CN102573923B - 皮肤渗透性、细胞摄取率及肿瘤传递性增强的纳米载体 - Google Patents
皮肤渗透性、细胞摄取率及肿瘤传递性增强的纳米载体 Download PDFInfo
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Abstract
本发明涉及一种使通过在末端的能够光交联的官能团来交联的水溶性的生物相容性聚合物与壳聚糖相结合的生物聚合物‑改性纳米载体,上述壳聚糖‑改性纳米载体的直径随着温度变化而变化,与未结合有壳聚糖的裸纳米载体相比,表现出皮肤渗透性或细胞摄取率以及向癌组织的选择传递性增加,且有利于光热治疗的特性。与没有壳聚糖的裸纳米载体相比,本发明的壳聚糖‑改性纳米载体的皮肤渗透性改善到惊人的程度,因而作为经皮载体发挥出非常优异的功效,本发明的壳聚糖‑改性纳米载体的向肿瘤细胞以及癌细胞的细胞摄取率大幅改善,因而能够非常有效地应用于肿瘤细胞以及癌细胞的成像以及光热治疗。
Description
技术领域
本发明涉及一种皮肤渗透性、细胞摄取率以及血管给药时的癌症传递性增强的纳米载体。
背景技术
为了将治疗用蛋白质或药物传递至生体内而使用的大部分纳米粒子都通过使用有机溶剂的乳剂蒸发(emulsion evaporation)法制备而成,由此会造成从制备到干燥的制备工序的复杂性,并导致制备时间延长,此外,使用有机溶剂,不仅引起费用增加,而且还会诱发生体内的问题。(T.G.Park,et al.,Biomacromolecules 8(2007)650-656;T.G.Park,et al.,Biomacromolecules7(2006)1864-1870;D.T.Birnbaum,et al.,J.Control.Rel.65(2000)375-387)。基于上述原因,诸多研究者一直潜心致力于开发出用于制备纳米粒子的新型技术,以防止充填到纳米粒子的药物的变性并确保它们的稳定性。
为了解决乳剂蒸发法中所存在的问题,其他研究者还曾使用超临界流体来制备纳米粒子。但在这种制备工艺中,由于大部分医疗用高分子在可溶解于超临界流体的溶解性上受到限制,因而未能普及使用(K.S.Soppimath etal.,J.Control.Rel.70(2001)1-20)。
并且,在美国专利第5,019,400号中,还通过将作为生物相容性高分子的聚(D,L-乳酸-co-乙醇酸)(以下称作“PLGA”)喷射到超低温制冷剂来制备了蛋白质药物传递用微粒子,但由于为了溶解PLGA而使用的有机溶剂的疏水性而引发了问题。此外,在美国专利第6,586,011号中,通过将蛋白质传递用纳米粒子体系喷射到超低温制冷剂的方式来进行了制备,但因在制备纳米粒子时所使用的交联剂而在蛋白质的稳定性上引发了严重问题。
并且,作为制备纳米粒子的方法,还使用溶剂蒸发法(solventevaporation),但这种方法也因使用有机溶剂而引发了诸多问题。另一方面,还开发出了盐析法(salting-out),该方法不使用疏水性和毒性强的有机溶剂,而使用与水充分混合的有机溶剂(丙酮等)取而代之来制备聚(D,L-乳酸)(以下称作“PLA”)纳米粒子,但不仅导致了蛋白质药物的活性降低,也未能解决稳定性问题(E.Allemann et al.,Pharm.Res.10(1993)1732-1737)。
另一方面,关于由作为天然聚合物的典型代表的壳聚糖引发的变性(modification)或功能化(functionalization),韩国专利第766820号提出了就作为一种聚合物的蛋白质使壳聚糖功能化来改善蛋白质的经粘膜递送的发明。并且,WO2008/136773号提出了用壳聚糖进行了表面变性的纳米粒子,这种纳米粒子能够用作分子成像剂、生物传感剂以及给药系统(drugdelivery system,DDS)。
另一方面,药物的经皮给药具有如下优点:能够以规定速度持续进行药物传递;能够降低产生副作用的可能性;能够增加治疗效果;能够改善口服给药时低的生体利用率;能够降低给药次数;需要时,能够中止药物给药。
然而,在经皮给药剂的开发方面,尤其在如分子量大的蛋白质等生物医药的经皮给药剂的开发方面,仍未开发出令人满意的经皮给药剂。
实体瘤的光热治疗(又名光热消融(ablation)、光热散发或光学温热现象)作为以最小限度的侵蚀性方式治疗实体瘤的方式,备受瞩目(1-6)。典型地包括通过非放射性机理将所吸收的光转换成局部热量的步骤的该项技术相对而言具有便于进行癌细胞消融,且恢复快、病发症发生率低、住院时间短等诸多优点(7)。尤其是,通过一般组织吸收低的近红外线,用于这种方法的近红外线(NIR)不会破坏一般的生体组织,并具有高的空间精密度,且能够渗透至组织深处(8-10)。
就几种纳米结构体,例如聚集性金纳米粒子(11)、金纳米壳(12-14)、金纳米笼(15)、空的AuAg树枝晶(7)、金纳米棒(Gold Nanorod)(16-18)以及碳纳米管等,都曾进行研究,以用于近红外线(NIR)光活性癌症治疗。其中,等离子-共振金纳米棒备受人们瞩目,其原因是它能够利用纵横比(aspect ratio)来精密地调整光的吸收区域,而这源于等离子-共振金纳米棒具有大规模有效合成的优点,且容易功能化,还具有高的光热转换性以及胶体稳定性(20-21)。尽管具有这些优点,但由于在金纳米棒的表面进行合成和包裹的过程中残留过多的用作模板的十六烷基三甲基溴化铵(CTAB)而造成若干细胞毒性,所以在临床应用上会受到限制(18)。由此,提出了通过金纳米棒的表面置换来降低细胞毒性效果的报告,例如,进行了磷脂酰胆碱(PC)处理的金纳米棒、涂敷有聚苯乙烯磺酸盐(PSS)的纳米棒、嵌入了金纳米棒的聚合物性纳米粒子以及进行了聚乙二醇(PEG)处理的金纳米棒相比用CTAB覆盖的金纳米棒表现出低的细胞毒性。
进而,用于进行有效的癌症的光热治疗的另一重要问题是,将金纳米棒选择性地传递到靶肿瘤。用适体(Aptamer)-结合金纳米棒以及RGD(氨酸-甘氨酸-天冬氨酸)结合树枝状聚合物进行处理的金纳米棒证明了选择性且有效的靶肿瘤细胞的光热治疗。虽然与这些特异基质相结合的金纳米棒在细胞实验(in vitro,生体外)中对癌细胞的光热治疗非常有效,但在动物实验(in vivo,生体内)中,却因在血管循环时金纳米棒过多地蓄积在肝中而导致光热治疗效果受到限制。基于金纳米棒坚硬的特性,在注射到静脉内后经过0.5小时之后,CTAB-稳定化的金纳米棒在肝中表现出高水平的局部化(27)。为了在这种动物实验中改善癌症光热治疗时存在的金纳米棒局限性效果,导入了金纳米棒的聚乙二醇化药物修饰(PEGylation)技术(27),但可能是因为体外排出进行得快(1小时的半衰期)而导致了癌症光热治疗效果受到限制。由此,需要想出有效地将金纳米棒传递至肿瘤部位内的新型方法。
本说明书全文中参考了大量论文以及专利文献,其引用均已标明。所引用的论文以及专利文献的公开内容以其整体作为参考通过引用结合在本说明书中,以更明确地说明本发明所属技术领域的水准以及本发明的内容。
发明内容
技术问题
本发明人一直致力于制备不仅表现出温度敏感性的同时大幅改善用于经皮给药的皮肤渗透性,而且有利于细胞摄取率、向癌组织的选择传递性以及光热治疗的纳米载体。其结果确认到,在利用带有能够光交联的官能团的水溶性的生物相容性聚合物以及壳聚糖来制备纳米载体的情况下,能够制备出上述特性得以改善的纳米载体,故而完成了本发明。
由此,本发明的一目的在于,提供一种皮肤渗透性、细胞摄取率(cellularuptake)以及向癌组织的传递性增强,且有利于光热治疗的纳米载体。
本发明的再一目的在于,提供一种经皮给药用组合物。
本发明的另一目的在于,提供一种在应用于生体(in vivo)时的肿瘤或癌的成像用组合物。
本发明的还一目的在于,提供一种癌症光热治疗用组合物。
本发明的又一目的在于,提供一种以皮肤渗透性、细胞摄取率(cellularuptake)或向癌组织的传递性增强为特征的壳聚糖-改性纳米载体的制备方法。
本发明的其他目的以及优点通过以下的发明内容、所附的权利要求书以及附图会更明确。
技术解决方法
根据本发明的一个实施方式,提供一种纳米载体(nano-carrier),其是使通过在末端的能够光交联(photo-crosslinkable)的官能团来交联的水溶性的生物相容性聚合物与壳聚糖相结合的壳聚糖-改性纳米载体,其特征在于,上述壳聚糖-改性纳米载体的直径随着温度变化而变化,与未结合壳聚糖的裸(bare)纳米载体相比,上述壳聚糖-改性纳米载体的皮肤渗透性、细胞摄取率(cellular uptake)、向癌组织的选择传递性或光热效应(photothermaleffect)增强。
本发明人一直致力于制备既表现出温度敏感性的同时大幅改善用于经皮给药的皮肤渗透性,而且有利于细胞摄取率、向癌组织的选择传递性以及光热治疗的纳米载体。其结果确认到,在利用带有能够光交联的官能团的水溶性的生物相容性聚合物以及壳聚糖来制备纳米载体的情况下,能够制备出上述特性得以改善的纳米载体。
在本说明书中,术语“生物相容性聚合物”是指具有不会因与生体组织或血液相接触而使组织坏死或使血液凝固的组织相容性(tissuecompatibility)以及抗血液相容性(blood compatibility)的高分子。术语“水溶性的生物相容性聚合物”是溶解于水或水-混合性溶剂(water-misciblesolvent,例如甲醇、乙醇、丙酮、乙腈、N,N-二甲基甲酰胺以及二甲基亚砜)的生物相容性聚合物,优选为表示溶解于水的生物相容性聚合物。
根据本发明优选实施列,本发明所能够利用的水溶性的生物相容性聚合物为具有聚乙二醇、聚环氧乙烷、聚乙烯醇、聚环氧乙烷-聚环氧丙烷嵌段共聚物、烷基纤维素、羟烷基纤维素、肝素、透明质酸、葡聚糖或藻酸盐结构的聚合物。从上述水溶性生物相容性聚合物中选用因具有疏水性及亲水性部分而表现出与表面活性剂类似状态的聚合物的情况下,优选为向该聚合物追加导入疏水性部分,这有利于实现本发明所要达成的技术目的。
更优选地,本发明所能够利用的水溶性的生物相容性聚合物为泊洛沙姆系列的聚合物。
最优选地,本发明所能够利用的水溶性的生物相容性聚合物为由以下化学式1表示的聚合物。
化学式1
(PC1)-(PE)x-(PPO)y-(PE)z-(PC2)
在上述化学式中,PE表示环氧乙烷,PPO表示环氧丙烷,PC1及PC2表示能够光交联的官能团,X、Y以及Z分别独立地表示1-10000的整数。
优选地,能够光交联的(photo-crosslinkable)官能团与生物相容性聚合物的两个末端结合。
根据本发明优选实施列,上述能够光交联的官能团为带有C=C双键的官能团。
更优选地,能够光交联的官能团为丙烯酸酯、二丙烯酸酯、低聚丙烯酸酯、丙烯酸甲酯、二甲基丙烯酸酯、低聚丙烯酸甲酯、香豆素、胸腺嘧啶或肉桂酸,进而优选为丙烯酸酯、二丙烯酸酯、低聚丙烯酸酯、丙烯酸酯甲酯、二甲基丙烯酸酯或低聚丙烯酸甲酯,最优选为丙烯酸酯。
本发明所利用的通过能够光交联的官能团来交联的水溶性的生物相容性聚合物,由适合的壳聚糖进行了改性(modification)。
在本发明中,为了使水溶性的生物相容性聚合物改性而使用的壳聚糖包含本领域公知的任意的壳聚糖,优选为壳聚糖、肝素、藻酸盐、透明质酸、硫酸软骨素、5-硫酸皮肤素(dermatan 5-sulfate)、硫酸角质素、纤维素、半纤维素、羧甲基纤维素、葡聚糖以及硫酸葡聚糖中的任一种或两种以上的组合,最优选为壳聚糖。
根据本发明优选实施列,壳聚糖通过能够光交联的(photo-crosslinkable)官能团结合在上述水溶性生物相容性聚合物。壳聚糖上的能够光交联的官能团如上所述。
另一方面,在本发明中,作为为了使生物相容性聚合物改性而使用的壳聚糖的最优选例子的壳聚糖(chitosan)是一种在自然界紧次于纤维素而存在最多的天然有机高分子,由年产量达1000亿吨以上的几丁质制备而成,通过使分布在螃蟹、虾等甲壳类,蚂蚱、蜻蜓等昆虫类,金针菇、香菇等真菌类,细菌的细胞膜等中的几丁质进行去乙酰化来获取。从化学结构上来讲,从有N-乙酰-D-葡萄胺(N-acetyl-D-glucosamine)单体以β-1,4键的直链状连接的几丁质中去除存在于胺基的乙酰基来形成壳聚糖(Errington N,et al.,Hydrodynamic characterization of chitosan varing in molecular weight anddegree of acetylation.Int J Biol Macromol.15:1123-7(1993))。与几丁质相比,壳聚糖由于存在于胺基的乙酰基被去除,因而在酸性溶液中以多聚阳离子(polycation)存在。由此,在酸性水溶液中针对水的溶解性变好,因而可加工性优异且干燥后的机械强度比较优异,所以壳聚糖成型成粉末、纤维、薄膜、凝胶、珠子等形态而进行使用(E.Guibal,et al.,Ind.Eng.Chem.Res.,37:1454-1463(1998))。壳聚糖根据所连接的单体的数量而分成具有12个左右的单体的低聚物和属于高分子的聚合物,聚合物分成分子量小于15万的低分子壳聚糖、分子量达到70万至100万的高分子壳聚糖以及分子量在中间范围的中分子壳聚糖。壳聚糖因其稳定性和环保性、生物降解性以及生物相容性优异而广泛地应用于诸多产业领域和医疗领域。并且,壳聚糖还被公知为安全、促进免疫力且无副作用。壳聚糖在生体内被溶菌酶(lysozyme)分解成N-乙酰葡糖胺,该N-乙酰葡糖胺使用于糖蛋白质合成之后以二氧化碳的形态排出(Chandy T,Sharma CP.Chitosan as a biomaterial.Biomat Art Cells Art Org.18:1-24(1990))。
本发明的特征在于,与其他生物相容性聚合物一同将生物相容性优异的壳聚糖用作载体,在壳聚糖-改性纳米载体用作经皮给药剂或癌靶向分子的情况下,发挥出非常优异的功效。
作为本发明所利用的壳聚糖,虽然也能够利用通常的任意的壳聚糖,但优选利用分子量为500-20000的壳聚糖。如果本发明所利用的壳聚糖的分子量小于500,则存在作为壳聚糖的载体的功能微弱的问题,而如果壳聚糖的分子量大于20000,则存在在水溶液中形成自聚体的问题。因而本发明所利用的壳聚糖优选为低聚物水平的壳聚糖。
根据本发明优选实施列,本发明的壳聚糖-改性纳米载体的直径随着温度降低而增大,相反,如果温度升高,本发明的壳聚糖-改性纳米载体的直径就减小。优选地,40℃条件下的壳聚糖-改性纳米载体的直径相比400℃下的直径增加3倍-20倍,更优选为4倍-15倍,进而优选为5倍-12倍,最优选为7倍-10倍。
本发明的壳聚糖-改性纳米载体的这种直径的增减是可逆的。
随着直径的增减,形成在壳聚糖-改性纳米载体的孔的大小发生变化。例如,在低温(例如4℃)下对要向孔的大小增加的壳聚糖-改性纳米载体递送的药物进行封装(encapsulation)之后将其应用于人体时,孔的大小减小而形成所封装的药物的缓释(sustained release)。
根据本发明优选实施列,本发明的温度敏感性壳聚糖-改性纳米载体在37℃下的孔大小为3nm-20nm,更优选为3nm-15nm,最优选为5nm-10nm。
根据本发明优选实施列,本发明的壳聚糖-改性纳米载体分散在水溶液分散相。根据本发明优选实施列,本发明的壳聚糖-改性纳米载体在37℃下的孔大小为3nm-20nm。
根据本发明优选实施列,本发明的壳聚糖-改性纳米载体为纳米粒子(nanoparticulate),而不是水溶胶。本发明的壳聚糖-改性纳米载体具有呈圆形状的纳米粒子形态。根据本发明优选实施列,本发明的纳米载体的直径为50nm-500nm,更优选为100nm-400nm,最优选为120nm-300nm。鉴于本发明的壳聚糖-改性纳米载体使用灭菌过滤器简单地进行灭菌过程,其直径优选为200nm以下。并且有利的是,壳聚糖-改性纳米载体的多分散(polydispersity)指数为0.1以下,这是因为,一般将多分散指数为0.1以下的情况视为具有稳定的单分散分布的纳米粒子。壳聚糖-改性纳米载体的优选多分散指数为0.01-0.1。
能够通过本发明的壳聚糖-改性纳米载体递送的物质不受特别限制,包含表现出治疗学功效的各种物质。根据本发明优选实施列,递送对象的物质是蛋白质、肽、核酸分子、糖类、脂质、纳米粒子、化合物、无机物或荧光物质。
通过本发明的壳聚糖-改性纳米载体递送的蛋白质或肽不受特别限制,包含激素、激素类似体、酶、酶抑制剂、信号传递蛋白质或其一部分、抗体或其一部分、单链抗体、结合蛋白质或其结合结构、抗原、黏附蛋白质、结构蛋白质、调节蛋白质、毒素蛋白质、细胞因子、转录调节因子、血凝因子以及疫苗等,但不局限于此。更详细地,通过本发明的药物载体递送的蛋白质或肽包含胰岛素、胰岛素样生长因子(insulin-like growth factor 1,IGF-1)、生长激素、促红细胞生成素、粒细胞-集落刺激因子(granulocyte-colonystimulating factors,G-CSFs)、粒细胞-巨噬细胞克隆刺激因子抗原(granulocyte/macrophage-colony stimulating factors,GM-CSFs)、干扰素-α、干扰素-β、干扰素-γ、白细胞介素-1α、白细胞介素-1β、白细胞介素-3、白细胞介素-4、白细胞介素-6,白细胞介素-2、表皮生长因子(epidermal growthfactors,EGFs)、降血钙素(calcitonin)、血管内皮细胞生长因子(vascularendothelial cell growth factor,VEGF)、成纤维细胞生长因子(fibroblast growthfactor,FGF)、血小板衍生生长因子(platelet-derived growth factor,PDGF)、肾上腺皮质激素(adrenocorticotropic hormone,ACTH)、转化生长因子-β(transforming growth factor beta,TGF-β)、骨形态发生蛋白(bonemorphogenetic protein,BMP)、肿瘤坏死因子(tumor necrosis factor,TNF)、阿托西班(atobisban)、布舍瑞林(buserelin)、西曲瑞克(cetrorelix)、地洛瑞林(deslorelin)、去氨加压素(desmopressin)、强啡肽A(dynorphinA)(1-13)、依降钙素(elcatonin)、章鱼唾腺精(eleidosin)、依替巴肽(eptifibatide)、生长激素释放激素-II(growth hormone releasing hormone-II,GHRH-II)、戈那瑞林(gonadorelin)、戈舍瑞林(goserelin)、组氨瑞林(histrelin)、亮丙瑞林(leuprorelin)、赖氨加压素(Iypressin)、奥曲肽(octreotide)、催产素(oxytocin)、加压素(pitressin)、胰泌素(secretin)、辛卡利特(sincalide)、特利加压素(terlipress in)、胸腺喷丁(thymopentin)、胸腺素(thymosine)α1、曲普瑞林(triptorelin)、比伐卢定(bivalirudin)、卡贝缩宫素(carbetocin)、环孢霉素、艾塞那肽(exedine)、兰瑞肽(lanreotide)、促黄体激素释放激素(luteinizing hormone-releasing hormone,LHRH)、那法瑞林(nafarelin)、甲状旁腺激素、普兰林肽(pramlintide)、T-20(enfuvirtide,恩夫韦地)、胸腺法新(thymalfasin)以及齐考诺肽,但不局限于此。
能够通过本发明的壳聚糖-改性纳米载体递送的核酸分子例如包含DNA、DNA适体、RNA适体、核酶、miRNA、反义寡核苷酸、siRNA、shRNA、质粒以及载体(例如,腺病毒载体、反转录病毒载体),但不局限此。
优选地,能够通过本发明的壳聚糖-改性纳米载体递送的物质为药物,例如包含抗炎药、止痛药、抗关节炎药、镇痉药、抗抑郁药、抗精神病药、镇静安定药、抗焦虑药、麻醉药品拮抗剂、抗帕金森疾病药物、胆碱能受体激动剂、抗癌药、血管生成抑制剂、免疫抑制剂、抗病毒药、抗生素、食欲抑制剂、镇痛剂、抗胆碱药、抗组胺药、抗偏头痛药、激素药、冠状血管、脑血管或末梢血管扩张剂、避孕药、抗血栓剂、利尿剂、抗高血压药、心血管疾病治疗药物、美容成分(例如,皱纹改善剂、抗皮肤衰老剂以及皮肤美白剂)等,但不局限于此。
最优选地,能够通过本发明的壳聚糖-改性纳米载体递送的物质为抗癌药。能够应用于本发明的抗癌药包含本领域所公知的任意的抗癌药,例如包含顺铂(cisplatin)、卡铂(carboplatin)、甲基苄肼(procarbazine)、氮芥(mechlorethamine)、环磷酰胺(cyclophosphamide)、异环磷酰胺(ifosfamide)、美法仑(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(bisulfan)、亚硝脲(nitrosourea)、放线菌素(dactinomycin)、柔红霉素(daunorubicin)、多柔比星(doxorubicin)、博来霉素(bleomycin)、普卡霉素(plicomycin)、丝裂霉素(mitomycin)、依托泊苷(etoposide)、他莫昔芬(tamoxifen)、紫杉醇(taxol)、吡啶类反铂(transplatinum)、5
氟尿嘧啶(5-fluorouracil)、阿霉素(adriamycin)、长春新碱(vincristin)、长春碱(vinblastin)以及甲氨蝶呤(methotrexate),但不局限于此。
能够通过本发明的壳聚糖-改性纳米载体递送的纳米粒子,例如包含金纳米粒子、银纳米粒子、铁纳米粒子、过度金属纳米粒子以及金属氧化物纳米粒子(例如铁氧体纳米粒子),但不局限于此。例如,在本发明的壳聚糖-改性纳米载体递送铁氧体纳米粒子的情况下,能够用作磁共振(magneticresonance,MR)显影剂(imaging agent)。
在利用本发明的壳聚糖-改性纳米载体来递送荧光物质的情况下,优选地,荧光物质结合在壳聚糖-改性纳米载体的表面。例如,能够使荧光物质与蛋白质或金属纳米粒子(例如,磁性纳米粒子)结合来加以利用。上述荧光物质的例子包含荧光素及其衍生物、若丹明及其衍生物、萤光黄、B-藻紅蛋白、9-吖啶异硫氰酸盐、萤光黄VS、4-乙酰氨基-4’-异硫-氰酸芪-2,2’-二磺酸、7-二乙氨基-3-(4’-异硫氰酸苯基)-4-甲基香豆素、琥珀酰亚胺基吡啶酸盐、4-乙酰氨基-4′-异硫氰酸芪-2,2’-二磺酸衍生物、LCTM-Red 640、LCTM-Red 705、Cy5、Cy5.5、丽丝胺、异硫氰酸酯、赤藓红异硫氰酸酯、二乙烯三胺五乙酸、1-二甲氨基萘-5-磺酸盐、1-苯胺基-8-萘磺酸盐、2-p-涛荻尼
-6-萘磺酸盐、3-苯基-7-异氰酸香豆素、9-异硫氰酸吖啶、吖啶橙、N-(p-(2-苯并恶唑基)苯基)马来酰亚胺、苯并氧杂恶二唑、芪以及芘,但不局限于此。
根据本发明优选实施列,本发明的纳米载体所包含的蛋白质、肽、核酸分子、糖类、脂质、化合物、无机物或荧光物质具有高分子量。
本发明的最大特征之一在于,在壳聚糖-改性纳米载体封装递送对象的物质的过程中,只要简单地将上述两种物质混合即可实现自然封装(spontaneous encapsulation)。即,不需要进行任何追加处理,而只需要进行能使纳米载体和递送对象的物质相接触(contacting)的操作,就能自然而然地在壳聚糖-改性纳米载体含有递送对象的物质。
根据本发明优选实施列,在将药物封装到壳聚糖-改性纳米载体的情况下,不使用有机分散相,而在水溶液分散相实施。
根据本发明优选实施列,在0℃-20℃,更优选为4℃-10℃,最优选为4℃-6℃的温度条件下实施封装的步骤。
通过本发明的壳聚糖-改性纳米载体进行的在水溶液相的自然封装具有大幅增强所要含有的药物、尤其是蛋白质医药的稳定性的优点。虽然能够通过自然封装而在本发明的壳聚糖-改性纳米载体含有药物,但封装效率(encapsulation efficiency)高达90%以上。并且,由于在含有药物的过程中不利用有机溶剂,且不需要高速均匀化过程或超声波处理过程,因而本发明的方法能够避免所要含有的药物的变性或凝聚。
根据本发明优选实施列,能够在本发明的壳聚糖-改性纳米载体的表面结合有靶向配位体。上述靶向配位体的例子包含激素、抗体、细胞-黏附蛋白质(cell-adhesion molecules)、糖类以及神经递质,但不局限于此。
根据本发明的其他实施方式,本发明提供一种包括使包含递送对象的物质的上述壳聚糖-改性纳米载体与对象(subject)接触的步骤的递送对象(cargo)的递送方法。
根据本发明的其他实施方式,本发明提供一种壳聚糖-改性纳米载体的制备方法,其特征在于,上述壳聚糖-改性纳米载体的直径随着温度变化而变化,与未结合壳聚糖的裸(bare)纳米载体相比,上述壳聚糖-改性纳米载体的皮肤渗透性、细胞摄取率(cellular uptake)或向癌组织的传递性增强。上述壳聚糖-改性纳米载体的制备方法包括如下步骤:
步骤(a),准备带有能够光交联(photo-crosslinkable)的官能团的水溶性的生物相容性聚合物的分散液;
步骤(b),准备带有能够光交联(photo-crosslinkable)的官能团的水溶性的壳聚糖的分散液;
步骤(c),准备上述生物相容性聚合物的分散液与壳聚糖的分散液的混合物;
步骤(d),向上述混合物添加引发剂;以及
步骤(e),向上述步骤(d)的产物照射光使上述聚合物和壳聚糖交联来制备壳聚糖-改性纳米载体。
适合于本发明的方法的引发剂不受特别限制,优选地,本发明所能够利用的引发剂为能够通过照射紫外线或可视光线来引发自由基(radical)反应的自由基型光引发剂(radical photoinitiator)。本发明所能够利用的光引发剂的例子有乙基曙红、2,2-二甲氧基-2-苯基苯乙酮、2-甲氧基-2-苯基苯乙酮、2-羟基-1-[4(2-羟乙氧基)苯基]-2-甲基-1-丙酮(Irgacure 2959或Darocur2959)、樟脑醌(camphorquinone)、苯乙酮、苯乙酮苄基缩酮、1-羟基环已基苯基甲酮、2,2-二甲氧基-2-苯基苯乙酮、氧杂蒽酮、芴酮、安息香醛、芴、蒽醌、三苯基胺、咔唑、3-甲基苯乙酮、4-氯二苯甲酮、4,4’-二甲氧基二苯甲酮、4,4’-二氨基二苯甲酮、安息香丙醚、安息香乙醚、苄基二甲基缩酮、1-(4-异丙苯基)-2-羟基-2-甲基丙烷-1-酮、2-羟基-2-甲基-1-苯基丙烷-1-酮、噻吨酮、二乙基噻吨酮、2-异丙基噻吨酮、2-氯噻吨酮、2-甲基-1-[4-(甲硫基)苯基]-2-吗啉基-丙烷-1-酮、2,4,6-三甲基苯甲酰基二苯基氧化膦以及双-(2,6-二甲氧基苯甲酰基)-2,4,4-三甲基戊基氧化膦。
如以下实施例所述,在本发明的一个具体实施例中使用了Irgacure2959,其被公知为生体内毒性非常小的引发剂(Kristi S.Anseth,et al.,Cytocompatibility of UV and visible light photoinitiating systems on culturedNIH/3T3 fibroblasts in vitro.J.Biomater.Sci.Polymer Edn.,2000.11(5):P.439-457)。
在步骤(e)中,通过照射可视光线或紫外线来使聚合物及壳聚糖的能够光交联的官能团来使聚合物及壳聚糖进行交联,从而制备纳米载体。优选地,利用紫外线来进行交联。根据本发明的一个具体实施例,为了照射紫外线,能够利用薄层色谱法(Thin Layer Chromatography)用紫外线灯,它具有价格比其他固化用紫外线灯低廉、且容易到手的优点,并且还适合于通过在特定365nm波长的紫外线照射来引发自由基反应的引发剂(例如,Irgacure2959)。
根据本发明的优选实施例,上述步骤(a)至步骤(e)不使用有机分散相,而唯独在水溶液分散相实施。即,在单相(single phase)实现制备纳米载体的全部过程。更详细地,通过向分散有生物相容性聚合物、壳聚糖以及引发剂的水溶液照射光,来实现纳米载体的完整制备。进而,本发明的反应可以通过一锅(one-pot)反应实施,在这种层面上,本发明的方法可谓是“一锅法,单相合成法(one-pot,single phase synthesis)”。
根据本发明的实施例,能够解决以往技术中所存在的问题,例如,利用有害的有机溶剂,过程复杂,生产成本高,含有能力低等。并且,本发明的方法由于不需要进行在以往技术中通常利用的高速均匀化过程或超声波处理过程,因而能够避免所要含有的药物的变性或凝聚。
根据本发明的其他实施方式,本发明提供一种包含上述壳聚糖-改性纳米载体的经皮给药用组合物。
根据本发明的其他实施方式,本发明提供一种包括使包含递送对象的物质的上述壳聚糖-改性纳米载体与对象(subject)的皮肤接触的步骤的递送对象的经皮递送方法。
根据本发明的其他实施方式,本发明提供一种包含上述壳聚糖-改性纳米载体的生体内肿瘤或癌的成像用组合物。
根据本发明的其他实施方式,本发明提供一种包括如下步骤的对象(subject)的生体内肿瘤或癌的成像用组合物:步骤(a),按包含递送对象的物质的上述壳聚糖-改性纳米载体的诊断学有效剂量向上述对象(subject)给药;以及步骤(b),扫描上述对象来获取可视(visible)图像。
根据本发明的其他实施方式,本发明提供一种包含上述壳聚糖-改性纳米载体的癌症光热治疗用组合物。
根据本发明的其他实施方式,本发明提供一种包括按包含递送对象的物质的上述壳聚糖-改性纳米载体的治疗学有效剂量向对象(subject)给药的步骤的癌症的光热治疗方法。
本发明的组合物包含上述壳聚糖-改性纳米载体作为有效成分,因而其之间的共同内容将省略其详细说明,以避免反复说明引起本说明书变得过于复杂。
如以下实施例所证明,与未结合有壳聚糖的纳米载体相比,本发明的壳聚糖-改性纳米载体表现出非常优异的皮肤渗透性。并且,与未结合有壳聚糖的纳米载体相比,本发明的壳聚糖-改性纳米载体的肿瘤细胞或癌细胞摄取率非常大,这种特性表明,本发明的壳聚糖-改性纳米载体能够用作生体(in vivo)肿瘤或癌的成像用组合物以及癌症光热治疗用组合物。
本发明的经皮给药用组合物基本为药剂学组合物,还包含药剂学上允许的载体。
通过本发明的经皮给药用组合物所利用的壳聚糖改性纳米载体递送的物质不受特别限制,优选为能够在皮肤或头皮发挥功效的皱纹改善剂、保湿剂、粉刺治疗剂、老年斑消除剂、皮肤弹力改善剂、毛发生长促进剂、抗皮肤衰老剂或皮肤表皮干细胞增殖剂。
根据本发明优选实施列,在经皮给药用组合物中,纳米载体包含高分子量的蛋白质、肽、核酸分子、糖类、脂质、化合物或无机物。
在本说明书中,术语“高分子量”表示具有无法穿透皮肤(优选为人的皮肤)”的大小的分子量,优选地,高分子量是指具有500Da以上的分子量的物质。一般众所周知,具有500Da以下的分子量的物质能够穿透皮肤(BosJD,et al,.Exp.Dermatol 9:165-169(2000))。
如上所述,本发明的纳米载体的皮肤渗透性大幅提高,因而能够封装被判断为不能穿透皮肤的高分子量的物质(例如,蛋白质药物)来实现经皮传递。
本发明的药剂学组合物所包含的药剂学上允许的载体通常用于制剂,其包含乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯橡胶、磷酸钙、藻酸盐、动物胶、硅酸钙、微细结晶性纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟苯甲酯、羟苯丙酯、滑石、硬脂酸镁以及矿物油等,但不局限于此。本发明的药剂学组合物除了上述成分之外,还包含润滑剂、湿润剂、甘味剂、香味剂、乳化剂、悬浮剂、保存剂等。适合的药剂学上允许的载体以及制剂已在Remington’s Pharmaceutical Sciences(19th ed.,1995)中详细记载。
本发明的经皮给药用药剂学组合物以经皮给药方式给药。
本发明的药剂学组合物的适宜给药量根据制剂化方法、给药方式、患者的年龄、体重、性别、病状、饮食、给药时间、给药途径、排泄速度以及反应过敏性等因素而各不相同,一般而言,技术娴熟的医生能够就所希望的治疗或预防有效的给药量轻松进行决定并下处方。根据本发明优选实施列,本发明的药剂学组合物的每日给药量为0.001-100mg/kg。
本发明的药剂学组合物通过按照本发明所属技术领域的普通技术人员能够容易实施的方法来利用药剂学上允许的载体和/或赋形剂来进行制剂化,从而制备成单位剂量形态或者封装到多容量容器内来进行制备。此时,剂型可以是油或水性介质中的溶液、悬浊液或乳化液形态或者浸膏剂、粉末剂、颗粒剂、片剂或胶囊剂形态,还包含分散剂或稳定剂。
本发明的经皮给药用药剂学组合物使递送对象的物质与各种对象(优选为哺乳动物,最优选为人类)的皮肤接触来经皮递送。
本发明的癌症光热治疗用组合物利用的是本发明的壳聚糖-改性纳米载体的肿瘤细胞或癌细胞摄取率非常高的特性。
在本发明的癌症光热治疗用组合物中,能够利用的药剂学上允许的载体以及制剂化方法将通过引用上述经皮给药用组合物中的记载加以了解。
本发明的癌症光热治疗用组合物所利用的壳聚糖-改性纳米载体作为光敏剂(photosensitizer)或放热物质包含适合的物质,优选为包含金属粒子。上述金属粒子例如包含金粒子、硅粒子以及磁性纳米粒子(例如,氧化铁纳米粒子、铁氧体、磁铁矿或坡莫合金(permalloy)),但不局限于此。
优选地,本发明的癌症光热治疗用组合物通过电磁辐射(electromagneticradiation)来放热。例如,在利用金粒子的情况下,照射红外线(infrared)激光而放热来杀灭肿瘤或癌细胞。在利用磁性纳米粒子的情况下,附加高频磁场来放热。
优选地,本发明的癌症光热治疗用组合物以非口服方式给药。在以非口服方式给药的情况下,能够通过静脉内注射、皮下注射、肌肉注射、腹腔注射、肿瘤内注射或病变内(intralesional)注射等方式进行给药。本发明的组合物的适宜给药量可根据制剂化方法、给药方式、患者的年龄、体重、性别、病状、饮食、给药时间、给药途径、排泄速度以及反应过敏性等因素而下各种处方。根据本发明优选实施列,本发明的药剂学组合物的每日给药量为0.001-100mg/kg。
本发明的药剂学组合物通过按照本发明所属技术领域的普通技术人员能够容易实施的方法来利用药剂学上允许的载体和/或赋形剂来进行制剂化,从而制备成单位剂量形态或者封装到多容量容器内来进行制备。此时,剂型可以是油或水性介质中的溶液、悬浊液或乳化液形态或者浸膏剂、粉末剂、颗粒剂、片剂或胶囊剂形态,还包含分散剂或稳定剂。
本发明的癌症光热治疗用组合物能够有效地靶向杀灭胃癌、肺癌、乳房癌、卵巢癌、肝癌、支气管癌、鼻窦癌、喉癌、胰脏癌、头颈癌、膀胱癌、结肠癌、宫颈癌、脑癌、前列腺癌、骨癌、皮肤癌、甲状腺癌、甲状旁腺癌以及尿管癌等各种癌症中的癌细胞。
根据本发明的其他实施方式,本发明提供一种包含上述壳聚糖-改性纳米载体的生体(in vivo)肿瘤或癌的成像用组合物。
如以下实施例所证明,本发明的壳聚糖-改性纳米载体因其肿瘤细胞或癌细胞摄取率非常高,而能够用作生体(in vivo)肿瘤或癌的成像剂。
在这种情况下,本发明的壳聚糖-改性纳米载体包含适合的显影剂或成像剂。
例如,用光学荧光进行生体(in vivo)肿瘤或癌的成像的情况下,将适合的荧光物质封装到壳聚糖-改性纳米载体的内部或使适合的荧光物质与壳聚糖-改性纳米载体的表面结合来进行使用。能够使用的荧光物质的例子如上所述。
在通过磁共振成像(MRI)方式进行生体(in vivo)肿瘤或癌的成像的情况下,为了进行适合的T1或T2显影,在壳聚糖-改性纳米载体包含顺磁性(paramagnetic)、超顺磁性(superparamagnetic)或质子密度(proton density)信号产生粒子。例如包含Gd(III)、Mn(II)、Cu(II)、Cr(III)、Fe(II)、Fe(III)、Co(II)、Er(II)、Ni(II)、Eu(III)、Dy(III)、纯铁、磁性氧化铁(例如、磁铁矿、Fe3O4)、γ-Fe2O3、铁酸锰、铁酸钴、铁酸镍以及全氟碳作为显影剂。
利用本发明的成像组合物来获取单光子发射计算机断层成像术(SinglePhoton Emission Computed Tomography,SPECT)或正电子发射断层成像术(Positron Emission Tomography,PET)图像的情况下,本发明的壳聚糖-改性纳米载体包含正电子发射同位素,例如11C、13O、14O、15O、12N、13N、15F、17F、18F、32CI、33CI、34CI、43Sc、44SC、45Ti、51Mn、52Mn、52Fe、53Fe、55Co、56Co、58Co、61Cu、62Cu、62Zn、63Zn、64Cu、65Zn、66Ga、66Ge、67Ge、68Ga、69Ge、69As、70As、70Se、71Se、71As、72As、73Se、74Kr、74Br、75Br、76Br、77Br、77Kr、78Br、78Rb、79Rb、79Kr、81Rb、82Rb、84Rb、84Zr、85Y、86Y、87Y、87Zr、88Y、89Zr、92Tc、93Tc、94Tc、95Tc、95Ru、95Rh、96Rh、97Rh、98Rh、99Rh、100Rh、101Ag、102Ag、102Rh、103Ag、104Ag、105Ag、106Ag、108ln、109ln、110ln、115Sb、116Sb、117Sb、115Te、116Te、117Te、117I、118I、118Xe、119Xe、1191、119Te、1201、120Xe、121Xe、121I、122I、123Xe、124I、126I、128I、129La、130La、131La、132La、133La、135La、136La、140Sm、141Sm、142Sm、144Gd、145Gd、145Eu、146Gd、146Eu、147Eu、147Gd、148Eu、150Eu、190Au、191Au、192Au、193Au、193Tl、194Tl、194Au、195Tl、196Tl、197Tl、198Tl、200Tl、200Bi、202Bi、203Bi、205Bi、206Bi或其衍生物。
利用本发明的成像组合物来获取电子计算机X射线断层(computedtomography,CT)成像的情况下,本发明的壳聚糖-改性纳米载体包含碘粒子或金粒子等CT显影剂。
发明效果
本发明的特征以及优点概括如下:
(a)与没有壳聚糖的裸(bare)纳米载体相比,本发明的壳聚糖-改性纳米载体的皮肤渗透性改善到惊人的程度,因而作为经皮载体发挥出非常优异的功效;
(b)本发明的壳聚糖-改性纳米载体的向肿瘤细胞以及癌细胞的细胞摄取率大幅改善,因而能够非常有效地应用于肿瘤细胞以及癌细胞的成像以及光热治疗;
(c)具有温度敏感性,且直径以及孔的大小随着温度变化而可逆地发生变化;
(d)根据本发明的方法,能够以一锅单相方式制备壳聚糖-改性纳米载体;
(e)能够在本发明的纳米载体自然封装药物;
(f)本发明的纳米载体在人体内温度条件下的孔的大小减小,因而能够用作缓释性药物载体;
(g)根据本发明,能够解决以往技术中所存在的问题,例如,利用有害的有机溶剂,过程复杂,生产成本高,含有能力低等;
(h)由于不需要进行在以往技术中通常利用的高速均匀化过程或超声波处理过程,因而能够避免所要含有的药物的稳定性。
附图说明
图1a是关于用于制备本发明的壳聚糖-改性纳米载体的甲基丙烯酸缩水甘油酯化壳低聚糖(glycidyl metaacrylated chiotooliogosaccharide,GMA-COS)的制备过程的示意图;
图1b是确认出图1a的GMA-COS的合成的1H-NMR(核磁共振)波谱结果;
图2是关于本发明的壳聚糖-改性纳米载体的制备过程的示意图;
图3是壳聚糖-改性纳米载体的大小以及电动电势的测定结果;
图4a是皮肤渗透性测定用斯泰特弗朗兹(Static Franz)类型扩散细胞的示意图;
图4b是含有FITC-BSA的壳聚糖-改性纳米载体的生体外皮肤渗透性的测定结果;
图4c是用荧光显微镜测定的含有FITC-BSA的壳聚糖-改性纳米载体的皮肤渗透分布结果;
图4d是含有Cy5.5的壳聚糖-改性纳米载体的生体外皮肤渗透性的测定结果;
图5a是测定壳聚糖-改性纳米载体针对SCC7细胞株的生体外细胞摄取的流式细胞术(Flow Cytometry)结果;
图5b是在移植了SCC7细胞的肿瘤小鼠模型中显示出壳聚糖-改性纳米载体(含有Cy5.5)的实时肿瘤靶向的生体内NIR荧光图像;
图5c是关于壳聚糖-改性纳米载体(含有Cy5.5)的生体内肿瘤靶向的定量结果以及速度论结果;
图5d是对壳聚糖-改性纳米载体(含有Cy5.5)的组织分布以及肿瘤蓄积结果进行了定量化的曲线图;
图5e表示用于确认壳聚糖-改性纳米载体(含有Cy5.5)的组织分布以及肿瘤蓄积的结果,是器官以及肿瘤的活体外NIR荧光图像;
图6a是关于利用于生活成像或生体内成像的壳聚糖-改性纳米载体的金纳米棒的TEM(透射电子显微镜)图像以及NIR光谱规律;
图6b是对含有金纳米棒的壳聚糖-改性纳米载体的稳定性进行分析的结果;
图6c是表示金纳米棒以及含有金纳米棒的壳聚糖-改性纳米载体的细胞摄取的图像;
图6d是利用含有金纳米棒的壳聚糖-改性纳米载体进行的生体外光热治疗结果的图像(利用41.5W/cm2的cw laser(a diode continuous-wave laser,二极管连续波激光器);
图6e利用含有金纳米棒的壳聚糖-改性纳米载体进行的生体外光热治疗结果的图像(利用26.4W/cm2的cw laser(a diode continuous-wave laser,二极管连续波激光器);
图7a是对金纳米棒、纳米载体所含有的金纳米棒、壳聚糖结合纳米载体所含有的金纳米棒所吸收的波长进行分析的TEM图像;
图7b是纳米载体以及含有金纳米棒的纳米载体的大小(直径)以及电动电势的测定结果;
图8是在PBS(磷酸盐缓冲液)中测定的纳米载体所含有的金纳米棒、壳聚糖结合纳米载体分别从载体内部向外漏出的金纳米棒值的曲线图;
图9是将金纳米棒、含有金纳米棒的纳米载体、含有壳聚糖-结合金纳米棒的纳米载体注射到细胞之后用显微镜在暗处观察是否进行细胞摄取的细胞图像;
图10为了观察针对SCC7癌细胞(图a)以及NIH/3T3成纤维细胞(图b)的选择性近红外线光热治疗效果,而在780nm波长下照射两种强度的电力密度(41.5以及26.4W/cm2)激光时用于判断是否发生细胞毒性的图像;
图11是将金纳米棒、含有金纳米棒的纳米载体、含有壳聚糖-结合金纳米棒的纳米载体注射到静脉内来用于观察是否吸收到肿瘤细胞以及肝细胞的银染色法照片;
图12a是表示将金纳米棒、含有金纳米棒的纳米载体、含有壳聚糖-结合金纳米棒的纳米载体注射到静脉内后经过24小时之后照射近红外线激光时发生的肿瘤大小变化的曲线图;
图12b是表示将金纳米棒、含有金纳米棒的纳米载体、含有壳聚糖-结合金纳米棒的纳米载体注射到静脉内后经过24小时之后照射近红外线激光时发生的肿瘤大小变化的小鼠肿瘤照片;
图12c是表示将金纳米棒、含有金纳米棒的纳米载体、含有壳聚糖-结合金纳米棒的纳米载体注射到静脉内后经过24小时、48小时之后照射一次到两次近红外线激光时发生的肿瘤大小变化的曲线图;
图12d是表示将金纳米棒、含有金纳米棒的纳米载体、含有壳聚糖-结合金纳米棒的纳米载体注射到静脉内后经过24小时、48小时之后照射一次到两次近红外线激光时发生的肿瘤大小变化的小鼠肿瘤照片;
图13是以静脉注射方式分别将嵌段共聚物纳米载体以及壳聚糖-结合嵌段共聚物纳米载体注射到裸鼠之后72小时内蓄积在肿瘤细胞的量的对比照片(A是整个小鼠体的图像,B是肿瘤部位的放大图像);
图14是嵌段共聚物纳米载体以及纳米载体内含有金纳米棒的制备方法的图表;
图15是分别对癌细胞以及成纤维细胞改变金纳米棒的浓度来将金纳米棒、含有金纳米棒的纳米载体、含有壳聚糖-结合金纳米棒的纳米载体注射到细胞内时判断出细胞生存率之差的曲线图;
图16是表示培养2小时、12小时及24小时后被SCC7癌细胞(a)以及NIH/3T3成纤维细胞(b)吸收的纳米载体量的曲线图。
具体实施方式
下面,将通过实施例对本发明进行更详细的说明。但这些实施例只用以更具体地说明本发明,根据本发明的主旨,本发明所属领域的技术人员应当理解,本发明的范围并不局限于这些实施例。
实施例
实施例1:GMA-chiotooligosaccharide(GMA-COS)的制备
根据图1a所述的方法,利用壳低聚糖以及甲基丙烯酸缩水甘油酯来制备甲基丙烯酸缩水甘油酯化壳低聚糖(glycidyl metaacrylatedchiotooliogosaccharide:GMA-COS)。图1b是关于最终制备而成的GMA-COS的1H-核磁共振波谱法(JNM-LA30WB FT-NMR光谱仪,日本电子株式会社,日本)分析结果,由此可知,GMA-COS已成功制备出。
实施例2:壳聚糖-改性纳米载体的制备
根据由本发明者在从前曾报告的方法(32、33),使二丙烯酸酯化嵌段共聚物(DA-Pluronic)以及丙烯酸酯化壳聚糖进行光聚合,制备出嵌段共聚物纳米载体(nano carrier,NC)的裸(bare)型(NC(PF 68))以及壳聚糖-改性型(Chito-NC(PF 68))。简要说明的话,就裸(bare)型而言,将二丙烯酸酯化嵌段共聚物溶液(0.5wt%)的稀释的水溶液(2mL)与光引发剂[0.05wt%,艳佳固(Irgacure)2959,4-(2-羟基乙氧基)苯基-(2-羟基-2-丙基)酮,汽巴精化有限公司]温和混合,并利用蒽彼得
紫外线灯(VL-4.LC,8W,韦伯路马特(VILBER LOURMAT)公司,法国)在1.3mW/cm2的强度下UV-照射15分钟。就壳聚糖-改性型而言,将水溶性甲基丙烯酸缩水甘油酯(GMA)-结合壳聚糖(2.8mg,0.2μmol)溶解于去离子水,并添加到DA-嵌段共聚物溶液来制备0.5wt%的DA-嵌段共聚物。在与利用于上述裸(bare)型的条件相同的条件下使上述混合物光聚合来使GMA-结合壳聚糖的乙烯基结合在交联纳米载体内。为了去除未反应物质,利用透析袋[纤维素酯(cellulose ester),300kDa的截留分子量(MWCO)]对整体溶液进行透析,第一次是在0.1M的NaCl中进行透析,接着在去离子水中进行透析。之后,利用安装有激光二极管光源(638nm)以及光电倍增管检测器(165°散射角)的电泳光散射测定器(ELS-Z2,大冢电子株式会社,日本)来分析纳米载体的大小以及表面电荷。就壳聚糖-改性型而言,壳聚糖结合量为16wt%,这是利用茚三酮(Ninhydrin)分析测定的值。
实施例3:壳聚糖-改性纳米载体的经皮渗透性的分析(利用FITC-BSA)
利用在上述实施例中制备的壳聚糖-改性纳米载体来填充作为模型蛋白质的异硫氰酸荧光素标记牛血清白蛋白(Fluoresceinisothiocyanate-labelled bovine serum albumin:FITC-BSA,西格玛)。向壳聚糖-改性纳米载体溶液添加作为模型蛋白质的FITC-BSA,在4℃下放置12小时,同时将模型蛋白质填充到自发性地膨胀的纳米载体内。使用旋转过滤器(spin filter)在常温下去除未填充的模型蛋白质。壳聚糖-改性纳米载体的FITC-BSA封装效率以及含有量在室温下以14000rpm旋转过滤10分钟之后根据如F.Q.Li,et al.,Int.J.Pharm.,2008,349,274所记载的方法进行计算。
含有FITC-BSA-的纳米载体的经皮渗透性利用斯泰特弗朗兹类型扩散细胞来进行测定(参照图4a)。实验组为,只有FITC-BSA(200ug)、NC(F127)+FITC-BSA、NC(F68)+FITC-BSA、Chito-NC(F127)+FITC-BSA、Chito-NC(F68)+FITC-BSA、只有壳聚糖(chitosan)以及Chito-F127。实验条件如下:给体槽(Donor chamber):在DIW(200μL)内1-5组;薄膜(Membrane):表皮和真皮(人类皮肤,M/58,背部或大腿)(源自韩士生科);受体槽(Receptor chamber):PBS(pH7.4)(5mL);37℃,600rpm,时间点(0.5小时、1小时、2小时、4小时、8小时、12小时、18小时和24小时);取样(Sampling):在一个给定时间500uL。利用荧光分光光度计来测定荧光强度,并通过荧光显微镜获取荧光图像。
由图4b确认出,本发明的壳聚糖-改性纳米载体相比未结合有壳聚糖的纳米载体[NC(F127)以及NC(F68)]表现出非常优异的皮肤渗透性。虽然,在本发明的壳聚糖-改性纳米载体中,壳聚糖结合在嵌段聚合物,但与未进行光交联的Chito-F127相比时也表现出了非常优异的皮肤渗透性。图4c是将含有FITC-BSA-的壳聚糖-改性纳米载体应用于人类皮肤而获取的荧光图像。在这种情况下也能确认出,本发明的壳聚糖-改性纳米载体相比未结合有壳聚糖的纳米载体[NC(F127)以及NC(F68)]表现出非常优异的皮肤渗透性。
实施例4:壳聚糖-改性纳米载体的经皮渗透性的分析(利用Cy5.5)
按照与实施例3相似的方法对结合有Cy5.5荧光物质的纳米载体进行皮肤渗透性分析。由图4b确认出,本发明的壳聚糖-改性纳米载体相比未结合有壳聚糖的纳米载体[NC(F127)以及NC(F68)]表现出非常优异的皮肤渗透性。
实施例5:利用壳聚糖-改性纳米载体的生体内成像
对结合有Cy5.5荧光物质的本发明的壳聚糖-改性纳米载体的生体(invivo,即为生体内)的成像应用性进行评价。
首先,对鳞状上皮细胞癌(squamous cell carcinoma,SCC7)进行细胞培养来调查(in vitro,生体外)细胞摄取。由图5a确认出,壳聚糖-改性纳米载体相比裸(bare)纳米载体所表现出的细胞摄取率非常高。如此增强的生体外细胞摄取与移植了SCC7细胞的肿瘤小鼠模型中的生体(in vivo)肿瘤蓄积密切相关(图5b、图5c及图5d),由图5b可看出,纳米载体的时间-依赖性释放规律以及肿瘤蓄积通过实时监测近红外线荧光强度来予以清晰的可视化。就裸(bare)纳米载体[NC(F68)以及NC(F127)]而言,注射到肿瘤部位后在16小时之内荧光强度快速减小。但本发明的壳聚糖-改性纳米载体的高荧光强度在肿瘤部位维持72小时。
由注射后第72小时开始的活体外(ex vivo)NIR荧光图像(图5d及图5e)确认出,组织分布(肝、肺、肾脏、脾脏以及心脏)以及肿瘤蓄积的分析结果,本发明的壳聚糖-改性纳米载体相比裸(bare)纳米载体在肿瘤位置表现出高的荧光强度。这表明,壳聚糖-改性纳米载体具有更加延长的血流时间以及更加增强的肿瘤蓄积能力。
实施例6:利用壳聚糖-改性纳米载体进行的生体外(in vitro)细胞培养中的癌症光热治疗(photothermal cancer therapy)
在上述实施例5中查明的壳聚糖-改性纳米载体的肿瘤细胞摄取增强能力以及肿瘤组织蓄积能力暗示,壳聚糖-改性纳米载体能够用作光热癌症治疗剂。下面对壳聚糖-改性纳米载体的癌症光热治疗功效进行调查。
首先,利用种子-介导的生长方法(seed-mediated growth method)在水溶性CTAB溶液中合成金纳米棒(36)。将HAuCl4[0.5mM,5mL,小岛化学药品株式会社(日本柏原,日本)]添加到CTAB(0.2M,5mL),接着充分混合来制备金种子。接着,在剧烈搅拌的条件下添加新制备的冰凉的NaBH4(0.01M,600μL,西格玛奥德里奇集团,美国),来形成呈褐色的黄色溶液。在室温下保管1-3小时上述溶液后用作用于合成金纳米棒的种子溶液。然后,在剧烈搅拌的条件下将HAuCl4(1mM,5mL)添加到CTAB溶液(0.2M,5mL,西格玛奥德里奇集团,美国)来制备生长溶液,将4mM的AgNO3(硝酸银)400μL以及0.0788M的抗坏血酸(西格玛奥德里奇集团,美国)70μL添加到上述溶液,之后温和混合。在该过程中,混合物(生长溶液)的颜色从黄色变成无色。接着,将12μL种子溶液注入到生长溶液内并进行剧烈搅拌,接着在37℃、100rpm的摇荡槽放置3小时。金纳米棒溶液呈亮紫色。为了去除过量CTAB,用离心分离器以11000rpm提纯金纳米棒溶液10分钟,直到充分提纯到最小5倍为止,并使其重新分散在去离子水。最终,利用UV-分光光度计(安捷伦(Agilent)8453,美国加利福尼亚州圣克拉拉,美国)来测定金纳米棒的紫外可见光线吸收光谱,并利用透射电子显微镜(TEM;JEM-2100,日本电子板式会社,日本)来测定金纳米棒的大小以及纵横比。
另一方面,按以下方法制备含有金纳米棒的嵌段共聚物纳米载体来调查其特性。为了将金纳米棒载入嵌段共聚物纳米载体内,在粉末状态的纳米载体(750μg)添加金纳米棒溶液(50μg/100μL),在4℃下培养12小时以上,诱导金纳米棒自发性地进入纳米载体内。与以往的研究相同,在常温下以11000rpm速度旋转过滤10分钟来分离出未载入的金纳米棒,并进行计算来测定胶囊化效率(90%以上)以及在纳米载体内含有的金纳米棒的量(44)。利用UV-分光光度计来在可见区域-近红外线区域带中测定只有金纳米棒的吸收光谱以及含有金纳米棒的纳米载体的吸收光谱。在2%(w/v)磷钨酸(西格玛奥德里奇集团,美国)溶液中进行负染并利用TEM来测定金纳米棒以及含有金纳米棒的纳米载体的形态学。在37℃的去离子水中利用电泳光散射测定器(ELS-Z2)分析金纳米棒以及含有金纳米棒的纳米载体的粒子直径以及表面电荷(电动电势)。所有测定均进行三次。
金纳米棒以及含有金纳米棒的纳米载体的形态学在利用TEM(图7a的插入物)用磷钨酸(phosphotungstic acid)进行负染(negative staining)之后进行成像。与纳米载体的球形变化无关,两种形态均适当地含有金纳米棒。在37℃下,纳米载体的粒子直径(hydrodynamic diameters)以及表面电荷(电动电势)没有因含有金纳米棒而受到影响。如图7b所示,纳米载体其本身与含有金纳米棒的纳米载体具有相似的平均大小。在CTAB溶液稳定化的金纳米棒的电动电势表现出带高的正电荷的表面状态(+36.5±2.4mV),相反,含有金纳米棒的纳米载体带有与纳米载体本身的电动电势相似的表面电荷,由此确认出,能够有效地在纳米载体内含有金纳米棒。
在特定时间点(time point)对分散在水溶液的金纳米棒以及含有金纳米棒的纳米载体的光学稳定性进行调查(图7a)。金纳米棒本身表现出蓝移(短波长)光谱,但已经在以往的研究中提出过金纳米棒在水溶相进行重构(reshaping)(37、38),由此确认出,在水溶相利用金纳米棒时受到限制。相反,在纳米载体内含有金纳米棒的情况下确认出,尽管到了第7天,吸收光谱仍未发生变化,由此因纳米载体与金纳米棒之间的相互作用而包含在纳米载体内,并防止金纳米棒的不稳定的重构化(38)。
下面对含有金纳米棒的纳米载体的生体内稳定性进行分析。为了分析在纳米载体内含有的金纳米棒的光学稳定性,在摇荡槽中以27℃、100rpm培养一周存在于去离子水(1mL)中的金纳米棒(对照用)以及含有金纳米棒的纳米载体溶液,在规定时间点监测350nm至1000nm区域的UV-Vis(紫外可见光吸收光谱)来进行分析。为了确认金纳米棒是否稳定地贮存在纳米载体内,测定从纳米载体漏出的金纳米棒。将含有金纳米棒的纳米载体溶液(100μL)放入到透析袋(纤维素酯,300kDa的MWCO)。将透析袋浸渍在含有10%胎牛血清(Gibco生物制剂公司,美国纽约州格兰德岛)的5mL的PBS中,并在37℃下以100rpm启动摇荡槽。每到各时间点就更换一次金纳米棒全部排放(release)的培养基,以维持最大的漏槽状态。在各时间点漏出的金纳米棒量利用UV-分光溶解度计进行分析,其浓度则用标准校正曲线(calibration curve)进行测定。作为对照组,在设置相同的透析袋的条件下分析所排放的金纳米棒的量。
与对照组中漏出近80%相比,包含在纳米载体内的金纳米棒的漏出量仅为15%左右,这就表明,纳米载体能够在其内部有效地捕获金纳米棒(图8)。
下面对含有金纳米棒的纳米载体的生体外细胞毒性进行分析。利用鳞状上皮细胞癌(squamous cell carcinoma,SCC7)肿瘤细胞株以及NIH/3T3(胚胎成纤维细胞)成纤维细胞株来对金纳米棒以及含有金纳米棒的纳米载体的细胞毒性进行分析。两种细胞类型均以5×104细胞密度接种到24-孔板,并在37℃条件下培养24小时。接着,在1-250μg/mL(以金纳米棒量为基础)的范围内将金纳米棒或含有金纳米棒的纳米载体(含有6.7wt%的金纳米棒)添加到板孔。在37℃下再培养2小时细胞。之后,将培养基更换成包含稀释10倍的WST-1(拜尔迪生物公司,美国山景城,美国)的825μL的新培养基,在37℃条件下再培养2小时细胞。利用扫描多孔分光光度计(FL600,伯腾,美国佛蒙特州,美国)来观察变色培养基吸收450nm波长的状况。从以往的研究开始便在SCC7细胞应用了嵌段共聚物纳米载体本身的细胞毒性(33),并使用如向NIH/3T3成纤维细胞的细胞毒性一样的协议来特定。
在SCC7以及NIH/3T3两种类型中,在金纳米棒为高浓度的情况下,细胞生存率相比含有金钠米棒的纳米载体的生存率非常低。相反,金纳米棒的浓度直到100μg/mL(以金纳米棒的量为基础)为止,金纳米棒以及含有金纳米棒的纳米载体均没有对细胞的两种类型的新陈代谢的活性造成任何影响(图15a及图15b)。在达到250μg/mL时,含有金纳米棒的纳米载体表现出相当高的细胞生存率,由此可以确认,纳米载体对细胞毒性效果造成的影响具有正面意义。
对含有金纳米棒的纳米载体的生体外细胞摄取程度进行分析。利用胰蛋白酶EDTA(乙二胺四乙酸)(Gibco生物制剂公司,美国纽约州格兰德岛,美国)来提取SSC7或NIH/3T3成纤维细胞,并在24-孔组织培养板中将5×104细胞接种到涂敷有动物胶的玻璃盖(12mm)上,并在37℃下培养24小时。玻璃盖预先放入于70%乙醇进行消毒处理,并暴露于UV下过一宿,为了确保最佳的细胞生长,而涂敷2%的动物胶。在培养基中培养2小时包含金纳米棒或含有金纳米棒的纳米载体(以金纳米棒计50μ/mL)的细胞,以进行细胞摄取。培养之后,利用PBS溶液清洗细胞,并在装有4%福尔马林溶液的PBS中固定30分钟,所固定的细胞用PBS清洗,之后再用去离子水清洗。利用配有TV透镜C-0.45摄像头的暗视野显微镜(ECLIPSE L150,尼康,日本东京)来记录光散射图像。
通过光散射图像(以金纳米棒计50μ/mL,图9)来区分金纳米棒的细胞摄取。通过金纳米棒被摄取到纳米载体内使得金纳米棒的细胞摄取得以大幅提高。与在直接处理金纳米棒的情况下未出现任何信号的情况相比,从细胞质中观察到了从金纳米棒排出的亮斑(spot),针对相同的纳米载体,与正常成纤维细胞相比,从肿瘤细胞观察到更高的细胞摄取,由此可确认,与正常细胞相比,向肿瘤细胞的金纳米棒的细胞摄取更加有效。进而,与裸(bare)纳米载体相比,在壳聚糖-改性纳米载体所表现出的金纳米棒的细胞摄取率更高。并且,使用Cy5.5-标记的纳米载体特定化的纳米载体本身的细胞摄取在光散射图像中表现出的相似的结果(图16a及图16b)(33)。正如所料,在各培养时间内,壳聚糖-改性纳米载体的细胞摄取程度相比裸(bare)纳米载体的细胞摄取程度明显高。
下面对含有金纳米棒的纳米载体的生体外光热效应进行分析。将SCC7或NIH/3T3成纤维细胞以8×104密度接种到24-孔组织培养板,在37℃下几乎在培养基一整面培养24小时。接着,将培养基更换成1mL的包含金纳米棒或含有金纳米棒的纳米载体(以金纳米棒计50μ/mL)的培养基。培养2小时之后,为了避免细胞非特异性地被吸收或去除在培养基残留的纳米物质,而用PBS缓冲溶液清洗三次。添加新的培养基之后,利用连续波钛宝石激光器(c.a.CW Ti-sapphire laser)(MlRA 900,相干公司,美国加利福尼亚州圣克拉拉,美国)将直径为1.3mm孔-大小以及不同输出密度(41.5W/cm2及26.4W/cm2)的780nm激光照射到各个孔,照射4分钟。细胞生存率通过利用吖啶橙(AO,西格玛奥德里奇集团,美国密苏里州圣路易斯)以及碘化丙啶(PI,西格玛奥德里奇集团,美国密苏里州圣路易斯)的双重染色过程进行判断,在这里,在AO中绿色荧光表示活细胞,在PI中的红色荧光表示死细胞。概括地说,向各个孔添加包含0.67μM的AO以及75μM的PI的培养基1mL,并在37℃下的暗处培养30分钟。用PBS清洗之后,利用倒立荧光显微镜(TE2000-U,尼康,美国纽约州梅尔维尔,美国)将活细胞以及死细胞可视化。
金纳米棒或含有金纳米棒的纳米载体(50μg/mL的金纳米棒量)与肿瘤细胞以及成纤维细胞一同进行处理,接着用不同的电力密度(41.5W/cm2及26.4W/cm2)照射4分钟波长为780nm的激光。之后,用吖啶橙以及碘化丙啶对细胞进行染色来了解细胞生存率。如图10a及图10b所示:1)利用含有金纳米棒的纳米载体的光热分解效果相比直接利用金纳米棒的情况提高,其结果,大部分细胞都没死;2)含有金纳米棒的纳米载体相比正常细胞(NIH/3T3)在癌细胞(SCC7)表现出更佳的光热效应;3)壳聚糖-改性纳米载体相比裸(bare)纳米载体表现出更强的光热分解。这些结果均如所料与细胞摄取结果一致,且激光强度越强得到的结果就越好。
实施例7:利用壳聚糖-改性纳米载体的实验动物(in vivo)中的癌症光热治疗(photothermal cancer therapy)
所有动物均从东方生物公司(韩国首尔)购买,并遵照韩国光州科学技术院(GIST)的实验动物管理委员会的方针进行处理。为了诱发实体瘤,在出生6-7周的无胸腺裸鼠(CAnN.Cg-Foxn)的后胯左右部位的各皮下层注射SCC7细胞(以1×106存在于50μLPBS)。当肿瘤长到直径约为5mm时,将在85%的生理盐水(100μL)处于混浊状态的金纳米棒或含有金纳米棒的纳米载体(以金纳米棒计的100μg)通过微静脉注射到静脉内。生理盐水作为对照组。首先,为了比较蓄积在肝或肿瘤的纳米物质,而在静脉注射(i.v.injection)后经过24小时之后从小鼠取下肝和肿瘤组织。切开肿瘤和肝组织后在4%福尔马林中固定24小时,并嵌入最佳切割温度(OCT)化合物(Tissue-Teks,日本樱花医疗集团,日本东京)。为了冷冻切片,在-20℃下冷冻块儿后切开。接着,利用银加强试剂盒(西格玛奥德里奇集团,美国密苏里州圣路易斯)根据制备人员的指示对组织切片进行10分钟的染色。利用倒立荧光显微镜检查被染色的组织切片。之后,为了比较实体瘤的光热消灭效果,给小鼠(左侧肿瘤:不照射激光,作为对照组,右侧肿瘤:照射激光)静脉(i.v.)注射纳米物质,经过24小时之后,照射4分钟近红外线光(808nm二极管激光器,900mW,在连续波4W/cm2下5mm光线直径,动力科技,美国阿肯色州亚力山大)。并且,为了后续实验,给小鼠静脉(i.v.)注射后经过24小时及48小时之后照射4分钟近红外线。在规定的时间点,用数字卡尺测定治疗后的肿瘤大小,并用数码相机拍照。所有测定均进行三次。用学生t分布进行统计分析,在所有比较实验中以p<0.05的最小注意量进行准备。
最终,为了在生体内模型动物中将光热治疗效果可视化而用银进行染色。图11是作为阴性对照组,从金纳米棒样本或来自用生理盐水处理的小鼠的肿瘤以及肝的代表区域的银染色图像。含有金纳米棒的壳聚糖-改性纳米载体在肿瘤细胞表现出非常高的强度(暗色),这表示更有效地向肿瘤细选择传递。相反,直接用金纳米棒处理时,银-染色图像在肝表现得最强,这表明金纳米棒本身更容易被摄取到肝中。就含有金纳米棒的纳米载体而言,被肿瘤细胞摄取有所增加,而被肝细胞摄取有所减小。但是用壳聚糖-改性纳米载体进行处理的情况下,在银染色分析时,被肿瘤细胞摄取显著增强。
为了在实体瘤的光热消融中分析含有金纳米棒的纳米载体的治疗效果,而向小鼠静脉内注射后经过24小时之后照射4分钟近红外线激光(808nm,4W/cm2)(左侧肿瘤:未照射激光,作为对照组,右侧肿瘤:照射激光),如图12a至图12d所示,含有金纳米棒的纳米载体表现出肿瘤成长的强效抵制,相反,与盐分处理的组的结果相比,直接用金纳米棒处理时在肿瘤消退上未示出统计性差别。正如所料,与裸(bare)形态相比,在壳聚糖-改性纳米载体表现出显著的肿瘤生长抑制,1周期间未出现肿瘤体积的增加,照射一次激光之后,观察到肿瘤体积缓慢增加,这表明,壳聚糖-改性纳米载体表现的有效的肿瘤蓄积以及非常有效的光热效应。
本发明人经过两次照射4分钟近红外线激光来进行追加测试,以挑战更有效的癌症光热治疗,含有金纳米棒的纳米载体的静脉内注射之后,第一次是经过24小时后及48小时之后照射激光。第二天再照射一次激光时,在壳聚糖-改性形态的情况下得到了肿瘤完全被去除的结果。在其他实验组中再次照射时,肿瘤大小也发生了若干变化,而在直接应用金纳米棒的事例中,肿瘤却没有受到充分抑制(图12c及图12d),其大小也没发生什么变化(没有统计性差别)。值得注意的是,壳聚糖-改性形态(Chito-NC(PF68))(参照图12c的放大照片)的情况下,在光热治疗后的初期到6天内,肿瘤被完全去除。
以上,对本发明的特定部分进行了详细说明。但对于本发明所属技术领域的普通技术人员来说,应当了解,具体技术只作为优选的实施例,并不用以限定本发明的范围。由此,本发明实际要求保护的范围由所附的权利要求书及其等同替代进行定义。
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Claims (19)
1.一种纳米载体,其是使通过在末端的能够光交联的官能团来交联的水溶性的生物相容性聚合物与壳聚糖相结合的壳聚糖-改性纳米载体,其特征在于,上述壳聚糖-改性纳米载体的直径随着温度变化而变化,与未结合壳聚糖的裸纳米载体相比,上述壳聚糖-改性纳米载体的皮肤渗透性、细胞摄取率、向癌组织的选择传递性或光热效应增强,
上述能够光交联的官能团为丙烯酸酯、二丙烯酸酯、低聚丙烯酸酯、丙烯酸甲酯、二甲基丙烯酸酯、低聚丙烯酸甲酯、香豆素、胸腺嘧啶或肉桂酸,
上述水溶性的生物相容性聚合物为具有淀粉、糖原、几丁质、肽聚糖、木质素磺酸盐、鞣酸、木质素、果胶、聚乙二醇、聚环氧乙烷、聚乙烯醇、聚环氧乙烷-聚环氧丙烷嵌段共聚物、纤维素、半纤维素、羧甲基纤维素、肝素、透明质酸、葡聚糖或藻酸盐结构的聚合物,
所述壳聚糖具有上述能够光交联的官能团,
上述壳聚糖通过能够光交联的官能团来结合在上述水溶性生物相容性聚合物。
2.根据权利要求1所述的纳米载体,其特征在于,上述水溶性的生物相容性聚合物为由以下化学式1表示的聚合物,
化学式1
(PC1)-(PE)x-(PPO)y-(PE)z-(PC2)
在上述化学式中,PE表示环氧乙烷,PPO表示环氧丙烷,PC1及PC2表示能够光交联的官能团,X、Y以及Z分别独立地表示1-10000的整数。
3.根据权利要求1所述的纳米载体,其特征在于,上述纳米载体的直径随着温度降低而增大。
4.根据权利要求1所述的纳米载体,其特征在于,上述纳米载体在其内部包含蛋白质、肽、核酸分子、糖类、脂质、荧光物质或者在上述纳米载体的表面结合有荧光物质。
5.根据权利要求4所述的纳米载体,其特征在于,上述蛋白质、肽、核酸分子、糖类、脂质为药物。
6.根据权利要求5所述的纳米载体,其特征在于,上述药物为抗癌药。
7.根据权利要求4所述的纳米载体,其特征在于,上述蛋白质、肽、核酸分子、糖类、脂质、荧光物质具有高分子量,其中,高分子量是指500Da以上的分子量。
8.一种经皮给药用组合物,其特征在于,包含如上述权利要求1至7中任一项所述的纳米载体。
9.根据权利要求8所述的经皮给药用组合物,其特征在于,上述纳米载体包含高分子量的蛋白质、肽、核酸分子、糖类、脂质,其中,高分子量是指500Da以上的分子量。
10.根据权利要求9所述的经皮给药用组合物,其特征在于,上述纳米载体所包含的高分子量的蛋白质、肽、核酸分子、糖类、脂质为药物。
11.一种生体内肿瘤或癌的成像用组合物,其特征在于,包含如上述权利要求1至7中任一项所述的纳米载体。
12.一种癌症光热治疗用组合物,其特征在于,包含如权利要求1至7中任一项所述的纳米载体。
13.一种如上述权利要求1至7中任一项所述的纳米载体在制备光热治疗癌症的药物中的应用。
14.一种壳聚糖-改性纳米载体的制备方法,其特征在于,包括如下步骤:
步骤(a),准备带有能够光交联的官能团的水溶性的生物相容性聚合物的分散液,
步骤(b),准备带有能够光交联的官能团的水溶性的壳聚糖的分散液,
步骤(c),准备上述生物相容性聚合物的分散液与壳聚糖的分散液的混合物,
步骤(d),向上述混合物添加引发剂,以及
步骤(e),向上述步骤(d)的产物照射光使上述聚合物和壳聚糖进行交联来制备壳聚糖-改性纳米载体;
上述壳聚糖-改性纳米载体的直径随着温度变化而变化,与未结合壳聚糖的裸纳米载体相比,上述壳聚糖-改性纳米载体的皮肤渗透性以及细胞摄取率增强,
上述能够光交联的官能团为丙烯酸酯、二丙烯酸酯、低聚丙烯酸酯、丙烯酸甲酯、二甲基丙烯酸酯、低聚丙烯酸甲酯、香豆素、胸腺嘧啶或肉桂酸,
上述水溶性的生物相容性聚合物为具有淀粉、糖原、几丁质、肽聚糖、木质素磺酸盐、鞣酸、木质素、果胶、聚乙二醇、聚环氧乙烷、聚乙烯醇、聚环氧乙烷-聚环氧丙烷嵌段共聚物、纤维素、半纤维素、肝素、透明质酸、葡聚糖或藻酸盐结构的聚合物,
上述壳聚糖通过能够光交联的官能团来结合在上述水溶性生物相容性聚合物。
15.根据权利要求14所述的壳聚糖-改性纳米载体的制备方法,其特征在于,上述水溶性的生物相容性聚合物为由以下化学式1表示的聚合物,
化学式1
(PC1)-(PE)x-(PPO)y-(PE)z-(PC2)
在上述化学式中,PE表示环氧乙烷,PPO表示环氧丙烷,PC1及PC2表示能够光交联的官能团,X、Y以及Z分别独立地表示1-10000的整数。
16.根据权利要求14所述的壳聚糖-改性纳米载体的制备方法,其特征在于,上述步骤(e)的光是紫外线。
17.根据权利要求14所述的壳聚糖-改性纳米载体的制备方法,其特征在于,上述壳聚糖-改性纳米载体的直径随着温度降低而增大。
18.根据权利要求14所述的壳聚糖-改性纳米载体的制备方法,其特征在于,上述步骤(a)至上述步骤(e)不使用有机分散相,而唯独在水溶液分散相实施。
19.根据权利要求14所述的壳聚糖-改性纳米载体的制备方法,其特征在于,上述壳聚糖-改性纳米载体在37℃下的孔大小为3nm-20nm。
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