限于特定形式。但是,考虑到血流中流动的顺畅性,与血流中的血细胞的相互作用的顺畅性以及红细胞的抗溶血性,优选采用球形。
在本发明的组合物中,多孔二氧化硅颗粒(介孔二氧化硅颗粒,MSP)的BET表面积可为例如200至700m2/g,具体地,在上述范围内的200至700m2/g、200至650m2/g、250至650m2/g、300至700m2/g、300至650m2/g、300至600m2/g、300至550m2/g、300至500m2/g、300至450m2/g等,但不限于此。
在本发明的组合物中,多孔二氧化硅颗粒(介孔二氧化硅颗粒,MSP)的每克(g)的体积可为例如0.7至2.2ml,具体地,在上述范围内的0.7至2.0ml、0.8至2.2ml、0.8至2.0ml、0.9至2.0ml、1.0至2.0ml等,但不限于此。如果每克(g)的体积过小,则降解速率过高。此外,难以制造过大的颗粒或颗粒可能不具有完整形状。
在本发明的组合物中,多孔二氧化硅颗粒(介孔二氧化硅颗粒,MSP)具有表面电荷,即具有除0mV以外的ζ电势。如上所述,以相同方式修饰的颗粒之间的电子排斥力可以抑制颗粒在血液中聚集或沉淀的现象,从而促进血液中的流动并将有效负载的生物活性物质递送至靶组织或细胞。
当带正电荷时,颗粒表面电荷的值,即ζ电势的值可以是例如+1至+150mV、+2至130mV或+3至+100mV,但不限于此。此外,当带负电荷时,ζ电势的值可以是例如-150至-1mV、-130至-10mV或-100至-18mV,但不限于此。ζ电势的值可以考虑不同方面例如要负载的生物活性物质的类型和量、或控制释放程度,来调节以满足其目的。然而,当ζ电势的值大于-18mV且小于+3mV时,多孔二氧化硅颗粒之间的排斥力降低从而使颗粒聚集,并且难以负载带电的生物活性物质。此外,如果ζ电势的值大于+100mV或小于-100mV,则与带电的生物活性物质的结合力过高,从而难以有效释放。
在本发明的组合物中,多孔二氧化硅颗粒(介孔二氧化硅颗粒,MSP)可以将上述生物活性物质负载在颗粒表面和/或孔的内部。
例如,可以通过将多孔二氧化硅颗粒和生物活性物质在溶剂中混合来进行用生物活性物质负载颗粒。在这方面,水和/或有机溶剂可以用作溶剂。本文所用的有机溶剂可包括,例如:醚类,例如1,4-二噁烷(特别是环状醚);卤代烃类,例如氯仿、二氯甲烷、四氯化碳、1,2-二氯乙烷、二氯乙烯、三氯乙烯、四氯乙烯、二氯丙烷、戊基氯、1,2-二溴乙烷,等;酮类,例如丙酮、甲基异丁基酮、环己酮,等;碳基芳族化合物,例如苯、甲苯、二甲苯,等;烷基酰胺,例如N,N-二甲基甲酰胺、N,N-二丁基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮,等;醇类,例如甲醇、乙醇、丙醇、丁醇,等。
此外,磷酸盐缓冲盐溶液(PBS)、模拟体液(SBF)、硼酸盐缓冲盐水、tris缓冲盐水可用作溶剂。
多孔二氧化硅颗粒和生物活性材料的比例没有特别限制,并且例如,重量比可为1:0.05~0.8,具体地,在上述范围内的1:0.05~0.7、1:0.05~0.6、1:0.1~0.8、1:0.1~0.6、1:0.2~0.8、1:0.2~0.6等。
在本发明的组合物中,多孔二氧化硅颗粒(介孔二氧化硅颗粒,MSP)可以在长时间内逐渐释放负载的生物活性物质。
随着颗粒生物降解,可以释放负载在颗粒上的生物活性物质,并且可以缓慢降解颗粒以允许负载的生物活性物质的持续释放。这可以通过例如调节表面积、粒径、孔径、颗粒表面和/或孔的内部的取代基、多孔二氧化硅颗粒的致密性等来控制,但不限于此。
此外,负载在颗粒上的生物活性物质可以在与多孔二氧化硅颗粒分离的同时释放并扩散,这受到多孔二氧化硅颗粒、生物活性物质和生物活性物质释放环境之间的关系的影响。因此,调节这些条件可以控制生物活性物质的释放。例如,可以通过借助表面修饰来增强或减弱多孔二氧化硅颗粒与生物活性物质的结合力来控制生物活性材料的释放。
更具体地,如果负载的生物活性物质水溶性差(疏水性的),则颗粒表面和/或孔的内部可以具有疏水性取代基以增加颗粒与生物活性物质之间的结合力,由此可以以持续的方式释放生物活性物质。这可以通过例如用具有疏水性取代基的烷氧基硅烷对颗粒进行表面修饰来实现。
如本文所用,“难溶”是指不溶(几乎不溶)或仅微溶(相对于水),这是“pharmaceutical Science”第18版(USP,Remington,Mack Publishing Company)中定义的术语。
水溶性差的生物活性材料在1大气压和25℃下可具有例如小于10g/L、具体地小于5g/L、更具体的小于1g/L的水溶性,但不限于此。
当负载的生物活性物质为水溶性的(亲水性的)时,颗粒表面和/或孔的内部可以具有亲水性取代基以增加多孔二氧化硅颗粒与生物活性物质之间的结合力,由此生物活性物质可以以持续的方式释放。这可以通过例如用具有亲水性取代基的烷氧基硅烷对多孔二氧化硅颗粒进行表面修饰来实现。
水溶性生物活性材料在1大气压和25℃下具有例如10g/L以上的水溶性,但不限于此。
当负载的生物活性材料带电荷时,颗粒表面和/或孔的内部可以带相反的电荷,因此增加了多孔二氧化硅颗粒与生物活性物质之间的结合力,由此生物活性物质可以以持续的方式释放。这可以通过例如用具有酸性基团或碱性基团的烷氧基硅烷对多孔二氧化硅颗粒进行表面修饰来实现。
具体地,如果生物活性物质在中性pH下带正电荷,则颗粒表面和/或孔的内部可以在中性pH下带负电荷,因此增加多孔二氧化硅颗粒与生物活性物质之间的结合力,由此生物活性物质可以以持续的方式释放。这可以通过例如用具有酸性基团如羧基(-COOH)、磺酸基团(-SO3H)等的烷氧基硅烷对多孔二氧化硅颗粒进行表面修饰来实现。
此外,如果生物活性材料在中性pH下带负电荷,则颗粒表面和/或孔的内部可以带正电荷,因此增加了多孔二氧化硅颗粒与生物活性物质之间的结合力,由此生物活性物质可以以持续的方式释放。这可以通过例如用具有碱性基团例如氨基、含氮基团等的烷氧基硅烷对多孔二氧化硅颗粒进行表面修饰来实现。
负载的生物活性物质取决于所需的处理类型、释放环境和要使用的多孔二氧化硅颗粒等可以释放例如7天至1年或更长时间。
在本发明的组合物中,由于多孔二氧化硅颗粒(介孔二氧化硅颗粒,MSP)是可生物降解的并且可以100%降解,因此负载在其上的生物活性物质可以释放100%。
由于颗粒的100%可生物降解性,可以根据相应的目的适当地设置负载的生物活性物质的量,并用于血管中的药物递送,从而具有如下的显著优势:避免如生物活性物质的过度使用引起的副作用等问题,防止如阻塞血管而颗粒没有完全降解等的严重情况,和克服下述的栓塞不可能发生在同一路径上的问题,这是常规栓塞的一个重要问题。
在本发明的组合物中,多孔二氧化硅颗粒(介孔二氧化硅颗粒,MSP)可以通过例如小孔颗粒制备和孔扩张方法来制备。如果需要,颗粒可以通过进一步的煅烧和表面修饰工艺等来制备。如果将颗粒同时进行煅烧和表面修饰工艺,则颗粒可以在煅烧之后进行表面修饰。
小孔颗粒可以是例如具有平均孔径为1至5nm的颗粒,其可以通过将表面活性剂和二氧化硅前体添加至溶剂中、然后将溶液搅拌并均匀化而获得。
水和/或有机溶剂可以用作溶剂,并且本文使用的有机溶剂可以包括,例如:醚类,例如1,4-二噁烷(特别是环状醚);卤代烃类,例如氯仿、二氯甲烷、四氯化碳、1,2-二氯乙烷、二氯乙烯、三氯乙烯、四氯乙烯、二氯丙烷、戊基氯、1,2-二溴乙烷,等;酮类,例如丙酮、甲基异丁基酮、γ-丁内酯、1,3-二甲基咪唑啉酮、甲基乙基酮、环己酮、环戊酮、4-羟基-4-甲基-2-戊酮,等;碳基芳族化合物,例如苯、甲苯、二甲苯、四甲基苯,等;烷基酰胺,例如N,N-二甲基甲酰胺、N,N-二丁基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮,等;醇类,例如甲醇、乙醇、丙醇、丁醇,等;二醇醚类(溶纤剂类),例如乙二醇单乙醚、乙二醇单甲醚、乙二醇单丁醚、二甘醇单乙醚、二甘醇单甲醚、二甘醇单丁醚、丙二醇单甲醚、丙二醇单乙醚、二丙二醇二乙醚、三甘醇单乙醚,等;和其他二甲基乙酰胺(DMAc)、N,N-二乙基乙酰胺、二甲基甲酰胺(DMF)、二乙基甲酰胺(DEF)、N,N-二甲基乙酰胺(DMAc)、N-甲基吡咯烷酮(NMP)、N-乙基吡咯烷酮(NEP)、1,3-二甲基-2-咪唑啉酮、N,N-二甲基甲氧基乙酰胺、二甲基亚砜、吡啶、二甲基砜、六甲基膦酰胺、四甲基脲、N-甲基己内酰胺、四氢呋喃、间二噁烷、对二噁烷、1,2-二甲氧基乙烷,等。具体地,可以使用醇,更具体地甲醇,但不限于此。
当使用水和有机溶剂的混合溶剂作为溶剂时,水和有机溶剂的比可以以例如1:0.7~1.5、例如1:0.8~1.3的体积比使用,但不限于此。
表面活性剂可以是例如鲸蜡基三甲基溴化铵(CTAB)、十六烷基三甲基溴化铵(TMABr)、十六烷基三甲基氯化吡啶鎓(TMPrCl)、四甲基氯化铵(TMAC1)等,并且具体地,可以使用CTAB。
例如,表面活性剂可以以每1升溶剂1至10g,具体地,在上述范围内的1至8g、2至8g、3至8g等的量加入,但不限于此。
二氧化硅前体可在添加表面活性剂至溶剂中的情况下在搅拌后添加。二氧化硅前体可以是例如原硅酸四甲酯(TMOS),但不限于此。
搅拌可以进行例如10分钟至30分钟,但不限于此。
二氧化硅前体可以以每1升溶剂0.5至5ml,具体地,在上述范围内的0.5至4ml、0.5至3ml、0.5至2ml、1至2ml等的量添加,,但不限于此。相反,必要时,可以进一步使用氢氧化钠作为催化剂,其中催化剂可以在将表面活性剂添加到溶剂中之后并且在将二氧化硅前体添加到溶剂之前在搅拌的同时添加。
催化剂,即氢氧化钠,可以以基于1M氢氧化钠溶液以每1升溶剂为0.5至8ml,具体地,在上述范围内的0.5至5ml、0.5至4ml、1至4ml、1至3ml、2至3ml等的量来添加,但不限于此。
在添加二氧化硅前体后,溶液可在搅拌下进行反应。搅拌可进行例如2至15小时,具体地,在上述范围内的3至15小时、4至15小时、4至13小时、5至12小时、6至12小时、6至10小时等,但不限于此。如果搅拌时间(反应时间)过短,成核可能不充分。
搅拌后,可使溶液老化。老化可进行例如8至24小时,具体地,上述范围内的8至20小时、8至18小时、8至16小时、8至14小时、10至16小时、10至14小时等,但不限于此。
其后,可以将反应产物清洗并干燥以获得多孔二氧化硅颗粒,并且必要时,可在清洗前分离未反应的材料,所述分离例如可通过离心而分离上清液来进行。
离心可在例如6,000至10,000rpm下进行例如3至60分钟,具体地,在上述范围内的3至30分钟、5至30分钟等,但不限于此。
可以用水和/或有机溶剂进行清洗。特别地,由于不同的物质分别溶于不同的溶剂,因此水和有机溶剂可以轮流使用一次或多次。可选择地,水和/或有机溶剂可单独用于清洗一次或几次。这样的几次可以包括例如两次以上且十次以下,具体地,三次以上且十次以下、四次以上且八次以下、四次以上且六次以下,等。
本文使用的有机溶剂可以包括,例如:醚类,例如1,4-二噁烷(特别是环状醚);卤代烃类,例如氯仿、二氯甲烷、四氯化碳、1,2-二氯乙烷、二氯乙烯、三氯乙烯、四氯乙烯、二氯丙烷、戊基氯、1,2-二溴乙烷,等;酮类,例如丙酮、甲基异丁基酮、γ-丁内酯、1,3-二甲基咪唑啉酮、甲基乙基酮、环己酮、环戊酮、4-羟基-4-甲基-2-戊酮,等;碳基芳族化合物,例如苯、甲苯、二甲苯、四甲基苯,等;烷基酰胺,例如N,N-二甲基甲酰胺、N,N-二丁基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮,等;醇类,例如甲醇、乙醇、丙醇、丁醇,等;二醇醚类(溶纤剂类),例如乙二醇单乙醚、乙二醇单甲醚、乙二醇单丁醚、二甘醇单乙醚、二甘醇单甲醚、二甘醇单丁醚、丙二醇单甲醚、丙二醇单乙醚、二丙二醇二乙醚、三甘醇单乙醚,等;和其他二甲基乙酰胺(DMAc)、N,N-二乙基乙酰胺、二甲基甲酰胺(DMF)、二乙基甲酰胺(DEF)、N,N-二甲基乙酰胺(DMAc)、N-甲基吡咯烷酮(NMP)、N-乙基吡咯烷酮(NEP)、1,3-二甲基-2-咪唑啉酮、N,N-二甲基甲氧基乙酰胺、二甲基亚砜、吡啶、二甲基砜、六甲基磷酰胺、四甲基脲、N-甲基己内酰胺、四氢呋喃、间二噁烷、对二噁烷、1,2-二甲氧基乙烷,等,具体地,可以使用醇,更具体地,可以使用乙醇,但不限于此。
清洗可在离心下以例如6,000至10,000rpm进行例如3至60分钟,具体地,在上述范围内的3至30分钟、5至30分钟等,但不限于此。
可以不离心而通过用过滤器过滤颗粒来进行清洗。过滤器可以包括直径小于或等于多孔二氧化硅颗粒的直径的孔。如果反应溶液通过这种过滤器过滤,则只有颗粒保留在过滤器上,并且可以通过在过滤器上倒水和/或有机溶剂来清洗。
为了清洗,水和有机溶剂可以轮流使用一次或多次。可选择地,即使单独使用水或有机溶剂也可以进行一次或多次清洗。数次可以包括例如两次以上且十次以下,具体地,三次以上且十次以下,四次以上且八次以下,四次以上且六次以下等。
干燥可以例如在20至100℃下进行,但不限于此。可选择地,可以在真空状态下进行干燥。
其后,可以使用例如孔扩张剂来使所获得的多孔二氧化硅颗粒的孔扩张。
本文使用的孔扩张剂可以包括例如三甲基苯、三乙基苯、三丙基苯、三丁基苯、三戊基苯、三己基苯、甲苯、苯等,并且具体地,可以使用三甲基苯,但不限于此。
可选择地,本文使用的孔扩张剂可以是例如N,N-二甲基十六烷基胺(DMHA),但不限于此。
上述孔扩张可以例如通过将多孔二氧化硅颗粒在溶剂中与孔扩张剂混合,加热混合物使并其反应来进行。本文使用的溶剂可以是例如水和/或有机溶剂。本文所用的有机溶剂可包括,例如:醚类,例如1,4-二噁烷(特别是环状醚);卤代烃类,例如氯仿、二氯甲烷、四氯化碳、1,2-二氯乙烷、二氯乙烯、三氯乙烯、四氯乙烯、二氯丙烷、戊基氯、1,2-二溴乙烷,等;酮类,例如丙酮、甲基异丁基酮、环己酮,等;碳基芳族化合物,例如苯、甲苯、二甲苯,等;烷基酰胺,例如N,N-二甲基甲酰胺、N,N-二丁基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮,等;醇类,例如甲醇、乙醇、丙醇、丁醇,等;具体地,可以使用醇,更具体地,可以使用乙醇,但不限于此。
多孔二氧化硅颗粒可以以例如每1升溶剂10至200g,具体地,在上述范围内的10至150g、10至100g、30至100g、40至100g、50至100g、50至80g、60至80g等的比例添加,但不限于此。
可以将多孔二氧化硅颗粒均匀地分散在溶剂中,例如,可以将多孔二氧化硅颗粒添加到溶剂中并在其中超声分散。在使用混合溶剂的情况下,可以在将多孔二氧化硅颗粒分散在第一溶剂中之后添加第二溶剂。
孔溶胀剂可以以基于100体积份例如10至200体积份(vol.份),具体地,在上述范围内的100至150体积份、10至100体积份、10至80体积份、30至80体积份、30至70体积份的量添加,但不限于此。
反应可以在例如120至180℃,具体地,在上述范围内的120至170℃、120至160℃、120至150℃、130至180℃、130至170℃、130至160℃、130至150℃等下进行,但不限于此。
反应可以进行例如24至96小时,具体地,在上述范围内的30至96小时、30至80小时、30至72小时、24至80小时、24至72小时、36至96小时、36至80小时、36至72小时、36至66小时、36至60小时、48至96小时、48至88小时、48至80小时、48至72小时等,但不限于此。
通过将时间和温度分别调节在上述范围内,反应可以充分进行而不会太多。例如,当反应温度较低时,可以增加反应时间,相反,当反应温度较高时,可以缩短反应时间。如果反应不充分,则孔扩张不充分。另一方面,如果反应过度进行,颗粒会由于孔的扩张而坍塌。
反应可以例如在逐渐升高温度的同时进行。具体地,可以在以从室温以0.5至15℃/min,具体地,在上述范围内的1至15℃/min、3至15℃/min、3至12℃/min、3至10℃/min等的速率在逐渐升高温度的同时进行反应,但不限于此。
反应后,可以将反应溶液缓慢冷却,例如,通过逐步降低温度来冷却。具体地,反应溶液可以通过以0.5至20℃/min,具体地,在上述范围内的1至20℃/min、3至20℃/min、3至12℃/min、3至10℃/min等的速率逐步降低温度至室温来冷却,,但不限于此。
冷却后,清洗并干燥反应产物以获得具有扩展的孔的多孔二氧化硅颗粒。
必要时,可在清洗前,例如通过离心以分离上清液来分离未反应的材料。
离心可以在例如6,000至10,000rpm下进行3至60分钟,具体地,在上述范围内的3至30分钟、5至30分钟等,但不限于此。
可以用水和/或有机溶剂进行清洗。特别地,由于不同的物质分别溶于不同的溶剂,因此水和有机溶剂可以轮流使用一次或多次。可选择地,水和/或有机溶剂可单独用于清洗一次或几次。这样的几次可以包括例如两次以上,十次以下,具体地,3次、4次、5次、6次、7次、8次等。
本文使用的有机溶剂可以包括,例如:醚类,例如1,4-二噁烷(特别是环状醚);卤代烃类,例如氯仿、二氯甲烷、四氯化碳、1,2-二氯乙烷、二氯乙烯、三氯乙烯、四氯乙烯、二氯丙烷、戊基氯、1,2-二溴乙烷,等;酮类,例如丙酮、甲基异丁基酮、环己酮,等;碳基芳族化合物,例如苯、甲苯、二甲苯,等;烷基酰胺,例如N,N-二甲基甲酰胺、N,N-二丁基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮,等;醇类,例如甲醇、乙醇、丙醇、丁醇,等,具体地,可以使用醇,更具体地,可以使用乙醇,但不限于此。
清洗可以在离心下以例如6,000至10,000rpm进行例如3至60分钟,具体地,在上述范围内的3至30分钟、5至30分钟等,但是不限于此。
可以不离心而通过用过滤器过滤颗粒来进行清洗。过滤器可以具有直径小于或等于多孔二氧化硅颗粒的直径的孔。如果反应溶液通过这种过滤器过滤,则只有颗粒保留在过滤器上,并且可以通过在过滤器上倒水和/或有机溶剂来清洗。
对于清洗,水和有机溶剂可以轮流使用一次或多次。可选择地,即使单独用水或有机溶剂也可以进行一次或多次清洗。数次可以包括例如两次以上且十次以下,具体地,三次以上且十次以下、四次以上且八次以下、四次以上且六次以下等。
干燥可以例如在20至100℃下进行,但不限于此。可选择地,可以在真空状态下进行干燥。
此后,可以对获得的多孔二氧化硅颗粒的孔进行煅烧,其是加热颗粒以使其表面和孔的内部具有更致密的结构,并去除填充孔的有机材料的工序。例如,煅烧可以在400至700℃下进行3至8小时,具体地,在500至600℃下进行4至5小时,但不限于此。
然后,可以将获得的多孔二氧化硅颗粒如上所述在其表面和/或孔的内部修饰。
在本发明的组合物中,多孔二氧化硅颗粒(介孔二氧化硅颗粒,MSP)还可以通过例如制备小孔颗粒、孔扩展、表面改性和/或孔的内部的改性而获得。
小孔颗粒的制备和孔扩展可以根据上述工序进行,然后可以进行清洗和干燥工序。
必要时,可在清洗前例如通过离心而分离上清液来分离未反应的材料。
离心可以在例如6,000至10,000rpm下进行例如3至60分钟,具体地,在上述范围内的3至30分钟、5至30分钟等,但不限于此。
制备小孔颗粒之后的清洗可以在上述范围内的条件下以任何方法进行,但不限于此。
与上述说明性实施方案相比,可以在更宽松的条件下进行孔扩展后的清洗。例如,清洗可以进行三次以下,但不限于此。
可以通过上述方法对颗粒表面和/或孔的内部进行改性,其中改性可以以颗粒表面,然后是孔的内部的顺序进行,并且在上述两个工序之间可以进一步进行颗粒清洗。
当在制备小孔颗粒和孔扩展之后在更宽松的条件下进行清洗时,用如颗粒制备和孔扩展中使用的表面活性剂等的反应溶液填充孔,使得表面改性期间不对孔的内部进行改性,而是仅可以对颗粒表面进行改性。然后,清洗颗粒可以除去孔中的反应溶液。
在表面改性和孔的内部改性之间的颗粒清洗可以用水和/或有机溶剂进行。特别地,由于不同的物质分别溶于不同的溶剂,因此水和有机溶剂可以轮流使用一次或多次。可选择地,水和/或有机溶剂可单独用于清洗一次或几次。这样的几次可以包括例如两次以上且十次以下,具体地,三次以上且十次以下、四次以上且八次以下、四次以上且六次以下,等。
清洗可以离心下以例如6,000至10,000rpm进行例如3至60分钟,具体地,在上述范围内的3至30分钟、5至30分钟等,但不限于此。
可以不离心而通过用过滤器过滤颗粒来进行清洗。过滤器可以包括直径小于或等于多孔二氧化硅颗粒的直径的孔。如果反应溶液通过这种过滤器过滤,则只有颗粒保留在过滤器上,并且可以通过在过滤器上倒水和/或有机溶剂来清洗。
为了清洗,水和有机溶剂可以轮流使用一次或多次。可选择地,即使单独用水或有机溶剂也可以进行一次或多次清洗。数次可以包括例如两次以上且十次以下,具体地,三次以上且十次以下、四次以上且八次以下、四次以上且六次以下等。
干燥可以例如在20至100℃下进行,但不限于此。可选择地,可以在真空状态下进行干燥。
为了实现递送负载在多孔二氧化硅颗粒上的生物活性材料的效率的目的或为了使用上述组合物的目的,根据本发明的用于在血管中递送生物活性材料的组合物可以进一步包括本领域公知的任何物质。这种在本领域公知并进一步添加到组合物中的物质可以包括荧光标记材料、凝血抑制剂、红细胞溶血剂、造影剂等,但不限于此。
凝血抑制剂可以是选自由以下组成的组的至少一种:1,2-二硬脂酰基-sn-甘油-3-(磷酸-lac-(1-甘油)、1,2-二硬脂酰基-sn-甘油-3-磷酸胆碱、西妥克罗唑1000(cetomacrozol 1000)、鲸蜡硬脂醇、鲸蜡醇、氯化十六烷基吡啶、胆固醇、二棕榈酰磷脂酰甘油、二硬脂酰磷脂酰胆碱、烷基多糖苷、EGG磷脂、脂肪酸酯、月桂酸甘油酯、油酸甘油酯、羟乙基哌嗪乙烷磺酸、乳糖一水合物、羊毛脂、乳酸月桂酯,
卵磷脂、硬脂酸镁、单硫代甘油、油酸、油醇、棕榈酸、PEG/PPG-18/18二甲硅油、聚乙二醇(PEG)、PEG-20山梨糖醇异硬脂酸酯、PEG-40蓖麻油、PEG-60氢化蓖麻油、戊酸戊酯、磷脂、泊洛沙姆(poloxamer)、泊洛沙姆188、泊洛沙姆407、聚氧乙烯脂肪酸酯、聚氧30蓖麻油、聚氧31蓖麻油、聚氧32蓖麻油、聚氧33蓖麻油、聚氧34蓖麻油、聚氧35蓖麻油、聚氧36蓖麻油、聚氧36蓖麻油、聚氧37蓖麻油、聚氧38蓖麻油、聚氧39蓖麻油、聚氧40蓖麻油、聚丙二醇、聚山梨酸酯、聚山梨酸酯20、聚山梨酸酯40、聚山梨酸酯80、聚维酮K12、聚维酮K17、聚维酮K30、聚维酮、丙二醇、单月桂酸聚丙二醇酯、硫酸鱼精蛋白、胆固醇基硫酸钠、油酸钠、脱水山梨糖醇、脱水山梨醇单硬脂酸酯、脱水山梨醇三硬脂酸酯、脱水山梨醇单月桂酸酯、脱水山梨醇单油酸酯、脱水山梨糖醇单棕榈酸酯、硬脂醇、硬脂酸、硫放线菌素、硬脂酸锌、椰油酰胺DEA、椰油酰胺MEA、癸基葡糖苷、癸基聚葡萄糖、单硬脂酸甘油酯、IGEPALCA-630、异鲸蜡醇聚醚-20、月桂基葡糖苷麦芽糖苷、单月桂酸酯、抗霉枯草菌素、乙氧基化物、nodidetP-40、壬苯聚醇、N-辛基β-D-硫代吡喃葡萄糖苷、辛基葡糖苷、油醇、PEG-10向日葵甘油酯、戊乙醇单十二烷基醚、聚乙氧基牛脂胺、聚甘油聚蓖麻油酸酯、TRITON X-100、右旋糖酐、聚乙烯吡咯烷酮、1,2-二油酰基-SN-甘油-3-磷酸胆碱、外泌体、胶束、脂质体、聚乙烯醇、硅酮、共聚物、核酸、肽和细胞膜,但不限于此。
造影剂可以是选自由以下组成的组的至少一种:甲泛葡胺(metrizamide)、碘帕醇(iopamidol)、碘克沙醇(iodixanol)、碘海醇(iohexol)、碘普罗胺(iopromide)、碘比醇(iobitridol)、碘美普尔(iomeprol)、碘喷托(iopentol)、碘帕醇(iopamiron)、碘克伦(ioxylan)、碘曲仑(iotrolan)、钆双胺(gadodiamide)、加多利多(gadoteridol)、碘醇(iotrol)、碘夫索尔(ioversol)、碘油(lipiodol)、碘化油(iodides oil)、油造影剂、油相造影剂、钡造影剂或其组合,但不限于此。
根据本发明的用于在血管中递送生物活性物质的组合物具体涉及根据本发明的组合物的“血管内施用”。术语“在血管中”将被理解为意指递送到患者的脉管系统中,其是指“进入血管”或“在血管中”。在某些实施方案中,施用是(静脉内)施用到被认为是静脉的血管中,而在另一实施方案中的施用可以是施用到被认为是动脉的血管中。静脉可包括颈内静脉、外周静脉、冠状静脉、肝静脉、门静脉、大隐静脉、肺静脉、上腔静脉、下腔静脉、胃静脉、脾静脉、肠系膜下静脉、肠系膜上静脉、头静脉和/或股静脉,但不限于此。动脉可包括冠状动脉、肺动脉、肱动脉、颈内动脉、主动脉弓、股动脉,外周动脉和/或睫状动脉,但不限于此。预期可以通过小动脉或毛细血管递送,或递送至小动脉或毛细血管。
根据本发明的用于在血管中递送生物活性物质的组合物的血管内施用可以通过将导管插入靶组织或细胞附近的血管中来进行,以便有效地实现负载在多孔二氧化硅颗粒上的生物活性物质的递送,这是组合物的目的。在这种情况下,负载在多孔二氧化硅颗粒表面上的生物活性物质会较少被血流冲走,或者负载在多孔二氧化硅颗粒表面上或孔的内部的生物活性物质通过血流中的扩散的释放会减少。此外,具有在负载的生物活性物质的递送中改善靶向性的优点。
本发明提供用于治疗特定疾病的药物组合物,其包括用于在血管中递送生物活性物质的组合物。
如本文所用,术语“治疗”是指获得有益的或期望的临床结果的方法。为了本发明的目的,有益的或期望的临床结果可包括但不限于症状减轻,疾病程度的减轻,疾病状态的稳定(即,不恶化),疾病进展的延缓或减缓,疾病状态(部分或全部)的改善、暂时缓解和缓解,无论是否可以检测到。此外,术语“治疗”还可以指与未治疗时的预期存活相比增加的存活。治疗是指治疗性治疗和预防性治疗二者或预防性措施。这样的治疗可以包括已经发生的病症以及要预防的病症所需的治疗。
如本文所用,术语“预防”是指抑制或延迟相关疾病发展的任何作用。对于本领域技术人员显而易见的是,在症状出现之前施用的情况下,本文提及的组合物可以预防初始症状或相关疾病。
这样的特定疾病可以包括选自由以下组成的组的至少一种:肝细胞癌、转移性肝癌、结肠癌、转移性结肠癌、肺癌、转移性肺癌、胃癌、胰腺癌、转移性胰腺癌、皮肤癌、黑色素瘤、转移性黑色素瘤、骨肉瘤、纤维肉瘤、脂肪瘤、胆囊癌、肝内胆管癌、膀胱癌、子宫癌、宫颈癌、卵巢癌、乳腺癌、头颈癌、甲状腺癌和肾癌、脑癌、胶质母细胞瘤、纵隔肿瘤、肠系膜淋巴结转移、血液癌症、血癌、白血病、非霍奇金淋巴瘤、霍奇金淋巴瘤、多发性骨髓瘤、淋巴瘤、恶性淋巴瘤、骨髓增生异常综合征、急性淋巴细胞白血病、急性髓性白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、孤立性骨髓瘤、再生障碍性贫血、脊髓性肌萎缩症、遗传性疾病、遗传性骨骼疾病、遗传畸形综合征、常染色体隐性遗传疾病、罕见疾病、传染病、缺血性疾病、鼻息肉、鼻窦炎、肥厚性瘢痕、瘢痕疙瘩、免疫疾病、自身免疫性疾病、传染性免疫疾病、病毒感染、细菌感染、类风湿性关节炎、糖尿病、糖尿病并发症、足溃疡、神经病、代谢综合征、肠道疾病、特应性、过敏、狼疮、痴呆、帕金森病、伤口疾病、裂伤病、皮肤病、褥疮、血管疾病、动脉疾病、静脉疾病、淋巴疾病、心血管疾病、缺血性心脏病、脑血管疾病、高血压、血脂异常、动脉硬化、外周血管疾病和下肢动脉闭塞,但不限于此。
包括根据本发明的负载有生物活性材料的多孔二氧化硅颗粒的用于预防或治疗上述疾病的药物组合物,可以进一步包括药学上可接受的载体并且可以与该载体一起配制。如本文所用,术语“药学上可接受的载体”是指不刺激生物体并且不抑制所施用化合物的生物学活性和性质的载体或稀释剂。在液体溶液中配制的组合物中的药学上可接受的载体是无菌的并且在生理上相容,并且可以包括盐水、无菌水、林格氏溶液、缓冲盐水、白蛋白注射液、右旋糖溶液、麦芽糊精溶液、甘油、乙醇和这些组分中的一个或多个的组合。此外,如果需要,还可以添加如抗氧化剂、缓冲剂和抑菌剂的其他常规添加剂。另外,还可以添加稀释剂、分散剂、表面活性剂、粘合剂和润滑剂,以将组合物配制成例如水溶液、悬浮液、乳剂等可注射制剂,丸剂,胶囊,颗粒或片剂等。
本发明的组合物适用于任何类型的制剂,所述制剂包含根据本发明的负载有生物活性物质的多孔二氧化硅颗粒作为活性成分,并且可以制备成口服或肠胃外制剂的形式。本发明的此类药物制剂可以包括适合于口服、直肠、鼻、局部(包括脸颊和舌下)、皮下、阴道或肠胃外(肌内,皮下)施用的任何一种,或者可以适于通过吸入或吹气入施用。
本发明的组合物可以以药学有效量施用。有效剂量水平可以考虑疾病类型、严重性、药物活性、对药物的敏感性、施用时间、施用途径和释放速率、治疗持续时间、包括同时使用药物在内的因素以及其他在医学领域众所周知的因素来确定。本发明的组合物可以作为单独的治疗剂或与其他治疗剂组合施用,可以与常规治疗剂顺序或同时施用,并且可以单剂量或多剂量施用。考虑到所有上述因素,重要的是施用能够获得最大效果而无副作用的最小量,这对于本领域技术人员而言是容易确定的。
本发明的组合物的剂量可根据患者的体重、年龄、性别和/或健康状况,饮食,施用时间,施用方法,排泄率和疾病严重程度而有很大变化。具体地,合适的剂量可以取决于体内累积的药物量和/或负载有要使用的生物活性物质的多孔二氧化硅颗粒的特定功效。通常,剂量可以基于确定为在体内动物模型以及体外有效的EC50来评估。例如,剂量可以在每千克体重0.01μg至1g的范围内,并且组合物可以在每天、每周、每月或每年的单位周期内每单位周期一次或几次施用。否则,组合物可通过输液泵长时间连续施用组。重复剂量的数目考虑药物在体内的保留时间、体内的药物浓度等来确定。即使在疾病治疗过程中的治疗之后,也可以施用组合物以防止复发。
本发明的组合物可进一步包括至少一种与上述疾病的治疗具有相同或相似功能的活性成分,或保持/增加活性成分的溶解度和/或吸收性的化合物。此外,可任选地包括化学治疗剂、抗炎剂、抗病毒剂和/或免疫调节剂等。
此外,本发明的组合物可以通过本领域已知的任何常规方法配制,以在向哺乳动物施用后提供活性成分的快速、持续或延迟释放。制剂可以是粉末、颗粒、片剂、乳剂、糖浆剂、气雾剂、软或硬明胶胶囊剂、无菌注射溶液、无菌粉末的形式。
本发明提供一种用于栓塞程序的组合物,其包括用于在上述血管中递送生物活性物质的组合物。
用于栓塞用组合物中的多孔二氧化硅颗粒的物理性质与上述提及的那些颗粒没有显著不同,但是可以根据栓塞的目的通过将粒径调节至合适的大小来使用。
更具体地,纳米级的颗粒用于进入肿瘤组织内的微血管,并积聚在针对肿瘤组织的血管和肿瘤组织内的血管中,由此阻塞肿瘤组织并阻止对其的氧气和养分供应。此外,使用微米级的颗粒可能会阻塞连接至肿瘤组织的动脉,因此栓塞更宽范围的肿瘤组织。
当使用纳米级颗粒时,颗粒的平均直径可以为例如100至1000nm,具体地,在上述范围内的100至800nm、100至500nm、100至400nm、100至300nm、100至200nm等,但不限于此。
当使用微米级的颗粒时,颗粒的平均直径可以为例如0.1至500μm,0.1至300μm、100至300μm、300至500μm、0.1以上至100μm、0.1至1μm、0.2至0.8μm等,但不限于此。
如上所述,多孔二氧化硅颗粒是可生物降解的颗粒,并且可以被活体内的体液或微生物降解,由此在注射后数小时至数百小时内以持续释放的方式释放抗癌药。如果肿瘤在化疗栓塞后未完全坏死/杀死,则颗粒不会永久性阻塞血管,并且可在第二程序期间以相同的途径(血管)重新施用。
尽管组合物可以进一步包括选自由以下组成的组的至少一种栓塞材料,但也可以适当地选择本领域公知的用于栓塞的任何组合物而没有特别限制,只要能够与本发明的组合物适当混合即可:聚乙烯醇、造影剂、碘化油(iodide oil)、油造影剂、油相造影剂、钡造影剂、碘油(lipiodol)、氰基丙烯酸N-丁酯、卷材(coil)、凝胶泡沫、明胶、乙醇、右旋糖酐、二氧化硅、气相二氧化硅、聚合物、共聚物、聚丙烯酸钠乙烯醇共聚物、放射性材料、玻璃、聚L-古洛糖醛酸藻酸酯、聚乙醇酸-聚乳酸、聚二噁烷酮、聚乙醇酸-己内酯、具有100μm以上的直径的聚丙烯和多孔二氧化硅颗粒。更优选地,考虑到用乳剂型注射进行栓塞为本领域公知常识,选择当与根据本发明的组合物的多孔二氧化硅颗粒混合时能够形成稳定乳剂的造影剂或碘油。
可以通过具有上述优点的导管来进行组合物的施用,并且当将组合物施用到通过导管直接与肿瘤相连的血管中时,可以防止对正常组织的损害,同时仅靶向靶肿瘤组织,从而增强靶向效果。
能够使用该组合物栓塞的疾病可包括选自由以下组成的组的至少一种:肝细胞癌、转移性肝癌、结肠癌、转移性结肠癌、肺癌、转移性肺癌、胃癌、胰腺癌、转移性胰腺癌、皮肤癌、黑色素瘤、转移性黑色素瘤、骨肉瘤、纤维肉瘤、脂肪瘤、胆囊癌、肝内胆管癌、膀胱癌、子宫癌、宫颈癌、卵巢癌、乳腺癌、头颈癌、甲状腺癌和肾脏癌症、脑癌、胶质母细胞瘤、纵隔肿瘤、肠系膜淋巴结转移、血癌、白血病、非霍奇金淋巴瘤、霍奇金淋巴瘤、多发性骨髓瘤、淋巴瘤、恶性淋巴瘤、骨髓增生异常综合征、急性淋巴细胞白血病、急性髓性白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、孤立性骨髓瘤、再生障碍性贫血、脊髓性肌萎缩症、遗传性疾病、遗传性骨骼疾病、遗传性畸形综合征、常染色体隐性遗传疾病、罕见疾病、传染病、缺血性疾病、鼻息肉、鼻窦炎、肥厚性瘢痕、瘢痕疙瘩、免疫疾病、自身免疫性疾病、传染性免疫疾病、病毒感染、细菌感染、类风湿性关节炎、糖尿病、糖尿病并发症、足溃疡、神经病、代谢综合征、肠道疾病、特应性、过敏、狼疮、痴呆、帕金森病、伤口疾病、裂伤病、皮肤病、褥疮、血管疾病、动脉疾病、静脉疾病、淋巴疾病、心血管疾病、缺血性心脏病、脑血管疾病、高血压、血脂异常、动脉硬化、外周血管疾病和下肢动脉闭塞,但不限于此。
在下文中,将参照以下实施例详细描述本发明。
在以下实施例中,本发明的多孔二氧化硅颗粒可被称为DegradaBALL(韩国商标注册号40-1292208)。
实施例1-多孔二氧化硅颗粒的制备
(1)颗粒1的制备
1)小孔颗粒的制备
将960ml的蒸馏水(DW)和810ml的MeOH置于2L的圆底烧瓶中。将7.88g的CTAB加入至烧瓶中,随后在搅拌的同时快速加入4.52ml的1M的NaOH。在搅拌下引入均匀混合物10分钟后,向其中加入2.6ml的TMOS。搅拌6小时以均匀混合后,将混合物老化24小时。
然后,将反应溶液在25℃和8000rpm下离心10分钟以除去上清液。在25℃和8000rpm下离心10分钟的过程中,用乙醇和蒸馏水轮流清洗产物五次。
此后,将所得物在70℃的烘箱中干燥以获得1.5g粉末状小孔多孔二氧化硅颗粒(孔平均直径:2nm,粒径:200nm)。
2)孔扩张
将1.5g的小孔多孔二氧化硅颗粒粉末加到10ml的乙醇中以进行超声分散,并且加入10ml的水和10ml的三甲基苯(TMB)以进行超声分散。
其后,将分散体(dispersion)置于高压灭菌锅中,并在160℃下反应48小时。
在高压灭菌锅中,反应在25℃开始进行,然后以10℃/min的速率升温,然后以1至10℃/min的速率缓慢冷却。
冷却的反应溶液在25℃和8000rpm下离心10分钟以除去上清液。在25℃和8000rpm下离心10分钟的过程中,用乙醇和蒸馏水轮流清洗产物五次。
其后,将所得物在70℃的烘箱中干燥以获得粉末状小孔多孔二氧化硅颗粒(孔平均直径为10至15nm且粒径为200nm)。
3)煅烧
将在以上部分2)中制备的多孔二氧化硅颗粒放入玻璃小瓶中,在550℃下加热5小时,并且在反应完成之后缓慢冷却至室温,从而制备颗粒。
(2)颗粒2的制备
用与实施例1-(1)相同的方式制备多孔二氧化硅颗粒,不同之处在于将孔扩张时的反应条件改为140℃和72小时。
(3)颗粒3的制备(10L规模)
用与实施例1-(1)相同的方式制备多孔二氧化硅颗粒,不同之处在于使用5倍大的容器并且每种物质以5倍体积使用。
(4)颗粒4的制备(粒径:300nm)
用与实施例1-(1)相同的方式制备多孔二氧化硅颗粒,不同之处在于使用920ml的蒸馏水和850ml的甲醇制备小孔颗粒。
(5)颗粒5的制备(粒径:500nm)
用与实施例1-(1)相同的方式制备多孔二氧化硅颗粒,不同之处在于使用800ml的蒸馏水,1010ml的甲醇和10.6g的CTAB制备小孔颗粒。
(6)颗粒6的制备(粒径:1000nm)
用与实施例1-(1)相同的方式制备多孔二氧化硅颗粒,不同之处在于使用620ml的蒸馏水,1380ml的甲醇和7.88g的CTAB制备小孔颗粒。
(7)颗粒7的制备(孔径:4nm)
用与实施例1-(1)相同的方式制备多孔二氧化硅颗粒,不同之处在于在孔扩张时使用2.5ml的TMB。
(8)颗粒8的制备(孔径:7nm)
用与实施例1-(1)相同的方式制备多孔二氧化硅颗粒,不同之处在于在孔扩张时使用4.5ml的TMB。
(9)颗粒9的制备(孔径:17nm)
用与实施例1-(1)相同的方式制备多孔二氧化硅颗粒,不同的是在孔扩张时使用11ml的TMB。
(10)颗粒10的制备(孔径:23nm)
用与实施例1-(1)相同的方式制备多孔二氧化硅颗粒,不同之处在于孔扩张时使用12.5ml的TMB。
(11)颗粒11的制备(双重修饰)
1)制备小孔颗粒
用与实施例1-(1)-1)相同的方式制备小孔颗粒。
2)孔扩张
用与实施例1-(1)-2)相同的方式使小孔颗粒与TMB反应,然后冷却并离心以除去上清液。在与实施例1-(1)-2相同的条件下离心后,用乙醇和蒸馏水轮流清洗产物3次,然后在与实施例1-(1)-2)相同的条件下干燥,由此制备多孔二氧化硅颗粒粉末(孔径:10至15nm,粒径:200nm)。
3)表面修饰
将0.8至1g具有扩张的孔的多孔二氧化硅颗粒分散在50ml的甲苯中后,向其中加入5ml(3-氨基丙基)三乙氧基硅烷,然后在120℃回流加热12小时。如上所述清洗并干燥后,将1ml的三甘醇(PEG3、2-[2-(2-甲氧基乙氧基)乙氧基]乙酸)和100mg的EDC(1-乙基-3-(3-二甲基氨基丙基)碳二亚胺)和200mg的N-羟基琥珀酰亚胺(NHS)分散在30ml的PBS中,然后在室温下搅拌的同时进行反应12小时。之后,如上所述清洗并干燥产物。
由于前一步骤的反应溶液保留在孔的内部,因此孔的内部未被修饰。
4)清洗孔的内部
将800mg的表面修饰的颗粒粉末溶于40ml的2M的HCl/乙醇中,并在剧烈搅拌下回流12小时。
其后,将冷却的反应溶液以8000rpm离心10分钟以除去上清液。在25℃和8000rpm下离心10分钟的过程中,用乙醇和蒸馏水轮流清洗产物五次。
在70℃的烘箱中干燥后,获得粉末状多孔二氧化硅颗粒。
5)孔的内部的修饰
(i)用与下述实施例2-(2)-1)相同的方式将丙基引入孔中。
(ii)用与下述实施例2-(2)-2)相同的方式将辛基引入孔中。
实施例2-多孔二氧化硅颗粒表面修饰
(1)正电荷
1)氨基-粒径为300nm的颗粒
使实施例1-(4)中的多孔二氧化硅颗粒与(3-氨基丙基)三乙氧基硅烷(APTES)反应,以使其带正电。
具体地,借助于浴超声仪将100mg的多孔二氧化硅颗粒分散在100ml的圆底烧瓶中的10ml的甲苯中。然后,加入1ml的APTES并在130℃和400rpm下搅拌12小时。
反应后,将产物缓慢冷却至室温,然后以8000rpm离心10分钟以除去上清液。在25℃和8000rpm下离心10分钟的过程中,用乙醇和蒸馏水轮流清洗产物五次。
然后,将清洗的产物在70℃的烘箱中干燥,以获得在颗粒表面和孔的内部具有氨基的粉末状多孔二氧化硅颗粒。
2)氨基-粒径为200nm的颗粒
(i)用与实施例2-(1)-1)相同的方式对实施例1-(1)中的多孔二氧化硅颗粒进行修饰,不同之处在于将颗粒与(3-氨基丙基)三乙氧基硅烷(APTES)反应以使其带正电荷,并且加入0.4ml的APTES和反应时间为3小时。
(ii)用与实施例2-(1)-1)相同的方式对实施例1-(9)的多孔二氧化硅颗粒进行修饰,不同之处在于将颗粒与(3-氨基丙基)三乙氧基硅烷(APTES)反应,以使其带正电荷。
(iii)用与实施例2-(1)-1)相同的方式对实施例1-(10)的多孔二氧化硅颗粒进行修饰,不同之处在于将颗粒与(3-氨基丙基)三乙氧基硅烷(APTES)反应,以使其带正电荷。
3)氨基-颗粒之间的表面修饰的差异
(i)用与实施例2-(1)-1)相同的方式对经历实施例1-(1)-1)至实施例1-(1)-3)程序的多孔二氧化硅颗粒进行修饰,不同之处在于将颗粒与(3-氨丙基)三乙氧基硅烷(APTES)反应,以使其带正电荷。
(ii)用与实施例2-(1)-1)相同的方式对实施例1-(9)中的多孔二氧化硅颗粒进行修饰,不同之处在于将颗粒与(3-氨基丙基)三乙氧基硅烷(APTES)反应,使其带正电荷,并且反应时间为24小时。
4)醛基
使实施例2-(1)-3)-(ii)中的多孔二氧化硅颗粒与戊二醛(GA)反应,使其带正电荷。
更具体地,通过浴超声仪将100mg的多孔二氧化硅颗粒分散在100ml的圆底烧瓶中的10ml的蒸馏水中。此后,加入10ml的GA并使其反应,同时在400rpm和室温下搅拌24小时。
反应后,通过8000rpm离心10分钟除去上清液。在25℃和8000rpm下离心10分钟的过程中,用蒸馏水清洗产物五次。
(2)疏水基团的引入
1)丙基
用与实施例2-(1)相同的方式对实施例1-(1)中的多孔二氧化硅颗粒进行修饰,不同之处在于将颗粒与三甲氧基(丙基)硅烷反应,以在颗粒表面和孔的内部引入丙基,加入0.35ml的三甲氧基(丙基)硅烷代替APTES,并且反应进行12小时。
2)辛基
用与实施例2-(1)相同的方式对实施例1-(1)中的多孔二氧化硅颗粒进行修饰,不同之处在于将颗粒与三甲氧基-正辛基硅烷反应以在颗粒表面和孔的内部引入辛基,加入0.5ml的三甲氧基-正辛基硅烷代替APTES,并且反应进行12小时。
(3)负电荷
1)羧基
用与实施例2-(1)-1)相同的方式对实施例1-(1)中的多孔二氧化硅颗粒进行修饰,不同之处在于将颗粒与琥珀酸酐(succinic anhydride)反应以使其带负电荷,使用二甲基亚砜(DMSO)代替甲苯,添加80mg的琥珀酸酐代替APTES,随后在室温搅拌24小时的同时进行反应,并且使用DMSO代替蒸馏水进行清洗。
2)硫醇基
用与实施例2-(1)-1)相同的方式进行修饰,不同之处在于使用1.1ml的MPTES代替APTES。
3)磺酸基
将实施例2-(3)-2)中的100mg多孔二氧化硅颗粒分散在1ml的1M硫酸水溶液和20ml的30%过氧化氢溶液中,在室温下搅拌以引起氧化反应,从而将硫醇基氧化为磺酸基。之后,用与实施例2-(1)-1相同的方式清洗并干燥产物。
4)甲基膦酸酯基
(i)使经历实施例1-(1)-1)至实施例1-(1)-3)程序的多孔二氧化硅颗粒与(3-三羟基甲硅烷基)丙基甲基膦酸酯(THMP)反应以使其带电荷。
更具体地,通过浴超声仪将100mg的多孔二氧化硅颗粒分散在100ml的圆底烧瓶中的10ml的蒸馏水中。然后,向其中加入3ml的THMP和1.5ml的1M的HCl水溶液,并将该混合物在130℃和400rpm下搅拌24小时。
反应后,将产物缓慢冷却至室温,并通过8000rpm离心10分钟除去上清液。在25℃和8000rpm下离心10分钟的过程中,用蒸馏水清洗产物五次。
(ii)用与以上部分(i)相同的方式对实施例1-(9)中的多孔二氧化硅颗粒进行修饰,不同之处在于将颗粒与3-(三羟基甲硅烷基)丙基甲基膦酸酯(THMP)反应以使其带负电荷。
(iii)用与以上部分(i)相同的方式对实施例1-(10)中的多孔二氧化硅颗粒进行修饰,不同之处在于将颗粒与3-(三羟基甲硅烷基)丙基甲基膦酸酯(THMP)反应以使其带负电荷。
(4)亲水基团-PEG的引入
将实施例1-(1)中的100mg的多孔二氧化硅颗粒以50μg/ml的浓度分散在20ml的N,N'-二琥珀酰亚胺基碳酸酯(DSC)溶液中,并在室温下搅拌以将DSC结合至多孔二氧化硅颗粒表面。然后,用10ml的蒸馏水清洗颗粒3次,然后将10mg具有4kDa分子量和末端氨基的PEG(HO-PEG-NH2)分散在10ml的上述溶液中并在室温下对其进行搅拌,由此PEG连接在多孔二氧化硅颗粒表面。之后,用与实施例2-(1)-1)相同的方式清洗并干燥产物。
实施例3-生物活性物质的负载
(1)多柔比星
将多柔比星负载到实施例2-(3)-4)中的带负电荷的多孔二氧化硅颗粒上。
具体地,将5mg的多孔二氧化硅颗粒粉末和2mg的多柔比星在蒸馏水中混合,然后将混合物在室温下沉降1小时。
(2)伊立替康
将5mg实施例2-(3)-4)中带负电荷的多孔二氧化硅颗粒粉末分散在1ml的1×PBS中,向其中加入2mg的伊立替康,然后将混合物分散15分钟,然后将其在室温下沉降1小时。
(3)索拉非尼
将索拉非尼负载到实施例1-(11)-5)-(i)中的多孔二氧化硅颗粒上。
具体地,将5mg的多孔二氧化硅颗粒粉末和2mg的索拉非尼以5:5的混合比(按体积计)混合在1ml的去离子水/乙醇中,然后在室温下孵育1小时。其后,用1ml的去离子水清洗产物3次。
(4)视黄酸
将1ml的视黄酸溶液(50mM的乙醇)加入到100μg实施例2-(1)-2)-(i)中的多孔二氧化硅颗粒粉末中,然后在室温下沉降4小时,然后用1ml的乙醇清洗3次。
(5)p53肽
使用实施例1-(11)-5)-(ii)中的颗粒作为多孔二氧化硅颗粒。
本文使用的p53肽模拟参与凋亡机制的p53蛋白序列的一部分。模拟的序列涉及其中p53蛋白与hMDM2蛋白结合的疏水性二级螺旋结构部分的序列。因此,p53肽可作为hMDM2蛋白的拮抗剂。
p53肽的氨基酸序列(Cal.m.w.2596.78,MALDI-TOF实测值2597.92)显示在下面的式1中(N末端→C末端)。
[式1]
Z-Gly-Gly-Qln-Ser-Qln-Qln-Thr-Phe-Y-Asn-Leu-Trp-Arg-Leu-Leu-X-Qln-Asn-NH2
(其中X是具有引入的叠氮化物官能团的非天然氨基酸,所述叠氮化物官能团为2-氨基-5-叠氮基-戊酸;Y为具有引入的炔烃官能团的非天然氨基酸,其中在D-Lys的侧链上引入4-戊炔酸;
X和Y通过叠氮化物-炔烃环加成或点击反应连接在一起形成三唑官能团;
Z是5(6)-羧基荧光素(FAM))。
将1.3mg的(500nmole)p53肽溶解在100μl的DMSO中后,在15ml的锥形管中将溶液与5ml的包括溶解在其中的5mg多孔二氧化硅颗粒粉末的水溶液混合,然后在室温下孵育12小时。
通过离心(9289rcf,8500rpm,20分钟,15ml的锥形管)纯化负载有p53肽的多孔二氧化硅颗粒,并用水重复清洗其三次。
(6)siRNA
根据要求,购买由Bionic,Inc.合成的靶向绿色荧光蛋白(GFP)的21个碱基对双链siRNA。(SEQ ID NO:正义;5'-GGCUACGUCCAGGAGCGCACC-3'(SEQ ID NO:1),反义;5'UGCGCUCCUGGACGUAGCCUU-3'(SEQ ID NO:2))。
在1×PBS条件下,将10μg实施例2-(1)-2)-(ii)中的多孔二氧化硅颗粒与50pmol的siRNA混合,然后在室温下负载30分钟。
(7)质粒DNA
从细菌中产生准备表达作为pcDNA3.3骨架的GFP的6.7k碱基对质粒DNA(SEQ IDNO:5),并在纯化后使用。
在1×PBS条件下将10μg实施例2-(1)-2)-(ii)中的多孔二氧化硅颗粒与0.25μg的质粒DNA混合,并在室温下负载30分钟。
(8)线性DNA
按顺序制备正向引物-CMV启动子-eGFP cDNA-反向引物,然后进行PCR扩增,从而获得要使用的1.9k碱基对的线性DNA(SEQ ID NO:6)。
在1×PBS条件下,将12.5μg实施例2-(1)-2)-(iii)中的多孔二氧化硅颗粒与0.25μg的线性DNA混合,并在室温下负载30分钟。
(9)蛋白质
1)BSA
将100μg实施例2-(1)-2)-(ii)中的多孔二氧化硅颗粒粉末与10μg的BSA(Sigma-Aldrich,A6003)混合在200μl的1×PBS中,然后在室温下孵育1小时。
2)IgG
将100μg实施例2-(1)-2)-(ii)中的多孔二氧化硅颗粒粉末与10μg的抗扭曲IgG(anti-twist IgG)(Santacruz,sc-81417)混合在200μl的1×PBS中,然后在室温下孵育1小时。
3)RNase A
将100μg实施例1-(9)中的多孔二氧化硅颗粒粉末与10μg的RNase A(Sigma-Aldrich,R6513)混合在200μl的1×PBS中,然后在室温下孵育1小时。
4)Cas9
将40μg实施例2-(1)-2)-(i)中的多孔二氧化硅颗粒粉末、4μg的Cas9蛋白(SEQ IDNO:3)和2.25μg的指导RNA(SEQ ID NO:4)混合在10μl的1×PBS中,然后在室温下孵育1小时。
(5)抗PD-1抗体
将100μg实施例2-(3)-4)-(ii)中的多孔二氧化硅颗粒粉末与50μg的抗PD-1(BioXCell,BP0146)混合在100μl的蒸馏水中,然后在室温下孵育5分钟。
(6)抗PD-L1抗体
将100μg实施例2-(3)-4)-(ii)中的多孔二氧化硅颗粒粉末和50μg的抗PD-L1(BioXCell,BP0101)混合在100μl的蒸馏水中,然后在室温下孵育5分钟。
实验例1-多孔二氧化硅颗粒形成和孔扩张的鉴定
在显微镜下观察实施例1-(1)至(3)中的小孔颗粒和制备的多孔二氧化硅颗粒,以确定小孔颗粒是否均匀形成和/或孔是否充分扩张以均匀形成多孔二氧化硅颗粒(图1至4)。
图1是实施例1-(1)中的多孔二氧化硅颗粒的显微图像,并且图2是实施例1-(2)中的多孔二氧化硅颗粒的显微图像,表明均匀地形成了具有充分扩张的孔的球形多孔二氧化硅颗粒。
图3是实施例1-(1)中的小孔颗粒的显微图像,和图4是实施例1-(1)与实施例1-(3)中的小孔颗粒显微图像的比较,表明均匀地形成了球形小孔颗粒。
实验例2-BET表面积和孔体积的计算
分别计算实施例1-(1)中的小孔颗粒和实施例1-(1)、(7)、(8)和(10)中的多孔二氧化硅颗粒的表面积和孔体积。表面积通过Brunauer-Emmett-Teller(BET)方法计算,而孔大小分布通过Barrett-Joyner-Halenda(BJH)方法计算。
颗粒的显微图像如图5所示,计算结果如下表1所示。
[表1]
实验例3-多孔二氧化硅颗粒的生物降解性的验证
为了证实实施例1-(1)中的多孔二氧化硅颗粒的生物降解性,在0小时、120小时和360小时于显微镜下观察在37℃和SBF(pH7.4)下的生物降解度,结果如图6所示。
参照结果,可以看出,多孔二氧化硅颗粒被生物降解并在360小时后几乎完全降解。
实验例4-多孔二氧化硅颗粒的吸光度比的测定
测定根据式1的吸光度比随时间的变化。
[式1]
At/A0
(其中A0为通过将5ml的包括1mg/ml多孔二氧化硅颗粒的悬浮液置于具有50kDa直径的孔的圆筒状渗透膜中来测定的多孔二氧化硅颗粒的吸光度,
将15ml与悬浮液实质上相同的溶剂在与渗透膜接触的同时置于渗透膜的外部,接着在60rpm和37℃下水平搅拌渗透膜的内部和外部,
At为在测定A0后t小时测定的所述多孔二氧化硅颗粒的吸光度)。
具体地,将5mg的多孔二氧化硅颗粒粉末溶解在5ml的SBF(pH7.4)中。之后,将5ml的多孔二氧化硅颗粒溶液置于图7所示的具有直径为50kDa的孔的渗透膜中。然后,将15ml的SBF加到外膜中,并且每12小时更换外膜的SBF。在37℃和60rpm下水平搅拌的同时进行多孔二氧化硅颗粒的降解。然后,通过UV-可见光谱法测定吸光度,并在λ=640nm下进行分析。
(1)吸光度比的测量
根据上述方法测定实施例1-(1)中的多孔二氧化硅颗粒的吸光度,结果如图8所示。
参照结果,可以看出,当吸光度比达到1/2时,t为约58小时,并且降解进行得非常缓慢。
(2)粒径测定
根据上述式1分别测定实施例1-(1)、(5)和(6)中多孔二氧化硅颗粒各自的吸光度,结果如图9所示(SBF用作悬浮液和溶剂)。
参照结果,可以看出,t随着粒径的增加而降低。
(3)孔平均直径下的测定
根据上述式1分别测定实施例1-(1)至(9)中多孔二氧化硅颗粒各自的吸光度,并且以实施例1-(1)中的小孔二氧化硅颗粒的吸光度作为对照,结果如图10所示(SBF用作悬浮液和溶剂)。
参照结果,可以看出,实施例中的多孔二氧化硅颗粒具有比对照显著较大的t。
(4)pH下的测定
在每个pH下测定实施例1-(4)中的多孔二氧化硅颗粒的吸光度。分别在pH2、5和7.4下在SBF和Tris中测定吸光度,结果如图11所示。
参照结果,针对pH,t存在差异,但是在所有情况下,当吸光度比达到1/2时,t为20以上。
(5)带电荷时的测定
测定实施例2-(1)-1)中的多孔二氧化硅颗粒的吸光度,结果如图12所示(Tris(pH7.4)用作悬浮液和溶剂)。
参照结果,在颗粒带正电荷的情况下,当吸光度比达到1/2时,t为20以上。
实验例5-生物活性物质的释放
(1)多柔比星
1)动态条件
这模拟血流速度非常高的环境或频繁发生高外部冲击的环境。
将5mg负载有多柔比星(1Mg)的多孔二氧化硅颗粒分散于SBF(pH7.4)中(总体积:1ml),然后将溶液置于1.5ml的管中,并保持在37℃和20rpm进行水平搅拌的动态条件下。在每个时间点,使用离心机将负载有多柔比星的多孔二氧化硅溶液沉淀,并测定上清液的吸光度(λab=480nm),以确定多柔比星的释放量。结果如图13(A)所示。
参照结果,可以发现,多柔比星以相对弱的结合力负载在颗粒表面,并且由于多柔比星在SBF中的高溶解度而相对较快地释放,经过约1.5小时达到50%的释放率,并且生物活性物质连续释放长达12小时或更长时间。
2)静态条件
这模拟如肿瘤组织、肌肉组织或肿瘤周围的血流流速缓慢的环境。
将10mg负载有多柔比星(2mg)的多孔二氧化硅颗粒分散在渗透膜内的SBF(pH7.4)中(总体积:0.5ml),然后将渗透膜放入1.5ml的SBF管中(pH7.4),并在37℃的静态条件下保持。在每个时间点,使用离心机使负载有多柔比星的多孔二氧化硅溶液沉降,并测定上清液的吸光度(λab=480nm),以确定多柔比星的释放量。结果如图13(B)所示。
参照结果,可以看出,尽管多柔比星以相对弱的结合力负载在颗粒表面,并且由于多柔比星在SBF中的高溶解度而相对较快地释放,但大约需要6天的时间达到50%的释放率,并且生物活性物质连续释放长达20天或更长时间。
(2)伊立替康
将1Mg负载有伊立替康(0.2mg)的多孔二氧化硅颗粒分散在1ml的人血浆中。将溶液保持在37℃和200rpm下进行水平搅拌的动态条件下。在每个时间点,使用离心机使负载有伊立替康的多孔二氧化硅溶液沉降,并测定上清液的吸光度(λab=255或278nm)以确定伊立替康的释放量。结果如图14所示。
参照结果,可以看出,在5.5小时后释放了约50%的伊立替康,并且生物活性物质连续释放长达120小时或更长时间。
(3)索拉非尼
将1Mg负载有索拉非尼(0.1Mg)的多孔二氧化硅颗粒分散在10ml的1×PBS中。将溶液维持在37℃和200rpm下进行水平搅拌的动态条件下。在每个时间点,使用离心机使负载有索拉非尼的多孔二氧化硅溶液沉降,并测定上清液的吸光度(λab=270nm)以确定索拉非尼的释放量。结果如图15所示。
参照结果,可以看出,难溶性生物活性物质索拉非尼通过与具有疏水性取代基的多孔二氧化硅颗粒相互作用而非常缓慢地释放。
(4)视黄酸
将0.1mg负载有视黄酸的颗粒置于含有5%乙醇的PBS(pH7.4)溶液中,并在进行水平搅拌的同时保持在37℃。每24小时,将包含颗粒的溶液离心以测定上清液在350nm的波长下的吸光度,从而确定视黄酸的释放量。结果如图16所示。
参照结果,可以看出,带负电荷的视黄酸由于与带正电荷的多孔二氧化硅颗粒的相互作用而非常缓慢地释放,并且约10天几乎100%释放。
(5)p53肽
将5mg负载有p53肽的颗粒置于5ml含有10%FBS的1×PBS或5ml的1×PBS中,并保持在动态环境中,同时在37℃和20rpm下旋转。在每个时间点,以8500rpm进行离心,测定5(6)-羧基荧光素(FAM)的荧光强度,所述5(6)-羧基荧光素(FAM)是上清液中p53肽结合的荧光标记(吸光度:480nm,发射:520nm)。结果如图17所示。
参照结果,可以看出,多孔二氧化硅颗粒通过内部疏水性(疏水作用)的结合力负载p53肽,因此,p53肽没有在PBS溶液中释放。然而,当溶液中存在如FBS(胎牛血清)等的蛋白质时,p53肽会与FBS蛋白质的疏水片段结合,并可溶解在溶液中,因此可以看出p53肽释放到多孔二氧化硅颗粒的外部。相反,当负载在颗粒内部的p53肽释放到颗粒外部时,FBS蛋白可引入至颗粒中。
(6)siRNA
1)条件1
将10μl负载有Cy5-siRNA的多孔二氧化硅颗粒重悬于SBF(pH7.4,37℃)中(总体积:0.5ml),并置于1.5ml管中。在37℃和60rpm水平搅拌的同时进行siRNA的释放。在每个时间点,使用离心机沉降负载siRNA的多孔二氧化硅溶液,并测定上清液的荧光强度。
在670nm波长(λex=647nm)下测定Cy5-siRNA的荧光强度,以确定siRNA的释放程度,结果如图19(A)所示。
参照结果,可以看出,释放50%的siRNA需要约6小时。
2)条件2
将20μg负载有上述1)的siRNA(1μg)的多孔二氧化硅颗粒分散在渗透膜内的SBF(pH7.4)中(总体积:0.5ml),并且将渗透膜置于1.5ml的SBF(pH7.4)管中,并保持37℃下的静态条件。在每个时间点,使用离心机沉降负载siRNA的多孔二氧化硅溶液,并测定上清液的吸光度(λab=480nm),以确定siRNA的释放量。结果示于图19(B)所示。
参照结果,可以看出,约48小时后,siRNA达到50%的释放率,并且生物活性物质连续释放长达100小时或更长时间。
(7)质粒DNA
将20μg负载有pDNA(1μg)的多孔二氧化硅颗粒分散在渗透膜内的SBF(pH7.4)中(总体积0.5ml),并将渗透膜置于1.5ml的SBF(pH7.4)管中,同时在37℃和60rpm下摇动。在每个时间点,用离心机沉淀负载有pDNA的多孔二氧化硅溶液,并测定上清液的吸光度(λab=480nm)以确定pDNA的释放量。结果如图20和21所示。
参照结果,可以看出,约24小时后,pDNA的释放量达到50%,并且生物活性物质连续释放长达100小时或更长时间。
(8)线性DNA
将负载有线性DNA的多孔二氧化硅颗粒(3μg的线性DNA,100μg的多孔二氧化硅颗粒)重悬于PBS(pH7.4,37℃)中,并且渗透膜具有20kDa的孔径(与图18中的管相同的管)。将悬浮液置于膜中后,将渗透管浸入1.5ml的PBS中。在37℃和60rpm下水平搅拌的同时进行质粒DNA的释放。
在24小时之前的0.5h、1h、2h、3h、4h、6h、12h和24h点回收释放溶剂,然后在24小时收集0.5ml的释放溶剂用于Hoechst结合测定,然后加入等量的PBS。
在460nm波长(λex=360nm)下测量Hoechst 33342的荧光强度,测定质粒DNA的释放程度,结果如图22所示。
参照结果,可以看出,50%的线性DNA的释放时间为约24小时。
(9)蛋白质
1)BSA
将100μg负载有荧光素荧光标记的BSA的多孔二氧化硅颗粒重悬于200μl的SBF(pH7.4)或PBS(pH7.4)中。在37℃和60rpm下水平搅拌的同时进行BSA的释放。
在6h、12h、24h、48h、96h、144h和240h点,回收200μl的释放溶剂用于荧光测定,并向其中加入等量的SBF或PBS。
在517nm波长(λex=492nm)下测定荧光素荧光标记的BSA的荧光强度,以确定BSA的释放程度,结果如图23所示。
参照结果,可以看出,BSA在SBF和PBS中均以持续方式释放,并且可以看出在每个时间段中,在PBS中的释放量均比在SBF中稍高,并且几乎100%在250小时或更长时间被释放。
2)IgG
将100μg负载有荧光素荧光标记的IgG的多孔二氧化硅颗粒重悬于200μl的SBF(pH7.4)或PBS(pH7.4)中。在37℃和60rpm下水平搅拌的同时释放IgG。
在6h、12h、24h、48h、96h、144h和240h点,回收200μl的释放溶剂用于荧光测定,并向其中加入等量的SBF或PBS。
在517nm波长(λex=492nm)下测量荧光素荧光标记的IgG的荧光强度,以确定BSA的释放程度,结果如图24(A)所示。
参照结果,可以看出,IgG在SBF和PBS中均缓慢释放,并且几乎100%在250小时或更长时间被释放。
3)其他抗体
将20μg负载有抗体1(抗PD-1)或抗体2(抗PD-L1)(10μg)的多孔二氧化硅颗粒分散在SBF(pH7.4)中(总体积:1ml),将该溶液置于1.5ml管中,并保持在37℃和20rpm下进行水平搅拌的动态条件下。在每个时间点,使用离心机沉降负载有抗体的多孔二氧化硅溶液,并测定上清液的吸光度(λab=480nm),以确定释放的抗体量。结果如图24(B)和(C)所示。
参照结果,可以看出,抗体1经过约45小时和抗体2经过约20小时,其释放速率达到约50%。可以看出,在开始时,PBS中的释放速率高于SBF,但是随着时间经过(以100小时为转折点),SBF中的释放速率增加,并且抗体持续释放长达250小时或更长时间。
4)RNase A
将100μg负载有荧光素荧光标记的RNase A的多孔二氧化硅颗粒重悬于200μl的SBF(pH7.4)或PBS(pH7.4)中。在37℃和60rpm下水平搅拌的同时进行RNase A的释放。
在6h、12h、24h、48h、96h、144h和240h点,回收200μl的释放溶剂用于荧光测定,并且向其中添加等量的SBF或PBS。
在517nm波长(λex=492nm)下测定荧光素荧光标记的RNase A的荧光强度,以确定BSA的释放程度,结果如图25所示。
参照结果,可以看出,尽管RNase A从SBF和PBS中缓慢释放,但是在每个时间段中,在PBS中的释放量略高于SBF,并且在250小时或者更长时间释放了几乎100%。
5)Cas9
将40μg负载有Cas9蛋白/指导RNA复合物的多孔二氧化硅颗粒悬浮于PBS(pH7.4)中,然后将多孔二氧化硅颗粒置于无血清培养基中,在50,000个称为小鼠成纤维细胞的NIH3T3细胞的载玻片上处理,然后在37℃和5%CO2下孵育。
在1h、3h、6h和24h点,除去培养基,用1×PBS溶液清洗产物,并与4%多聚甲醛孵育15分钟以固定细胞。
用PBS清洗后,将细胞在封闭缓冲液(1×PBS,5%正常山羊血清,0.3%triton X-100)中孵育1小时。
用PBS清洗后,将His标签抗体(Santa Cruz,sc-8036)孵育16小时。
再次用PBS清洗后,将Alexa Fluor 488连接的抗小鼠二抗(Abcam,ab150113)孵育2小时。
用PBS清洗后,用DAPI处理载玻片以染色细胞核。使用荧光显微镜鉴定细胞中蛋白质的分布,结果如图26所示。
在图26中,DAPI是用于核染色的试剂,其在荧光显微镜图像中显示为蓝色,并且指示细胞核的位置。此外,Alexa Fluor 488是一种用Cas9蛋白标记的荧光染料,在荧光显微镜图像中显示为绿色并指示细胞内Cas9蛋白的位置。当将负载有Cas9蛋白标记的AlexaFluor488的二氧化硅颗粒施于细胞并进行DAPI染色时,荧光显微镜图像可以显示Cas9蛋白通过二氧化硅颗粒在细胞中的存在与否以及细胞核的位置。
参照结果,可以看出,引入细胞中的Cas9蛋白主要在引入后3小时在细胞质部分中观察到,而在24小时后在细胞核中观察到。由于所使用的二氧化硅颗粒基本上几乎不进入细胞核,因此可以理解,Cas9蛋白在细胞中24小时后从二氧化硅颗粒中释放出来,并进入已知为Cas9蛋白积累的细胞内细胞器的细胞核。
实验例6-生物活性物质的递送和疾病的治疗
(1)癌症中的直接递送
为了在动物水平上验证载体在siRNA递送研究中的可能作用,研究通过在小鼠中释放生物活性物质来抑制肿瘤。
从Orient Bio,Inc.购买Balb/c裸鼠雄性小鼠(5周大),将300万HeLa细胞(宫颈癌细胞)分散在无菌的1×PBS中,以扩增皮下注射到小鼠体内的异种移植肿瘤。当观察到70mm3大小的实体瘤时,分别将PBS、FITC-多孔二氧化硅颗粒(实施例2-(1)-2)-(ii)中的多孔二氧化硅颗粒)和负载有Cy5-siRNA的FITC-多孔二氧化硅颗粒(实施例2(1)-2)-(ii)中的多孔二氧化硅颗粒)注入小鼠的肿瘤中。然后,通过FOBI荧光体内成像系统(Neoscience,Korea),在施用之前即刻、施用之后即刻和施用之后48小时测定荧光强度及其分布。
通过以下方式进行FITC标记:将50mg的二氧化硅颗粒分散在1ml二甲基亚砜(DMSO)中;向其中加入25μg(10μl)的FITC-NHS(N-羟基琥珀酰亚胺)溶液(2.5mg/mL);使混合物在室温下反应18小时,同时用铝箔遮光;通过离心(8500rpm,10分钟)纯化反应产物;丢弃上清液,同时收集沉淀的颗粒;将颗粒均匀分散在乙醇中,其中用乙醇和蒸馏水重复上述过程三到四次进行纯化,直到在上清液中看不到FITC颜色。结果如图27(A)所示。
在图27(A)中,对照是指单独施用PBS,cy5-siRNA是指单独施用cy5-siRNA,FITC-DDV是指单独施用FITC标记的多孔二氧化硅颗粒,复合物是指施用负载有cy5-siRNA并用FITC标记的多孔二氧化硅颗粒。从该图中可以看出,负载在颗粒上并递送至体内的siRNA具有更长的活性持续时间,并在注射部位停留更长的时间,因此即使在48小时后仍显示出强荧光。
(2)通过静脉内注射递送
1)实验方法
(i)多柔比星
使用HepG2细胞作为人类肝癌细胞系在Balb/C裸鼠中制备Xeno。当Xeno的大小适合于实验(50至100mm3)时,将实施例2-(3)-4)-(i)中的颗粒用多柔比星负载,分散在100μl的PBS水溶液中,并通过小鼠尾静脉注射。多柔比星的注射剂量为4mg/kg(小鼠体重),基于5至8周大的Balb/C裸鼠的20g的平均体重,使用80μg的多柔比星和160μg的颗粒。
(ii)VEGF抑制性siRNA
使用MDA-MB-231细胞作为人乳腺癌细胞系在Balb/C裸鼠中制备Xeno。当Xeno的大小适合实验(50至100mm3)时,将实施例2-(1)-2)-(ii)中的颗粒用VEGF抑制性siRNA(SEQID NO:7正义;5'-GGAGUACCCUGAUGAGAUCdTdT-3',SEQ ID NO:8反义;5′-GAUCUCAUCAGGGUACUCCdTdT-3′)负载,分散于100μl的PBS水溶液中,并通过小鼠尾静脉注射。VEGF抑制性siRNA的注射剂量为1mg/kg(小鼠体重),基于5至8周大的Balb/C裸鼠的20g的平均体重,使用20μg的siRNA和400μg的颗粒。
(iii)RNase A
使用HeLa细胞作为人宫颈癌细胞系在Balb/C裸鼠中制备Xeno。当Xeno的大小变得适合实验(50至100mm3)时,将实施例1-(9)中的颗粒用RNase A负载,分散于100μl的PBS水溶液中,并通过小鼠尾静脉注射。RNase A剂量的注射剂量为2mg/kg(小鼠体重),基于5至8周大的Balb/C裸鼠的20g的平均体重,使用40μg的RNase A和400μg的颗粒。
(iv)p53
使用HeLa细胞作为人宫颈癌细胞系在Balb/C裸鼠中制备Xeno。当Xeno的大小适合实验(50至100mm3)时,将实施例1-(11)-5)-(ii)中的颗粒用p53肽负载,分散于100μl的PBS水溶液中,并通过小鼠尾静脉注射。p53肽的注射剂量为2.5mg/kg(小鼠体重),基于5至8周大的Balb/C裸鼠的20g的平均体重,使用50μg的p53肽和200μg的颗粒。
2)实验结果
参照图27(B),在将多柔比星、VEGF抑制性siRNA、RNase A或p53负载于本发明的多孔二氧化硅颗粒上,然后注射颗粒的所有情况下,与分别单独注射多柔比星、VEGF抑制性siRNA、RNase A或p53相比,肿瘤生长抑制和VEGF表达抑制均表现优异。这些结果显示基于如根据本发明的颗粒的例如优异的血管内递送和生物降解性等内在性质的功能效果。
(3)通过导管向肿瘤周围的血管的递送
为了将生物活性物质有效地递送至肿瘤,在将导管插入到与肿瘤相关的血管接近的动脉中之后,将负载有抗癌剂的本发明的多孔二氧化硅颗粒通过血管进行递送(图27(C))。参照图27(C),可以看出,如图27(C)的黑滴(black drop)所示,包括与造影剂混合的本发明的多孔二氧化硅颗粒的组合物准确地进行靶向递送而不堵塞导管和血管和/或不发生沉淀或聚集。
实验例7-多孔二氧化硅颗粒中ζ电势的测定
(1)实验方法
将100μg的多孔二氧化硅颗粒分散在1ml的PBS(pH7.4)中,转移至一次性折叠毛细管(DTS1070),然后安装在ζ电势测定装置上以测定ζ电势。
(2)实验结果
参照图28,P=O振动峰,P-CH3摇摆峰和P-CH3摆动峰出现在FT-IR光谱中,表明阴离子官能团引入到颗粒表面并且使其带负电。
参照下表2,可以看出,多孔二氧化硅颗粒可以具有多种ζ电势,这取决于要修饰的官能团,并且还可以看出,负载的生物活性物质的类型是多样化的。具体地,可以看出,本发明的多孔二氧化硅颗粒表现出+3mV以上或-18mV以下的ζ电势,并且通过双重修饰(例如,PEG)更有效地负载生物活性物质至疏水性官能团。
[表2]
实验例8-血液中多孔二氧化硅颗粒的稳定性分析
(1)实验方法
将10mg实施例1-(1)中的颗粒和10mg实施例2-(3)-4)-(i)中的颗粒分别分散在PBS水溶液和1ml的25%血浆溶液中,然后置于室温下1小时,接着除去上清液。对上述溶液进行比较,比较的是未分散但沉降在溶液中的颗粒量。此外,通过比较去除的上清液的吸光度,比较分别稳定地分散在PBS水溶液和25%血浆溶液中的颗粒的量。
将4ml人血液分散在15ml的PBS溶液中后,使用离心机将该溶液以10,000rpm离心5分钟,并弃去15ml的上清液。重复此过程五次以除去残留在血液中的红细胞以外的蛋白质。将分离的红细胞分散在40ml的PBS溶液中。分别将实施例1-(1)和实施例2-(3)-4)-(i)中的颗粒以从最高值20mg开始依次降低浓度制备,然后分散在0.8ml的PBS溶液中。将0.2ml上述单独制备的、然后分散在PBS溶液中的红细胞溶液添加到上述溶液中,随后在室温下遮光并将混合物在80rpm的旋转搅拌器中放置4小时。4小时后,使用离心机在4℃和10,000rpm下离心3分钟使颗粒完全沉降,并且对上清液进行577nm的吸光度测定以比较红细胞的溶血度。100%溶血定义为表示用0.8ml的蒸馏水代替分散颗粒的溶液,而0%溶血定义为表示用0.8ml的PBS溶液代替分散有颗粒的溶液。
(2)实验结果
参照图29,可以看出,在PBS水溶液和25%血浆溶液条件下,根据本发明的多孔二氧化硅颗粒的沉淀或聚集程度均显著更低。更具体地,对照组在PBS水溶液和25%血浆溶液中分别显示出80%和70%的沉淀率。另一方面,本发明的颗粒分别显示出仅4%和5%的沉淀率。原因是通过对本发明的多孔二氧化硅颗粒进行表面处理而产生了表面电荷(ζ电势(mV)),并且在颗粒之间产生了排斥力,从而维持了稳定的溶液。
参照图30,可以看出,即使用高浓度的本发明的颗粒处理红细胞,也不会发生溶血。另一方面,参照图31,在没有用其他官能团进行表面修饰的多孔二氧化硅颗粒(Silanol-MSN)的情况下,可以看出,红细胞的溶血增加,这取决于颗粒的浓度。原因是本发明的二氧化硅颗粒大部分被包括磺酸盐、醛、聚乙二醇、甲基膦酸酯和胺官能团的其他官能团代替硅烷醇基团而修饰。因此,认为:与红细胞表面的季铵基的相互作用不强;由于包括许多孔的多孔结构,与红细胞接触的表面积小,从而减少了相互作用;并且该颗粒的直径为100nm以上,从而认为红细胞溶血较常规二氧化硅颗粒溶血显著更低。
实验例9-多孔二氧化硅颗粒的生物活性物质负载能力
(1)实验方法
1)多柔比星
用多柔比星负载实施例2-(3)-4)-(i)中的带负电荷的多孔二氧化硅颗粒后,测定上清液的吸光度,以确定多柔比星的负载量,并且计算颗粒负载率(“负载能力”)。
具体地,将5mg的多孔二氧化硅颗粒粉末和2mg的多柔比星在1ml的蒸馏水中混合,然后在室温下沉降1小时。随后,将溶液在8000rpm下离心10分钟以沉降颗粒,并且测定上清液的吸光度(λab=480nm)以确定无负载下残留在上清液中的低分子量化合物的量。此外,计算出负载的低分子量化合物的量(负载的低分子量化合物的量=最初添加的低分子量化合物的量–上清液中残留的低分子量化合物的量),以便确定负载能力(负载能力=生物活性物质/多孔二氧化硅颗粒,w/w%)
2)伊立替康
用伊立替康负载实施例2-(3)-4)-(i)中的带负电荷的多孔二氧化硅颗粒后,测定上清液的吸光度,并计算出伊立替康的负载量,并确定其负载能力。除了在λab=255nm下测定吸光度以外,用与实验例9-(1)-1)同样地方式进行计算负载能力的程序。
3)索拉非尼
将5mg实施例1-(11)-5)-(i)中的多孔二氧化硅颗粒和2mg的索拉非尼以5:5的混合比(按体积计)混合在1ml的去离子水/乙醇中,然后在室温下负载1小时。除了在λab=270nm下测定吸光度以外,用与实验例9-(1)-1)同样地方式进行计算负载能力的程序。
4)视黄酸
将1ml的视黄酸溶液(50mM的乙醇)加入到100μg的实施例2-(1)-2)-(i)中的多孔二氧化硅颗粒中,然后在室温下负载4小时。除了在λab=350nm下测定吸光度以外,用与实验例9-(1)-1)同样地方式进行计算负载能力的程序。
5)p53肽
将5mg实施例1-(11)-5)-(ii)中的多孔二氧化硅颗粒分散在100μl荧光(FAM)标记的p53肽溶液(13mg/ml,DMSO)中,置于15ml锥形管中,然后在室温下孵育12小时。此后,将包含p53肽的多孔二氧化硅颗粒离心(9289rcf,8500rpm,20分钟,15ml锥形管),然后测定上清液的荧光以计算负载在颗粒上的肽的量。
6)siRNA
用siRNA负载实施例2-(1)-3)-(ii)中的带正电的颗粒后,测定上清液中残留的siRNA以计算siRNA的负载量,从而确定其负载能力。具体地,将20μg的多孔二氧化硅颗粒分散在10μl的PBS水溶液中,然后向其中添加1μg的siRNA,并将混合物在室温下沉降30分钟。然后,将溶液以8000rpm离心10分钟,并且使用聚丙烯酰胺凝胶电泳(PAGE)测定上清液中残留的siRNA的量,并计算负载在颗粒上的siRNA的量。
7)mRNA
用具有下式(2)的序列的mRNA负载实施例2-(1)-3)-(ii)中的带正电的颗粒后,测定上清液中残留的mRNA的量以计算其负载量,从而确定其负载能力。具体地,将20μg的多孔二氧化硅颗粒分散在10μl的PBS水溶液中,向其中添加1μg的mRNA,并将混合物在室温下沉降30分钟。此后,将溶液以8000rpm离心10分钟,然后使用琼脂糖凝胶测定上清液中残留的mRNA的量,并计算负载在颗粒上的mRNA的量。
[式2]
TTTGTTCATAAACGCGGGGTTCGGTCCCAGGGCTGGCACTCTGTCGATACCCCACCGAGACCCCATTGGGGCCAATACGCCCGCGTTTCTTCCTTTTCCCCACCCCACCCCCCAAGTTCGGGTGAAGGCCCAGGGCTCGCAGCCAACGTCGGGGCGGCAGGCCCTGCCATAGCAGATCTGCGCAGCTGGG(A)≥100
8)pDNA
用pDNA负载实施例2-(1)-3)-(iii)中的带正电荷的颗粒后,测定上清液中残留的pDNA的量以计算负载的pDNA的量,从而确定其负载能力。具体地,将20μg的多孔二氧化硅颗粒分散在10μl的PBS水溶液中,向其中添加1μg的pDNA,并将混合物在室温下沉降30分钟。之后,将溶液以8000rpm离心10分钟,然后使用琼脂糖凝胶测定保留在上清液中的pDNA的量,并且计算负载在颗粒上的pDNA的量。
9)线性DNA
用线性DNA负载实施例2-(1)-3)-(iii)中的带正电荷的颗粒后,测定上清液中残留的DNA的量以计算出负载的线性DNA的量,从而确定其负载能力。具体地,将20μg的多孔二氧化硅颗粒分散在10μl的PBS水溶液中,向其中添加1μg的线性DNA,并将混合物在室温下沉降30分钟。之后,将溶液以8000rpm离心10分钟,然后使用琼脂糖凝胶测定上清液中残留的线性DNA的量,并计算负载在颗粒上的线性DNA的量。
10)蛋白质
(i)BSA
用BSA负载带正电荷的多孔二氧化硅颗粒后,测定残留在上清液中的BSA的量,以计算BSA的负载量,从而确定其负载能力。
具体地,将100μg实施例2-(1)-2)-(ii)中的多孔二氧化硅颗粒粉末和10μg的BSA(Sigma-Aldrich,A6003)混合在200μl的1×PBS中,然后在室温下孵育1小时。之后,将溶液以8000rpm离心10分钟沉淀颗粒,然后收集10μl的上清液并与200μl的5倍稀释的Bradford试剂充分混合,并在λab=595nm下测定其吸光度,从而确定上清液中没有负载的残留的BSA量。此时,在稀释溶液的同时将BSA溶液与Bradford试剂混合以降低其浓度,然后测定溶液的吸光度并将其与BSA的标准曲线进行比较,从而准确地计算BSA的负载能力。
(ii)IgG
进行与实验例9-(1)-10)-(i)相同的程序,不同之处在于将100μg实施例2-(1)-2)-(ii)中的多孔二氧化硅颗粒粉末与10μg的抗扭曲IgG(Santacruz,sc-81417)混合在200μl的1×PBS中,然后在室温下孵育1小时,然后将其负载。
(iii)RNase A
进行与实验例9-(1)-10)-(i)相同的程序,不同之处在于将100μg实施例1-(9)中的多孔二氧化硅颗粒粉末与10μg的RNase A(Sigma-Aldrich,R6513)混合在200μl的1×PBS中,然后在室温下温育1小时并将其负载。
(iv)Cas9
进行与实验例9-(1)-10)-(i)相同的程序,不同之处在于将40μg实施例2-(1)-2)-(i)中的多孔二氧化硅颗粒粉末、4μg的Cas9蛋白(SEQ ID NO:3)和2.25μg的指导RNA(SEQID NO:4)混合在10μl的1×PBS中,然后在室温下孵育1小时并将其负载。
(v)抗PD-1抗体
进行与实验例9-(1)-10)-(i)相同的程序,不同之处在于将100μg实施例2-(3)-4)-(ii)中的多孔二氧化硅颗粒粉末与50μg的抗PD-1(BioXCell,BP0146)混合在100μl的蒸馏水中,然后在室温下孵育5分钟并将其负载。
(vi)抗PD-L1抗体
进行与实验例9-(1)-10)-(i)相同的步骤,不同之处在于将100μg实施例2-(3)-4)-(ii)中的多孔二氧化硅颗粒粉末与50μg的抗PD-L1(BioXCell,BP0101)混合在100μl的蒸馏水中,然后在室温下孵育5分钟并将其负载。
(2)实验结果
参照图32,作为通过离心作用使负载有多柔比星的多孔二氧化硅颗粒沉淀的结果,可以看出,多柔比星主要负载在颗粒上,由此与对照组相比,溶液的颜色显著透明。
参照下表3,可以显示根据上述实验程序的多孔二氧化硅颗粒对不同生物活性物质(生物活性物质/多孔二氧化硅颗粒)的负载能力(w/w%)。
[表3]
实验例10-多孔二氧化硅颗粒的细胞毒性试验
以每孔10,000个HepG2细胞置于96孔板中,然后在24小时后,将实施例2-(3)-4)中的颗粒以较低浓度至最高浓度为1Mg依次分散在每个孔中,然后静置24小时。使用细胞计数试剂盒(CCK)测定HepG2细胞的存活率,结果如图33所示。
从图33中可以看出,包括本发明的多孔二氧化硅颗粒的组合物无论浓度如何均不影响HepG2细胞系的存活率,并且未观察到细胞毒性。
实验例11-包括多孔二氧化硅颗粒的栓塞用组合物的稳定性和可靶向性
(1)与栓塞物质混合时的稳定性验证
通过将1.6ml的广泛用作栓塞物质的碘油与0.4ml的负载有多柔比星的多孔二氧化硅颗粒混合来制备乳剂,将其以液滴形式滴到透明塑料板上并用荧光显微镜拍照。如图34显示拍照的荧光图像。
参照图34,可以看出,与单独的碘油乳剂(A)相比,与多孔二氧化硅颗粒混合的乳剂形式(B)在更长的时间内保持乳剂的均匀大小。因此,应理解,本发明的多孔二氧化硅颗粒适合与如碘油等栓塞物质混合并使用,可以减少聚集和/或沉淀,从而获得优异的栓塞效果和治疗效果。
(2)基于正常肝组织损伤的可靶向性验证
1)实验方法
兔实验完成后,收集肝脏并拍照以目视检查肝组织的梗塞,从而确定对正常肝组织是否有损害。
2)实验结果
参照下面的表4和图35,当将负载多柔比星的多孔二氧化硅颗粒与碘油混合并以乳剂形式进行肝癌栓塞时,除了肝癌细胞以外的周围正常肝组织没有表现出如炎症等肝毒性。因此,可以基于包括本发明的多孔二氧化硅颗粒和碘油的栓塞用组合物的高靶向性来显示栓塞效果,以及显示对应于特定疾病的负载的生物活性物质的治疗效果。
[表4]
(3)根据肝癌组织或细胞中生物活性物质的释放量验证可靶向性
1)实验方法
(i)TACE
通过兔耳内的动脉插入微导管,在肝脏中植入VX2肿瘤,当微导管到达肝动脉时,将0.4ml负载有多柔比星的实施例2-(3)-4)-(i)中的颗粒与1.6ml的碘油混合制备乳剂,并且通过插入肝动脉的微导管注入0.2ml的乳剂。
(ii)荧光信号分析装置
对于颗粒表面具有荧光的多孔二氧化硅颗粒,将TACE后收集的兔子的肿瘤、肝脏、脾脏和肾脏精细研磨,并以各组织每1g与2ml的1.5%的盐酸-乙醇溶液混合,然后使用匀浆器将组织和溶液充分混合。然后,将该混合物在4℃下放置24小时,同时遮光以洗脱组织中的颗粒。通过在4℃和5000rpm下离心10分钟将溶液离心,然后测定上清液的荧光以确定在每个组织中残留的颗粒的量。
(iii)流式细胞术
对于颗粒表面具有荧光的多孔二氧化硅颗粒,将TACE后收集的兔子的肿瘤、肝脏、脾脏和肾脏精细研磨,并以各组织每200mg与10ml的0.25%的胰蛋白酶混合。将混合物在室温下放置30分钟,以使细胞从组织上剥离。30分钟后,收集上清液,然后比较通过流式细胞术提取的细胞中所含颗粒的量。
(iv)药代动力学
在TACE程序后的0、1、5、10、30、60分钟,收集兔子的血液,并从血液中分离血浆。然后,通过HPLC分析血浆中存在的多柔比星的量。
(v)组织中剩余的多柔比星量
将收集的肿瘤和正常肝组织进行精细研磨,并以各组织每1g与2ml的1.5%的盐酸-乙醇溶液混合,然后使用匀浆器将组织和溶液充分混合。然后,将该混合物在4℃下放置24小时,同时遮光以洗脱组织中的颗粒。通过在4℃和5000rpm下离心10分钟将该溶液离心,然后测定上清液中多柔比星在480nm处的荧光,以确定在肿瘤和正常肝组织两者中残留的多柔比星的量。
2)实验结果
参照图36(A)和(B),当使用包括本发明的多孔二氧化硅颗粒和碘油的栓塞用组合物进行栓塞(DegradaBALL-TACE)时,在肝癌组织(A)或肝癌细胞(B)中观察到大部分被注射的颗粒。因此,可以确认根据本发明的栓塞用组合物的优异的靶向递送效果。
参照图36(C),当使用包括根据本发明的负载有多柔比星的多孔二氧化硅颗粒的栓塞用组合物(不含碘油的DegradaBALL-TACE)进行栓塞时,从肿瘤周围细胞释放的多柔比星的量明显低于单独使用碘油栓塞术时肿瘤周围细胞释放的多柔比星的量。此外,在使用本发明的栓塞用组合物和碘油进行栓塞的情况下(DegradaBALL-TACE),可以看出,多柔比星的释放量非常微不足道。另一方面,参照图36(D),当使用包括根据本发明的负载有多柔比星的多孔二氧化硅颗粒的栓塞用组合物(不含碘油的DegradaBALL-TACE)进行栓塞时,肝癌组织相对于正常肝组织的多柔比星残留量比单独使用碘油栓塞(cTACE)的显著更高。此外,在使用本发明的栓塞用组合物和碘油(DegradaBALL-TACE)进行栓塞的情况下,可以看出,多柔比星的释放量甚至高于上述情况。该结果显示包括根据本发明的多孔二氧化硅颗粒的栓塞用组合物的高靶向性,并且表明该组合物与碘油结合可以表现出更大的协同作用并获得优异的栓塞结果。
实验例12-包括多孔二氧化硅颗粒的栓塞用组合物对肝癌的治疗效果的验证
(1)实验方法
1)存活率
根据收集的肿瘤的组织病理学,制备肿瘤薄片,并进行TUNEL分析以区分死细胞和活细胞,从而可以在目视区分肿瘤中的活细胞和死细胞。在目视确认并确定活癌细胞和死癌细胞之后,将活肿瘤的大小与总肿瘤大小进行比较,从而确定存活率。
2)AST和ALT
在TACE程序后的第0、1、4和7天,分别收集1ml的兔血,然后通过比色法分析,从血液中分离血浆以分析AST和ALT的浓度,所述AST和ALT是识别血浆中肝脏特异性毒性的蛋白质。
(2)实验结果
参照图37(A)和(B),兔子的肝癌组织部分被褐色(A)染色。此外,当使用包括根据本发明的负载有多柔比星的多孔二氧化硅颗粒和碘油的栓塞用组合物进行栓塞时,可以看出,染色的肝癌组织中肝癌细胞的存活率显著降低,这取决于负载的多柔比星(B)的浓度。这说明通过使用本发明的组合物进行栓塞显示出优异的药物递送和治疗效果。
参照图37(C)和(D),作为使用本发明的组合物在栓塞过程中测量AST(天冬氨酸转氨酶;(C))和ALT(丙氨酸转氨酶;(D))的浓度的结果,这些浓度维持在低水平,表明栓塞期间未出现肝毒性。
Claims (9)
1.一种用于在血管中递送生物活性物质的可注射制剂,其包含多个多孔二氧化硅颗粒,
其中,所述生物活性物质被负载在所述多个颗粒的表面上或所述颗粒的孔的内部,并且所述多个多孔二氧化硅颗粒的pH7.4下的ζ电势为+3mV以上或-18mV以下,且所述多个颗粒之间具有排斥力,和
在所述多个颗粒的表面上或所述孔的内部对所述多个颗粒进行化学修饰,
其中所述多个颗粒为生物降解性的,
其中当下式1中的吸光度比达到1/2时,t为20以上:
[式1]
At/A0
其中A0为通过将5ml的包括1mg/ml所述多孔二氧化硅颗粒的悬浮液置于具有50kDa直径的孔的圆筒状渗透膜中来测定的所述多孔二氧化硅颗粒的吸光度,
其中15ml的与所述悬浮液相同的溶剂存在于所述渗透膜的外部并与所述渗透膜接触,所述渗透膜的内部和外部在37℃和60rpm下水平搅拌,
所述悬浮液的pH为7.4,和
At为在测定A0后t小时测定的所述多孔二氧化硅颗粒的吸光度,
其中所述生物活性物质为用于治疗选自由血管疾病、动脉疾病、静脉疾病、淋巴疾病、心血管疾病、缺血性心脏病、脑血管疾病、高血压、血脂异常、动脉硬化、外周血管疾病和下肢动脉闭塞组成的组的疾病的药物。
2.根据权利要求1所述的可注射制剂,其中所述颗粒的表面上或所述颗粒的孔的内部的至少一部分硅烷醇基被选自由以下组成的组的至少一种官能团取代:醛、酮、氨基甲酸酯、硫酸酯、磺酸酯、氨基、胺、氨基烷基、甲硅烷基、羧基、磺酸、硫醇、铵、巯基、磷酸酯、酯、酰亚胺、硫代酰亚胺、醚、茚、磺酰基、甲基膦酸酯、聚乙二醇、取代或未取代的C1至C30烷基、取代或未取代的C3至C30环烷基、和取代或未取代的C6至C30芳基。
3.根据权利要求1所述的可注射制剂,其中所述颗粒的表面上或所述颗粒的孔的内部的至少一部分硅烷醇基被选自由以下组成的组的至少一种官能团取代:氨基、胺、PEG、丙基、辛基、羧基、硫醇、磺酸、甲基膦酸酯和醛基基团。
4.根据权利要求1所述的可注射制剂,其中所述颗粒的直径为100至1000nm。
5.根据权利要求1所述的可注射制剂,其中所述颗粒的pH7.4下的ζ电势为+3mV至+100mV或-100mV至-18mV。
6.根据权利要求1所述的可注射制剂,其中所述颗粒具有每克为0.7至2.2ml的体积。
7.根据权利要求1所述的可注射制剂,其中负载在所述颗粒上的所述生物活性物质的最大释放量为99重量%以上。
8.根据权利要求1所述的可注射制剂,其中所述生物活性物质是选自由以下组成的组的至少一种:核酸、核苷酸、蛋白质、肽、氨基酸、化合物、抗原、生长因子和组成它们的要素。
9.根据权利要求1所述的可注射制剂,其中所述可注射制剂通过导管释放至靶组织中。
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EP3659585A4 (en) | 2020-12-02 |
KR102160279B1 (ko) | 2020-09-25 |
JP7115784B2 (ja) | 2022-08-09 |
CN111132666A (zh) | 2020-05-08 |
EP3659585A2 (en) | 2020-06-03 |
AU2018308332A1 (en) | 2020-03-12 |
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JP6865491B2 (ja) | 2021-04-28 |
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