CN113952463B - 一种纳米诊疗剂及其制备方法与应用 - Google Patents
一种纳米诊疗剂及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开一种纳米诊疗剂,涉及抗肿瘤药物技术领域,所述纳米诊疗剂的内核以共价偶联的小分子抗肿瘤药物‑小分子配体与具有配位能力的金属离子配位形成,所述纳米诊疗剂的***以共价偶联的多酚结构的化合物‑荧光染料形成。本发明还公开纳米诊疗剂的制备方法及应用。本发明的有益效果在于:本发明中的纳米诊疗剂能够克服传统脂质体剂型药物包封率低、稳定性差等缺点,同时避免靶向性小分子前药耐药性强等问题。
Description
技术领域
本发明涉及抗肿瘤药物技术领域,具体涉及一种纳米诊疗剂及其制备方法与应用。
背景技术
过去的几十年,恶性肿瘤的死亡率一直居高不下,造成这种高死亡率的主要原因之一是不能有效的将药物递送到肿瘤部位。目前化疗在恶性肿瘤治疗中占有十分重要的地位如紫杉醇(PTX),其作用机制发现及***的临床应用被全球抗肿瘤医药领域誉为是近20年来全球肿瘤化疗的重大进展。但由于紫杉醇化疗药物在体内缺乏选择性以及肿瘤细胞的多重耐药性,造成毒副作用明显,使患者难以耐受,限制了其在治疗中的给药剂量,导致化疗的效果较差。随着对恶性肿瘤不断深入地研究发现仅单一治疗方法不足以控制住恶性肿瘤的发生发展,而多个治疗方法相结合其协同作用能取得较好的治疗效果。最近研究表明纳米诊疗剂在实现恶性肿瘤多种治疗方法一体化模式的同时,可改善药物的靶向性,使药物有效地释放在肿瘤部位,从而提高治疗效果。
在早期的紫杉醇靶向性药物改造的研究主要集中在:
(1)前药:紫杉醇前体药物研发主要可以解决紫杉醇水溶性差、细胞毒性大、提高抗肿瘤活性等问题。如用靶向性的小分子配体或是小分子抑制剂修饰紫杉醇制备紫杉醇前药,虽然提高其溶解性、增加了主动靶向性的目的,但仍会造成肾堆积、体内循环较短、剂量较大等问题。
(2)临床上使用的紫杉醇纳米剂型:a.紫杉醇脂质体脂质体是球形囊泡,能将疏水性药物包封于类脂质双层膜内,脂质体抗肿瘤药物是美国食品药品监督管理局批准的第1个用于治疗癌症的纳米制剂,而我国首个紫杉醇脂质体注射剂—力朴素已投入临床应用,用于治疗乳腺癌、非小细胞肺癌等恶性肿瘤。尽管脂质体可被用于向选定的组织传递细胞毒性化合物,但其可被肝脏和脾脏的单核吞噬***迅速清除,从而降低了紫杉醇的药效,另外脂质体作为传统剂型,也存在包封率低、不稳定、纳米粒子较大等问题。
b.白蛋白结合型紫杉醇:白蛋白结合型紫杉醇是将人血白蛋白与紫杉醇通过高压振动技术制成的平均直径为130nm的冻干颗粒。白蛋白结合型紫杉醇通过gp60-窖蛋白-SPARC的特殊转运通路,导致其进入细胞膜穴样凹陷,完成跨膜转运,促进紫杉醇进入肿瘤细胞。与传统PTX制剂比较,能显著提高肿瘤组织中的药物浓度,且不需聚氧乙烯蓖麻油溶剂作为载体,已于2005年在国内上市。但白蛋白紫杉醇通过gp60蛋白进入肿瘤细胞,易产生耐药性且价格昂贵。
(3)其他紫杉醇纳米颗粒:a.聚合物纳米颗粒,常用的聚合物纳米粒子有聚乳酸(PLA)、PLA-羟基乙酸共聚物(PLGA)和聚己内酯(PCL),如公开号为CN106967211A的专利制备紫杉醇-聚乳酸-紫杉醇共聚物。与PTX单体相比,可提高其药效,降低其细胞毒性,但存在分子量大,纳米粒子聚集等问题。
目前临床上所用紫杉醇纳米载药***:国内为脂质体剂型包裹紫杉醇药物传递***存在药物传递***不稳定,不能准确将小分子药物输送到病灶部位发挥药效,同时其药物载体所包裹药物量较少,降低其药效等缺点。国外:白蛋白-紫杉醇纳米药物,但仍存在易产生耐药性,价格昂贵等缺点。而在研究阶段的紫杉醇前药和两性大分子包裹PTX的纳米胶束载药***也存在在体内分解成大分子两亲性嵌段聚合物,很难释放自由PTX,从而降低PTX的药效。具有多酚结构的化合物如MYR,虽然具有较好实施抗氧化和抗癌等功能,但存在水溶性差,结构不稳定等问题,不能实现MYR+PTX协同用药和提高PTX的药效的目的。
二氢杨梅素(dihydromyricetin),又名蛇葡萄素,是一类广泛存在于水果、蔬菜和草药中的黄酮类化合物。二氢杨梅素具有抗菌、抗炎、抗氧化、保肝、保护心血管***等药理活性。近年研究发现二氢杨梅素对多种肿瘤均有抑制作用而对正常细胞的毒性较低,并能提高PTX耐药肿瘤细胞株对PTX/DOX的化疗敏感性。目前研究的侧重点对其联合用药抗肿瘤机制有更深层次的探究。多项研究表明,二氢杨梅素多药联合应用较单药应用的抗肿瘤效果更强。但由于二氢杨梅素水溶性较差、结构不稳定、在体内生物利用度低,单独使用MYR作为抗氧化、抗炎症和抗癌药具有用量大,效率低等缺点。单宁酸(Tannic acid,TA),又称鞣酸,属于水解类单宁,可水解为没食子酸和葡萄糖,化学式C76H52O46。单宁酸属于多酚类化合物,由于其含有多个酚羟基而具有一系列的化学及生理特性,如能与多糖、蛋白质、生物碱、金属离子等结合或者络合,并且具有捕捉自由基的活性,因而具有抗氧化功能。近年来,人们愈加关注单宁酸的生物学作用及其机理,除了在生物体内的抗氧化作用外,还发现了其抗肿瘤、减肥、抑菌等功效。近期研究表明,单宁酸可与其他药物协同发挥抗肿瘤作用,如与丝裂霉素C、5-氟尿嘧啶联用抗胆管癌,与三氧化二砷联用抗人类白血病,与顺铂CDDP联用抗卵巢癌等。此外,研究表明口服TA较为安全,可作为食品添加物,因此,TA可能作为一种低毒的化疗药物增敏药物,辅助肿瘤的预防和治疗。
研究表明恶性肿瘤治疗行之有效的方法之一是将药物有效地被递送到靶部位,且能实现药物的控制释放及最小化毒性,但由于病人个体以及恶性肿瘤之间的差异,使这一目标是很难实现的。纳米诊疗剂是将恶性肿瘤的诊断与治疗一体化,同时具备诊断和治疗的功能,在实现药物靶向递送的同时,可缓释药物,减少毒副作用,在肿瘤治疗过程中实现“分子影像-化疗”协同治疗,对于个体化治疗有很好的应用前景。
发明内容
本发明所要解决的技术问题在于提供一种新的纳米诊疗剂及其制备方法与应用。
本发明通过以下技术手段实现解决上述技术问题:
一种纳米诊疗剂,所述纳米诊疗剂的内核以小分子抗肿瘤药物与小分子配体共价偶联的前药与具有配位能力的金属离子配位形成,所述纳米诊疗剂的***以多酚结构的化合物与荧光染料共价偶联体形成;
所述小分子配体包括多巴胺、伊文斯兰(EB)、叶酸或5甲基四氢叶酸所述多酚结构的化合物包括二氢杨梅素、单宁酸、杨梅素、杨梅黄素或杨梅黄酮中的一种或多种。
有益效果:本发明中的纳米诊疗剂能够克服传统脂质体剂型药物包封率低、稳定性差等缺点,同时避免靶向性小分子前药耐药性强等问题。
本发明中的纳米诊疗剂承载多酚结构的化合物和小分子抗肿瘤药物,具有载药量高,稳定性好,可实现两者的协同药效、体内外诊断和提高小分子抗肿瘤药物的目的。
将肿瘤治疗中,诊断与治疗两个分开的过程,一体化,实现在肿瘤治疗中诊断-治疗同步进行,可及时调整治疗方案。
纳米诊疗剂在运载抗肿瘤药物的同时,可同时担载多种抗肿瘤药物或是增敏剂与抗肿瘤药物,可实现多种药物的协同作用,提高治疗效果。
纳米诊疗剂具有纳米结构,可首先肿瘤组织的EPR效应,提高药物在体内的循环时间和在肿瘤部位的药物浓度。
优选地,所述小分子抗肿瘤药物包括紫杉醇、多西紫杉醇、阿霉素、柔红霉素、吉西他滨、培美曲塞、铂类药物、恩曲他滨、替诺福韦二吡呋酯中的一种或多种。
优选地,所述具有配位能力的金属离子包括三价铁离子、二价锌离子和铂离子、一价银离子或金离子中的一种或多种。
优选地,所述荧光染料包括伊文斯兰、Alexa Fluor 488、吲哚菁绿(ICG)、Ce6、亚甲蓝、荧光素纳、5-氨基酮戊酸(5-ALA)、异硫氰酸荧光素(FITC)或罗丹明。
优选地,所述小分子抗肿瘤药物为紫杉醇(PTX),所述多酚结构的化合物为二氢杨梅素(MYR)或单宁酸,所述具有配位能力的金属离子为三价铁离子。
有益效果:PTX作为一线小分子抗癌药物,但存在难溶性、无靶向、毒副作用大等问题,限制其临床上的应用。MYR可通过提高机体抗氧化***的能力,减少PTX产生的毒性,增强PTX的药效。
MYR作为强还原剂具有溶解性差、稳定性差,生物利用度差等缺点,利用Fe3+-MYR为平台可增加MYR的溶解性和稳定性,提高在体内的生物利用度,从而增强MYR协同抗肿瘤的功能。
一种纳米诊疗剂的制备方法,包括以下步骤:
(1)将小分子抗肿瘤药物与小分子配体共价偶联得到小分子抗肿瘤药物-小分子配体,即为小分子抗肿瘤药物前药;
(2)将小分子抗肿瘤药物前药与过量的具有配位能力的金属离子混合,形成第一配位复合物;
(3)将第一配位复合物与共价偶联的多酚结构的化合物-荧光染料混合,形成纳米诊疗剂。
有益效果:步骤(1)中得到小分子抗肿瘤药物前药,然后在具有配位能力的金属离子过量的情况下,与金属离子配位形成纳米诊疗剂的内核,其次,共价偶联的多酚结构的化合物-荧光染料与具有配位能力的金属离子配位组合成纳米诊疗剂的***,从而构成纳米诊疗剂。
优选地,所述小分子抗肿瘤药物包括紫杉醇、多西紫杉醇、阿霉素,柔红霉素、吉西他滨、培美曲塞、铂类药物、恩曲他滨、替诺福韦二吡呋酯中的一种或多种。
优选地,所述小分子抗肿瘤药物为紫杉醇。
利用紫杉醇的结构,与Linker共价偶联的小分子配体(多巴胺、伊文斯兰(EB)、叶酸、5甲基叶酸)共价偶联紫杉醇制备多酚-紫杉醇前药/荧光染料-多酚-紫杉醇前药。纳米诊疗剂共担载MYR与靶向性紫杉醇前药,具有载药量高,稳定性好,可实现两者的协同药效、体内外诊断和提高PTX药效的目的。
MYR与三价铁配位所形成的配位化合物,可解决MYR不溶、稳定性差等问题,提高MYR在体内实施抗氧化和抗肿瘤的功能。
利用MYR清除氧自由基,增强机体抗氧化***的功能,从而实现MYR和紫杉醇的协同用药,提高抗肿瘤小分子化疗药物的药效。
紫杉醇在纳米诊疗剂中以靶向性前药的形式存在,在提高紫杉醇主动靶向性的前提下,减少PTX的毒性,实现PTX在低毒状态下,促进免疫蛋白表达的功能,提高PTX的药效。
利用PTX-多酚-荧光染料或是多酚-荧光染料,进一步修饰纳米诊疗剂,在增加纳米诊疗剂的生物相容性的同时,可实现监测药物在体内的代谢途径。
优选地,所述步骤(1)具体包括以下步骤:将丁二酸酐-紫杉醇溶于二氯甲烷,加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(EDC)和N-羟基琥珀酰亚胺(NHS),室温搅拌后,加入多巴胺,室温搅拌过夜,将反应液经硅胶柱纯化,得到多巴胺-紫杉醇。
优选地,所述小分子抗肿瘤药物的溶剂为二氯甲烷或二甲基甲酰胺溶液,浓度为1-10mg/mL。
优选地,所述步骤(2)中将小分子抗肿瘤药物前药与过量的具有配位能力的金属离子的金属盐溶液混合,所述有配位能力的金属离子的金属盐溶液为卤化物水溶液。
优选地,所述卤化物水溶液为氯化物溶液,浓度为1-10mg/mL,优选3mg/mL。
优选地,所述具有配位能力的金属离子选自三价铁离子、二价锌离子和铂离子、一价银离子和金离子或其组合。
优选地,所述多酚结构的化合物-荧光染料的制备步骤为:利用多酚结构化合物中氨基在EDC/NHS或DDC/NHS催化下,与具有NHS的及聚乙二醇或是荧光染料反应制备聚乙二醇-多酚或多酚-荧光染料。
其中/表示和。
优选地,所述聚乙二醇分子为羧基聚乙二醇分子,更优先地,聚乙二醇分子羧基为NHS,所述聚乙二醇分子的分子量为5000-100000,优选地100000-200000,更优选地200000。
优选地,所述多酚结构的化合物以水溶液形式加入,浓度100-600mg/mL,优选200mg/mL。
优选地,将所述小分子抗肿瘤药物溶液加入所述具有配位能力的金属离子的可溶性金属盐溶液后进行涡旋,可选1-10分钟,优选,3分钟;
优选地,将所述多酚溶液加入与小分子抗肿瘤药物前药混合后进行涡旋,可选1-10分钟,优选,3分钟;
优选地,将所述多酚结构的化合物-荧光染料与第一配位复合物混合后进行涡旋,可选1-10分钟,优选,3分钟;
优选地,所述多酚化合物溶液与所述外壳分子溶液的用量体积比为:40%:60%。
优选地,纯化纳米诊疗剂的步骤为将所述纳米诊疗剂放入透析袋中在双蒸水溶液中透析。
优选地,将所述纳米诊疗剂置于分子量为5000-10000的透析袋中透析过夜,其转子转速为200-500rpm/分钟,更优选,透析袋分子量为8000,转速为300rpm/分钟。
本发明还提供一种联合用药***,包括上述纳米诊疗剂。
本发明还提供一种试剂盒,所述试剂盒包括上述纳米诊疗剂。
本发明的优点在于:本发明中的纳米诊疗剂能够克服传统脂质体剂型药物包封率低、稳定性差等缺点,同时避免靶向性小分子前药耐药性强等问题。
本发明中的纳米诊疗剂承载多酚结构的化合物和小分子抗肿瘤药物,具有载药量高,稳定性好,可实现两者的协同药效、体内外诊断和提高小分子抗肿瘤药物的目的。
将肿瘤治疗中,诊断与治疗两个分开的过程,一体化,实现在肿瘤治疗中诊断-治疗同步进行,可及时调整治疗方案。
纳米诊疗剂在运载抗肿瘤药物的同时,可同时担载多种抗肿瘤药物或是增敏剂与抗肿瘤药物,可实现多种药物的协同作用,提高治疗效果。
纳米诊疗剂具有纳米结构,可首先肿瘤组织的EPR效应,提高药物在体内的循环时间和在肿瘤部位的药物浓度。
PTX作为一线小分子抗癌药物,但存在难溶性、无靶向、毒副作用大等问题,限制其临床上的应用。MYR可通过提高机体抗氧化***的能力,减少PTX产生的毒性,增强PTX的药效。
MYR作为强还原剂具有溶解性差、稳定性差,生物利用度差等缺点,利用Fe3+-MYR为平台可增加MYR的溶解性和稳定性,提高在体内的生物利用度,从而增强MYR协同抗肿瘤的功能。
附图说明
图1为本发明实施例1中多巴胺-紫杉醇的合成路线图;
图2为本发明实施例4和实施例5中纳米诊疗剂的TEM图;
图3为本发明实施例4和实施例5中纳米诊疗剂的DLS图;
图4为本发明中逆转录PCR检测U87MG和293T细胞的多巴胺受体mRNA的表达量图,图中a为U87MG,b为293T;b图中右边的柱状表示U87MG;
图5为本发明在激光共聚焦显微镜下观察肿瘤细胞U87MG对DA-PTX-FITC和FITC-TDPP NPs的摄取情况图;
图6为本发明流式细胞仪定量测定肿瘤细胞U87MG对DA-PTX-FITC和FITC-TDPPNPs的摄取率;
图7为本发明动物水平研究TDPP NPs在U87MG肿瘤组织的靶向性结果图;
图8为本发明肿瘤抑制率测定结果图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将结合本发明实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
下述实施例中所用的试验材料和试剂等,如无特殊说明,均可从商业途径获得。
实施例中未注明具体技术或条件者,均可以按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。
实施例1
多巴胺-紫杉醇(DA-PTX)前药的制备,其制备流程如图1所示。
(1)丁二酸酐-紫杉醇(SUC-PTX)的合成
称取100mg(0.117mmol)PTX溶于15ml的DCM,同时加入59.7mg(0.1404mmol,1.2eqv)丁二酸酐(SUC)和14.29mg DMAP(0.117mmol),将44.85mg(0.234mmol,2eqv)EDC溶于10ml DCM中,在冰浴条件下,将10mL溶于EDC溶液缓慢滴入PTX反应体系中,大约25分钟滴加完毕,除去冰浴,室温下搅拌26个小时,用TLC示踪。待反应完后用同体积的DCM稀释,然后用同体积的蒸馏水洗2次,加入无水硫酸镁干燥,真空旋蒸后得晶状体产物丁二酸酐-紫杉醇(SUC-PTX)。
(2)多巴胺-紫杉醇(DA-PTX)前药的制备
产物0.01mmol SUC-PTX中溶于8mL DCM,加入EDC和NHS(摩尔比1:1.2:2)活化SUC-PTX的羧基,室温搅拌4小时后,加入0.01mmol DA,室温搅拌过夜,将反应液经硅胶柱纯化,得到纯化的多巴胺-紫杉醇(DA-PTX),并表征其化学结构。
实施例2
本实施例与实施例1的区别之处在于:将500mgPEG与6mgDA共价偶联,获得DA-PEG。其中PEG的分子量为200000。
实施例3
本实施例与实施例1的区别之处在于:将5mg的异硫氰酸荧光素(FITC)与2mg DA共价偶联,得到DA-FITC。
实施例4
自组装纳米诊疗剂的制备
(1)配制浓度为4mg/mL的三氯化铁水溶液,浓度为1mg/mL的二氢杨梅素(MYR)DMF溶液;
(2)取30μL以二甲基甲酰胺为溶剂的浓度为5mg/mL DA-PTX,并加入80μL的浓度为3mg/mL的三氯化铁溶液,涡旋2分钟(2000次/分);
(3)往步骤(2)滴加150μL浓度为1mg/mL的MYR DMF溶液,并涡旋3分钟(1500次/分);
(4)往步骤(3)中缓慢滴加实施例3中获得的20μL浓度为150mg/mL DA-FITC,并涡旋3分钟(1500次/分)形成。
(5)在分子量为8000的透析袋中在水溶液中透析过夜,其转子转速为320次/分钟,得到透析液即为纳米诊疗剂,命名为MDPP NP-a,-20℃储存备用。
实施例5
本实施例与实施例4的区别之处在于:将步骤(3)滴加150μL浓度为1mg/mL的MYRDMF溶液替换成滴加100μL浓度为1mg/mL的单宁酸(TA)水溶液,得到透析液即为纳米诊疗剂,命名为TDPP NP-b,-20℃储存备用。
实验数据与表征:
(1)从图2和图3可以看出,两种纳米诊疗剂的粒径分别为:MDPP NP-a:77.3±5.3nm,TDPP NP-b:52.2±4nm。
(2)纳米诊疗剂在肿瘤细胞中的摄取:
材料:人胶质瘤细胞U87MG肿瘤细胞,购买于中科院细胞库。
试验步骤:用PCR技术检测293T和U87MG上DRs(D2)的表达量。用FITC荧光染料标记DA-PTX和TDPP NP-b,并分别用0.68μM(PTX的浓度)孵育肿瘤细胞U87MG,用激光共聚焦显微镜和流式细胞仪对细胞摄取量进行定性和定量分析。
实验结果如图4-图6所示,用逆转录PCR的方法检测正常细胞293T和肿瘤细胞U87MG上多巴胺受体的表达量,图4a-b显示在肿瘤细胞表面多巴胺的受体表达量远远大于正常细胞293T的表达量。图6所示,在激光共聚焦显微镜下可看到用荧光标记的DA-PTX前药和纳米诊疗剂TDPP NP-b(图中为FITC-TDPP NPs)都随着时间的增加,其荧光强度越来越强,说明肿瘤细胞U87MG对DA-PTX-FITC和FITC-TDPP NPs的摄取与时间成正比关系。用流式细胞仪定量分析DA-PTX-FITC和FITC-TDPP NPs在U87MG肿瘤细胞中的摄取率,在8h时其细胞高达为87.19%,摄取后其荧光强度有明显的位移,证明TDPP NP-b比DA-PTX前药在肿瘤细胞中有较好的摄取率。
(3)应用试验
将30只U87MG肿瘤鼠(肿瘤体积:95±28mm3)分为3组:PTX,DA-PTX和TDPP NP-b,分别注射6mg/kg PTX或是相当于6mg/kg PTX的DA-PTX和TDPP NP-b。每3只肿瘤鼠在注射后的0.15,0.25,0.5,1,2,4,6,8,24,and 48h时间点取血。每100μL血浆用3mL***进行萃取,并加入30μL内标安定(500ng/mL),以转速为15000进行离心3min,取上清并吹干,重新溶解于200μL的甲醇中用于HPLC检测。同样,组织0.2g匀浆为2mL盐溶液,用***进行萃取3次,离心10min后,将溶液用氮气吹干,重新溶解在300μL甲醇中,用于HPLC的分析。
成像结果参见图7,可以看出,用药代动力学的方法研究紫杉醇在体内血液及组织中分布情况,证明TDPP NP-b与紫杉醇单体和DA-PTX紫杉醇前药相比,增加其在体内的半衰期及在肿瘤组织中的滞留量和时间,同时减少紫杉醇在肝脏中的堆积,从而提高药物的靶向性,降低毒性。
在荧光显微镜下观察用FITC标记的DA-PTX和TDPP NP-b纳米载药***在肿瘤组织中的分布,在尾静脉注射48、72h后取少量肿瘤组织做成肿瘤组织切片,图7所示在肿瘤组织中显示出较强的荧光,同时FITC-TDPP NPs组的荧光强度,明显强于DA-PTX-FITC组,证明TDPP NP-b纳米载药***在肿瘤组织中的EPR效应可增强其靶向性。
(4)药效实验
将U87MG肿瘤小鼠平均随机分为五组:a.Control,PBS pH7.4溶液组;b.PTX单品,剂量为6mg/kg;c.TA+PTX,以所含PTX量为准6mg/kg;d.TDPP NP-b,以所含PTX量为准6mg/kg。当肿瘤均长到2cm时,隔天尾静脉注射,连续三天,结束实验考察,将小鼠处死,剥下肿瘤称重,在此期间每天对各组裸鼠的体重进行称重,并计算其生存率。用U87MG肿瘤模型,隔天注射尾静脉共三次,观察肿瘤鼠体重,肿瘤大小的变化,并计算死亡率。
如图8所示,实验结果显示PTX单体组的抑瘤率是51.06%,TA+PTX组的抑瘤率是58.09%,而TDPP NP-b组的抑瘤率高达76.8%,其抑瘤效果明显好于PTX单体和TA+PTX组,而且在治疗的16天后,其肿瘤开始坏死缩小,这说明以TA作为载体的药物不仅将PTX靶向肿瘤部位发挥疗效,而且TA载体可促进PTX对肿瘤也有抑制作用,其TDPP NP-b的药效是PTX和TA的叠加效应。
本发明选用具有靶向性的多酚(5-羟基多巴胺)共价偶联抗肿瘤小分子药紫杉醇和荧光染料或其他小分子药物制备靶向性药物前药或是酚羟基结构的小分子抗癌药物阿霉素(DOX)、多酚化合物(MYR)、多酚-荧光染料和多酚共价偶联可溶性高分子PEG(5-羟基多巴胺-PEG)。在配位金属离子Fe3+过量的条件下,可逐步由核向外从而形成Fe3+-多酚-PTX-荧光染料@MYR-PEG/Fe3+-多酚-PTX@MYR-PEG-Y荧光染料形成稳定的纳米粒子配位化合物。其中Fe3+-多酚-PTX作为纳米粒子的内核,Fe3+-MYR为纳米粒子的表面,多巴胺-PEG/多巴胺-荧光染料为纳米粒子的***。
本发明利用有机合成与金属-多酚配位相结合的技术形成纳米粒子,第一步Fe3+与多酚-PTX结构上一个结合位点形成配位组成Fe3+-PTX化合物如图1第一步,红色代表Fe3+-PTX化合物,第二步过量的Fe3+与MYR有二个结合位点形成配位,进一步形成Fe3+-多酚-PTX@MYR/TA,第三步,过量的铁与PEG-多酚/荧光染料-多酚配位形成自组装纳米诊疗剂。
本发明应用有机合成与纳米制备相结合的技术制备含紫杉醇前药/荧光标记-紫杉醇前药的内核,Fe3+-MYR/PEG-荧光染料-多酚作为纳米诊疗剂的***,自组装新型纳米诊疗剂。利用“荧光染料→监测药物分布及代谢”、“多酚和Fe3+清除→氧自由基ROS和“小分子多酚增强小分药物/化疗药物疗效”相结合,杀死肿瘤细胞,实现分子影像与化疗的精准治疗。
本发明利用有机合成和化学配位法,通过第一步小分子药物如紫杉醇,多西紫杉醇和阿霉素(DOX)等)利用有机合成将紫杉醇或是多西紫杉醇制备成多酚前药如多巴胺-紫杉醇/多西紫杉醇,或是荧光染料标记-多巴胺-紫杉醇/多西紫杉醇,或是阿霉素DOX,制备成小分子抗肿瘤药物的前药,第二步将具有活性部位的二氢杨梅素与过量的三价铁离子形成配位化合物作为纳米诊疗剂的骨架,第三步用小分子多酚共价偶联PEG/PEG-多酚-荧光染料进一步与过量铁离子配位制备纳米诊疗剂的***Fe3+-PEG-多酚/PEG-荧光染料-多酚,增加其生物相容性/标记功能,从而自组装成纳米诊疗剂,利用“荧光染料→监测药物分布及肿瘤位置”、“Fe3+-多酚清除→氧自由基ROS和“二氢杨梅素增强小分子药物/化疗药物疗效”相结合,杀死肿瘤细胞,实现分子影像与化疗的精准治疗。
以上实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (5)
1.一种纳米诊疗剂,其特征在于:所述纳米诊疗剂的内核以小分子抗肿瘤药物与小分子配体共价偶联的前药与具有配位能力的金属离子配位形成,所述纳米诊疗剂的***以多酚结构的化合物与荧光染料共价偶联体形成;
所述小分子配体为多巴胺;所述小分子抗肿瘤药物为紫杉醇,所述多酚结构的化合物为二氢杨梅素或单宁酸,所述具有配位能力的金属离子为三价铁离子;
所述荧光染料包括伊文斯兰、Alexa Fluor 488、吲哚菁绿、Ce6、亚甲蓝、荧光素纳、5-氨基酮戊酸、异硫氰酸荧光素或罗丹明。
2.制备权利要求1所述的纳米诊疗剂的方法,其特征在于:包括以下步骤:
(1)将小分子抗肿瘤药物与小分子配体共价偶联得到小分子抗肿瘤药物-小分子配体,即为小分子抗肿瘤药物前药;
(2)将小分子抗肿瘤药物前药与过量的具有配位能力的金属离子混合,形成第一配位复合物;
(3)将第一配位复合物与共价偶联的多酚结构的化合物-荧光染料混合,形成纳米诊疗剂。
3.根据权利要求2所述的制备纳米诊疗剂的方法,其特征在于:所述步骤(1)具体包括以下步骤:将丁二酸酐-紫杉醇溶于二氯甲烷,加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和N-羟基琥珀酰亚胺,室温搅拌后,加入多巴胺,室温搅拌过夜,将反应液经硅胶柱纯化,得到多巴胺-紫杉醇。
4.根据权利要求2所述的制备纳米诊疗剂的方法,其特征在于:所述步骤(2)中将小分子抗肿瘤药物前药与过量的具有配位能力的金属离子的金属盐溶液混合,所述有配位能力的金属离子的金属盐溶液为卤化物水溶液。
5.包括权利要求1所述的纳米诊疗剂的试剂盒。
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