CN110354099B - 一种基于质子触发的具有亲疏水-尺寸双转换特性的纳米药物体系及其制备方法和用途 - Google Patents
一种基于质子触发的具有亲疏水-尺寸双转换特性的纳米药物体系及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种基于质子触发的具有亲疏水‑尺寸双转换特性的纳米药物体系及其制备方法和用途。所述体系由含苯环的芳香族小分子抗肿瘤活性药物、多酚类化合物及吲哚菁类衍生物或CY系列荧光染料自组装而成。本发明体系基于静电作用力及芳香环间的相互作用而组装，具有在血液等中性环境下稳定的亲水性，而在肿瘤的酸性环境下由质子触发转换为大尺寸疏水性微粒，促进纳米药物进入肿瘤细胞并发生溶酶体逃逸，在恢复至细胞质的中性环境时再次转换为亲水性纳米粒而释放药物。同时，该发明形成的基于质子触发的亲疏水‑尺寸双转换纳米药物体系实现了肿瘤生物成像及化疗、光热和光动力联合治疗等方面的应用。
Description
技术领域
本发明涉及纳米药物体系及其制备方法和应用，特别涉及一种基于质子触发的具有亲疏水-尺寸双转换特性的纳米药物体系及其制备方法和用途。
背景技术
肿瘤是目前世界上最常见的疾病死亡原因之一，通常游离化疗药物不能有效递送至肿瘤生长部位，且容易导致多药耐药、毒副作用大等负面治疗效果。因此，制备纳米药物载体靶向递送化疗药物受到广泛关注，纳米抗肿瘤药物基于实体瘤的高通透性和滞留效应(Enhanced permeability and retention effect，EPR效应)可在肿瘤部位靶向滞留蓄积以提高抗肿瘤药物的治疗效率，展示其极具潜力的发展前景。然而，网状内皮系统的清除，低于游离药物的肿瘤细胞摄取效率，溶酶体酸性环境经质子化作用对所负载药物活性的抑制，肿瘤细胞中无效的药物释放以及较弱的肿瘤组织深层穿透能力等体内递送过程中的不同生理递送屏障仍大大限制了肿瘤靶向治疗纳米药物的治疗效果(Kommareddy S，AmijiM.Targeted Drug Delivery to Tumor Cells Using Colloidal Carriers[M]//CellularDrug Delivery.Humana Press，2004.Taylor S，Spugnini E P，Assaraf Y G，etal.Microenvironment acidity as a major determinant of tumor chemoresistance：Proton pump inhibitors(PPIs)as a novel therapeutic approach[J].Drug ResistUpdat，2015.)。文献报道，亲水性药物可以增强药物在水环境中的稳定性，延长血液循环时间(Torchilin，Vladimir P.Passive and Active Drug Targeting：Drug Delivery toTumors as an Example[J].Handbookofexperimentalpharmacology，2015(197)：3-53)，而疏水性纳米载药系统则有利于肿瘤细胞的摄取(Bourdon O，Blais J，Bolard J，etal.Hydrophobic Photosensitizers Delivery to Tumor Tissues by anAmphiphilicPeptide[M]//Analytical Use of Fluorescent Probes inOncology.Springer US，1996.)。此外，大尺寸的纳米药物可撕裂溶酶体膜以促进纳米药物的溶酶体逃逸(Li Y，Hu Q，Miao G，et a1.Size-Dependent Mechanism of IntracellularLocalization and Cytotoxicity of Mono-Disperse Spherical Mesoporous Nano-andMicron-Bioactive Glass Particles[J].Journal of Biomedical Nanotechnology，2016.)，而小尺寸的纳米药物更有利于肿瘤组织的深层穿透与递药(Zhao P，Zheng，Mingbin，Yue，Caixia，et a1.Improving drug accumulation and photothermalefficacy in tumor depending on size of ICG loaded lipid-polymer nanoparticles[J].Biomaterials，2014，35(23)：6037-6046.)。可见，想要连续克服上述纳米药物肿瘤靶向递送过程中的多重生理屏障，纳米药物需要适应性地进行多次亲疏水及尺寸变换。
目前肿瘤环境响应性的纳米转换递药体系大多依赖于敏感化学键的断裂，常常需要较长的化学反应时间，转换效率低，最终将影响肿瘤靶向治疗纳米药物的肿瘤抑制的治疗效果。
含苯环的芳香族小分子抗肿瘤活性药物由于苯环结构而稳定性好，且抗瘤谱广，抗瘤作用强，疗效确切，能作用在肿瘤细胞生长繁殖的不同环节上，抑制或杀死肿瘤细胞，但单一使用含苯环的芳香族小分子抗肿瘤活性药物往往会产生严重的毒副作用和耐药性。多酚类化合物是一类具有多个酚基团，结构稳定的植物次生代谢产物，可以通过捕获或清除自由基，阻止癌细胞增殖，诱导癌细胞的凋亡(Yang，G.Inhibition ofgrowth andinduction ofapoptosis in human cancer cell lines by tea polyphenols[J].Carcinogenesis，1998，19(4)：611-616.)，但其清除自由基的活性易受多种因素的影响。吲哚菁类衍生物或CY系列荧光染料是一类在近红外光谱范围内有较强的吸收、灵敏度高、毒性小、不参与体内生物转化的荧光染料(Borg R E，Jonathan R.MolecularPhotoacoustic Contrast Agents (MPACs)：Design Principles&Applications[J].Photochemistry and Photobiology，2018.)，磺化的CY系列荧光染料在水性环境下溶解度好，分散性较好，无需借助有机助溶剂，可以为肿瘤细胞定位、细胞内吞及体内代谢分布提供实时成像检测，吲哚菁类衍生物或CY系列荧光染料除了具有荧光和基于核成像的肿瘤成像特性外，还可以作为药物载体，安全地向肿瘤运送化疗药物，其中吲哚菁类衍生物突出表现为可作为光热及光动力治疗的有效药物，通过光依赖细胞毒活性具有显著的杀瘤活性及并逆转了化疗药物耐药性(Shi C，Wu J B，Pan D.Review on near-infraredheptamethine cyanine dyes as theranostic agents for tumor imaging，targeting，and photodynamic therapy[J].Journal of Biomedical Optics，2016，21(5)：50901.)，但是单一吲哚菁类化合物如吲哚菁绿、IR820等缺乏肿瘤靶向性，对肿瘤摄取率及亲和力有限。
发明内容
发明目的：本发明目的是提供一种高转换率、通过对质子浓度梯度适应性进行多次亲疏水-尺寸双转换从而实现药物深层递送并在胞内的有效释药，基于质子触发的具有亲疏水-尺寸双转换特性的纳米药物体系。
本发明的另一目的是提供所述纳米药物体系的制备方法。
本发明的最后一个目的是提供所述纳米药物体系在制备抗肿瘤药物或生物成像中的用途。
技术方案：本发明提供一种基于质子触发的具有亲疏水-尺寸双转换特性的纳米药物体系，其成分包括含苯环的芳香族小分子抗肿瘤活性药物、多酚类化合物及吲哚菁类衍生物或CY系列荧光染料。
体系中含苯环的芳香族小分子抗肿瘤活性药物与多酚类化合物通过芳香环间相互作用及静电吸附进行初步组装，而吲哚菁类衍生物或CY系列荧光染料在二者的基础上进一步以相同机制或其他复合机制组装。
该体系基于静电作用力及芳香环间的相互作用组装而成，在血液等中性环境下具有亲水性，稳定性良好；在肿瘤酸性微环境及胞内溶酶体酸性环境下由于质子触发的再组装作用转换为具有疏水性且大尺寸的微粒，以促进肿瘤细胞对纳米药物的摄取及纳米药物的溶酶体逃逸，在恢复至中性环境时可再次转换为亲水性纳米药物，以促进药物的胞质内释放。
进一步地，所述含苯环的芳香族小分子抗肿瘤活性药物、多酚类化合物以及吲哚菁类衍生物或CY系列荧光染料的质量比为1-9∶1-15∶2-20。该比例范围下制备的质子触发的亲疏水-尺寸双转换体系具有生物学应用所需的合适的粒径尺寸、分散均匀且稳定性良好。
进一步地，所述含苯环的芳香族小分子抗肿瘤活性药物为盐酸阿霉素、盐酸表阿霉素、盐酸柔红霉素、盐酸阿柔比星、盐酸伊达比星、盐酸氨柔比星、盐酸吡柔比星、盐酸苯达莫司汀、长春碱、盐酸米托蒽醌、丝裂霉素C、盐酸伊立替康中、硼替佐米、舒尼替尼、甲磺酸伊马替尼或多西他赛。
进一步地，所述多酚类化合物为鞣酸、儿茶素、表儿茶素、没食子酚儿茶素、表没食子酚儿茶素、白藜芦醇、茶多酚、花青素、木酚素、大豆黄素、苹果多酚或茶黄素。
进一步地，所述吲哚菁类衍生物或CY系列荧光染料为吲哚菁绿、新吲哚菁绿、IR780、IR783、IR808、IR820、IR825、IR908、IR1045、MHI-148、磺化Cy3、磺化Cy5或磺化Cy7。
进一步地，其尺寸为10nm-1000nm。
一种基于质子触发的具有亲疏水-尺寸双转换特性的纳米药物体系的制备方法，包括如下步骤：
(1)将含苯环的芳香族小分子抗肿瘤活性药物、多酚类化合物及吲哚菁类衍生物或CY系列荧光染料分别溶于超纯水、醇或醇与水的混合溶剂，制备得到相应的溶液，所述水与醇的体积比为1∶1～200∶1；
(2)混合含苯环的芳香族小分子抗肿瘤活性药物水溶液和多酚类化合物水溶液，混合过程中注入水、醇或水和醇的混合物；该水、醇或水醇混合溶剂的溶解范围广，可为该组装体系提供低离子强度的溶剂环境，极性合适，有利于各组分分子经π-π相互作用、静电作用、配位作用而发生自组装。
(3)向步骤(2)的混合体系中匀速加入吲哚菁类衍生物或CY系列荧光染料水溶液，继续混合搅拌，经离心、复溶、超声后收集产物，即可。
进一步地，所述步骤(2)中水、醇或水和醇的混合物的体积是步骤(1)中三种水溶液体积的5-25倍。
一种基于质子触发的具有亲疏水-尺寸双转换特性的纳米药物体系在制备抗肿瘤药物或生物成像中的用途。该纳米药物体系在肿瘤制剂中的应用，还可实现实时成像检测及光热、光动力、化疗联合治疗。
进一步地，所述抗肿瘤药物的给药类型为注射、口服、外用或非经胃肠道给药。
正常组织的中性pH环境与肿瘤组织酸性微环境及溶酶体内的酸性的质子浓度梯度差，是可利用作为触发纳米药物转换的触发因子。本发明利用小分子自组装技术，设计制备了基于含苯环的芳香族小分子抗肿瘤药物、多酚类化合物以及吲哚菁类衍生物或CY系列荧光染料的组装型纳米药物。该纳米药物体系在血液循环过程中呈现亲水性纳米表面性质，经酸性肿瘤微环境质子触发发生疏水性自组装，形成疏水性纳米药物，以促进药物的肿瘤细胞摄取。经肿瘤细胞摄取后进入肿瘤细胞溶酶体，受溶酶体中进一步升高的质子浓度触发，进一步组装成尺寸大于溶酶体的纳米组装体，通过撕裂溶酶体膜发生溶酶体逃逸。随后进入肿瘤细胞细胞质中性环境后，可发生快速解组装，恢复至小尺寸亲水性纳米药物，在细胞质中有效释放药物，促进药物的深层渗透，发挥抗肿瘤作用。
而通过静电相互作用力及芳香环间的相互作用，含苯环的芳香族小分子抗肿瘤活性药物、多酚类化合物及吲哚菁类衍生物或CY系列荧光染料组装为基于质子触发的亲疏水-尺寸双转换纳米药物体系可降低含苯环的芳香族小分子抗肿瘤活性化疗药物，逆转肿瘤多药耐药，改善吲哚菁类化合物及CY系列荧光染料在肿瘤治疗方面的弊端，形成化疗、光热光动力治疗及肿瘤生物成像治疗三位一体的治疗体系。
本发明的原理详细阐述如下：
该质子触发亲疏水-尺寸双转换纳米体系在血液中具有亲水性可保持良好的稳定性，不被血液中的蛋白吸附及网状内皮系统所吞噬进而顺利靶向肿瘤部位。但该亲疏水-尺寸双转换纳米体系可在肿瘤微酸性环境下蓄积，穿透肿瘤细胞膜进入肿瘤细胞内后，被溶酶体所吞噬，该纳米体系在酸性较强的溶酶体内可由质子触发转换为疏水特性而聚集。聚集后的大尺寸纳米体系将溶酶体涨破，发生溶酶体逃逸，进而顺利进入细胞质，在细胞质的中性环境下该亲疏水转换系统可再次转换为小尺寸亲水性的纳米结构靶向细胞核。在肿瘤细胞内含苯环的芳香族小分子抗肿瘤药物发挥杀伤肿瘤的作用，而吲哚菁类衍生物或CY系列荧光染料由于在近红外光谱范围内有较强的的吸收，因此，可以提供肿瘤实时成像检测，同时触发光热或光动力反应可以辅助化疗药物治疗。该基于质子触发的亲疏水-尺寸双转换纳米药物体系不仅可以进行化疗和光热光动力联合治疗，同时保留了含苯环的芳香族小分子抗肿瘤活性药物的活性和吲哚菁类衍生物或CY系列荧光染料的生物成像功能，实现药物靶向肿瘤细胞的深层递送和实时的生物检测。而且该体系有效降低了药物的毒副作用，拓宽了含苯环的芳香族小分子抗肿瘤活性药物的治疗窗。
有益效果：
(1)该体系在肿瘤微酸性环境由质子触发逐渐由亲水转换为疏水，在肿瘤部位蓄积，准确定位在肿瘤部位，提高药物递送效率；
(2)该纳米体系的制备仅通过静电作用力及含芳香环间的相互作用而组装，未使用复杂的化学合成技术，避免对药物活性分子的共价结构修饰，从而规避修饰后构效关系改变带来的潜在的药效学行为改变及潜在的毒性增加的风险。本发明仅通过物理方式组装，与传统需要经过化学反应而接枝修饰的聚合物胶束或构造载体相比具有制备工艺简单，制备周期短，未改变药物化学结构，构效关系明确的优势；
(3)本发明制备工艺中未使用任何有机溶剂，从而避免了有机试剂残留导致的毒副作用，提高制剂安全性，符合绿色化学的基本原则；
(4)本发明是一种高效低毒的新型可降解纳米材料；
(5)本发明实现化疗、光热或光动力治疗的联合治疗，治疗高度协同，改善单一治疗方案的不足，充分拓宽了肿瘤治疗的治疗窗；
(6)本发明提供了肿瘤组织实时成像检测及监测制剂在体内的分布代谢的功能；
(7)该纳米体系在中性环境中保持稳定，亲水特性延长了血液循环时间；
(8)该纳米体系不仅可以实现在肿瘤组织的深层递送和释放药物，同时可以进行肿瘤实时成像检测以及制剂在体内的分布代谢进行监测；
(9)该体系亲疏水-尺寸双转换过程迅速，亲疏水-尺寸双转换过程可在几分钟到十几分钟不等的时间内完成，无需经历耗时的化学反应，可避免耗时化学反应迟滞效应带来的转换敏感度低等问题。
附图说明
图1为盐酸阿霉素/单宁酸/吲哚菁绿基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图；
图2盐酸柔红霉素/茶多酚/IR820基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图；
图3盐酸阿柔比星/茶多酚/IR825基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图；
图4盐酸苯达莫司汀/花青素/IR820基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图；
图5长春碱/茶黄素/IR908基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图；
图6盐酸伊立替康/花青素/IR1045基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图；
图7盐酸米托蒽醌/茶黄素/IR825基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图；
图8丝裂霉素C/白藜芦醇/IR1045基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图；
图9盐酸吡柔比星/白藜芦醇/磺化Cy3基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图；
图10盐酸氨柔比星/儿茶素/磺化Cy5基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图；
图11盐酸表阿霉素/没食子酸/磺化Cy7基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图；
图12长春碱/没食子酚儿茶素/IR908基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图；
图13硼替佐米/木酚素/IR783基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图；
图14舒尼替尼/大豆黄素/IR1045基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图；
图15甲磺酸伊马替尼/苹果多酚/MHI-148基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图；
图16多西他赛/木酚素/IR1045基于质子触发的亲疏水-尺寸双转换体系在不同环境下的粒径变化图。
其中，图1-16不同环境中的原始制剂、pH6.5、pH4.5、细胞液分别是指纳米溶液、纳米体系于pH值6.5PBS溶液、纳米体系于pH值4.5PBS溶液、纳米体系在pH值4.5溶液中的沉淀复溶于肿瘤细胞细胞质提取液。
具体实施方式
实施例1：盐酸阿霉素/单宁酸/吲哚菁绿纳米体系的制备
按照质量比为2∶3∶3精密称取盐酸阿霉素、单宁酸、吲哚菁绿分别溶于超纯水，涡旋混匀。将盐酸阿霉素溶液与单宁酸溶液混合搅拌，在搅拌条件下注入体积为盐酸阿霉素溶液及单宁酸溶液体积和的10倍的超纯水。搅拌5min后注入吲哚菁绿溶液，继续搅拌30min。离心，取沉淀复溶，超声5min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例2：盐酸柔红霉素/茶多酚/IR820纳米体系的制备
按照质量比为2∶5∶4精密称取盐酸柔红霉素、茶多酚、IR820分别溶于醇，涡旋混匀。将盐酸柔红霉素溶液与茶多酚溶液混合搅拌，在搅拌条件下注入体积为盐酸柔红霉素溶液及茶多酚溶液体积和的5倍的超纯水。搅拌10min后注入IR820水溶液，继续搅拌40min。离心，取沉淀复溶，超声10min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例3：盐酸阿柔比星/茶多酚/IR825纳米体系的制备
按照质量比为4∶10∶8精密称取盐酸阿柔比星、茶多酚、IR825分别溶于超纯水，涡旋混匀。将盐酸阿柔比星溶液与茶多酚溶液混合搅拌，在搅拌条件下注入体积为盐酸阿柔比星溶液及茶多酚溶液体积和的20倍的超纯水。搅拌8min后注入IR825水溶液，继续搅拌20min。离心，取沉淀复溶，超声15min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例4：盐酸苯达莫司汀/花青素/IR820纳米体系的制备
按照质量比为3∶8∶6精密称取盐酸苯达莫司汀、花青素、IR820分别溶于超纯水，涡旋混匀。将盐酸苯达莫司汀溶液与花青素溶液混合搅拌，在搅拌条件下注入体积为盐酸苯达莫司汀溶液及花青素溶液体积和的15倍的超纯水。搅拌10min后注入IR820水溶液，继续搅拌90min。离心，取沉淀复溶，超声20min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例5：盐酸伊立替康/花青素/IR1045纳米体系的制备
按照质量比为1.5∶4∶6精密称取盐酸伊立替康、花青素、IR1045分别溶于超纯水，涡旋混匀。将盐酸伊立替康溶液与花青素溶液混合搅拌，在搅拌条件下注入体积为盐酸伊立替康溶液与花青素溶液体积和的25倍的超纯水。搅拌6min后注入IR1045水溶液，继续搅拌40min。离心，取沉淀复溶，超声10min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例6：长春碱/茶黄素/IR908纳米体系的制备
按照质量比为1∶1∶2精密称取长春碱、茶黄素、IR908分别溶于醇与水的混合溶剂，水与醇的体积比为1∶1，涡旋混匀。将长春碱溶液与茶黄素溶液混合搅拌，在搅拌条件下注入体积为长春碱溶液及茶黄素溶液体积和的5倍的超纯水。搅拌5min后注入IR908水溶液，继续搅拌20min。离心，取沉淀复溶，超声5min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例7：盐酸米托蒽醌/茶黄素/IR825纳米体系的制备
按照质量比为4∶8∶8精密称取盐酸米托蒽醌、茶黄素、IR825分别溶于超纯水，涡旋混匀。将盐酸米托蒽醌溶液与茶黄素溶液混合搅拌，在搅拌条件下注入体积为盐酸米托蒽醌溶液及茶黄素溶液体积和的10倍的超纯水。搅拌5min后注入IR908水溶液，继续搅拌45min。离心，取沉淀复溶，超声15min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例8：丝裂霉素C/白藜芦醇/IR1045纳米体系的制备
按照质量比为3∶7∶6精密称取丝裂霉素C、白藜芦醇、IR1045分别溶于醇与水的混合溶剂，水与醇的体积比为200∶1，，涡旋混匀。将丝裂霉素C溶液与白藜芦醇溶液混合搅拌，在搅拌条件下注入体积为丝裂霉素C溶液与白藜芦醇溶液体积和的15倍的超纯水。搅拌10min后注入IR1045水溶液，继续搅拌60min。离心，取沉淀复溶，超声18min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例9：盐酸吡柔比星/白藜芦醇/磺化Cy3纳米体系的制备
按照质量比为1∶4∶2精密称取盐酸吡柔比星、白藜芦醇、磺化Cy3分别溶于醇与水的混合溶剂，水与醇的体积比为100∶1，涡旋混匀。将盐酸吡柔比星溶液与白藜芦醇溶液混合搅拌，在搅拌条件下注入体积为盐酸吡柔比星溶液与白藜芦醇溶液体积和的5倍的超纯水。搅拌5min后注入磺化Cy3水溶液，继续搅拌25min。离心，取沉淀复溶，超声7min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例10：盐酸氨柔比星/儿茶素/磺化Cy5纳米体系的制备
按照质量比为3∶8∶5精密称取盐酸盐酸氨柔比星、儿茶素、磺化Cy5分别溶于超纯水，涡旋混匀。将盐酸氨柔比星溶液与儿茶素溶液混合搅拌，在搅拌条件下注入体积为盐酸氨柔比星溶液与儿茶素溶液体积和的20倍的超纯水。搅拌10min后注入磺化Cy5水溶液，继续搅拌80min。离心，取沉淀复溶，超声20min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例11：盐酸表阿霉素/没食子酸/磺化Cy7纳米体系的制备
按照质量比为1.5∶3∶5精密称取盐酸表阿霉素、没食子酸、磺化Cy7分别溶于超纯水，涡旋混匀。将盐酸表阿霉素溶液与没食子酸溶液混合搅拌，在搅拌条件下注入体积为盐酸表阿霉素溶液与没食子酸溶液体积和的10倍的超纯水。搅拌5min后注入磺化Cy7水溶液，继续搅拌40min。离心，取沉淀复溶，超声16min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例12：长春碱/没食子酚儿茶素/IR908
按照质量比为2∶7∶3精密称取长春碱、没食子酚儿茶素、IR908分别溶于超纯水，涡旋混匀。将长春碱溶液与没食子酚儿茶素溶液混合搅拌，在搅拌条件下注入体积为长春碱溶液与没食子酚儿茶素溶液体积和的8倍的超纯水。搅拌8min后注入IR908水溶液，继续搅拌35min。离心，取沉淀复溶，超声10min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例13：硼替佐米/木酚素/IR783
按照质量比为3∶9∶7精密称取硼替佐米、木酚素、IR783分别溶于超纯水，涡旋混匀。将硼替佐米溶液与木酚素溶液混合搅拌，在搅拌条件下注入体积为硼替佐米溶液与木酚素溶液体积和的12倍的超纯水。搅拌8min后注入IR783水溶液，继续搅拌20min。离心，取沉淀复溶，超声5min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例14：舒尼替尼/大豆黄素/IR1045
按照质量比为9∶7∶15精密称取舒尼替尼、大豆黄素、IR1045分别溶于超纯水，涡旋混匀。将舒尼替尼溶液与大豆黄素溶液混合搅拌，在搅拌条件下注入体积为舒尼替尼溶液与大豆黄素溶液体积和的20倍的超纯水。搅拌10min后注入IR1045水溶液，继续搅拌45min。离心，取沉淀复溶，超声18min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例15：甲磺酸伊马替尼/苹果多酚/MHI-148
按照质量比为9∶15∶20精密称取甲磺酸伊马替尼、苹果多酚、MHI-148分别溶于超纯水，涡旋混匀。将甲磺酸伊马替尼溶液与苹果多酚溶液混合搅拌，在搅拌条件下注入体积为甲磺酸伊马替尼溶液与苹果多酚溶液体积和的25倍的超纯水。搅拌5min后注入MHI-148水溶液，继续搅拌80min。离心，取沉淀复溶，超声8min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例16：多西他赛/木酚素/IR1045
按照质量比为5∶9∶7精密称取多西他赛、木酚素、IR1045分别溶于超纯水，涡旋混匀。将多西他赛溶液与木酚素溶液混合搅拌，在搅拌条件下注入体积为多西他赛溶液与木酚素溶液体积和的18倍的超纯水。搅拌10min后注入IR1045水溶液，继续搅拌25min。离心，取沉淀复溶，超声12min，制得一种基于质子触发的亲疏水-尺寸双转换的纳米体系。
实施例17：基于质子触发的亲疏水-尺寸双转换纳米药物体系的粒径测定
取实例1-16制备得到的质子触发亲疏水转换纳米体系进行8倍稀释，通过电位粒度测定仪(OmniNanoBrook，布鲁克，美国)测得粒径如表1所示。由表1可知，通过实例1-16制备所得的亲疏水转换纳米体系粒度在纳米尺度范围内，且粒径分布均匀。
表1基于质子触发的亲疏水-尺寸双转换纳米药物体系粒径表征
| 纳米体系 | 粒径(nm) | PDI |
| 盐酸阿霉素/单宁酸/吲哚菁绿 | 73.97±2.35 | 0.230±0.028 |
| 盐酸柔红霉素/茶多酚/IR820 | 80.65±3.24 | 0.297±0.036 |
| 盐酸阿柔比星/茶多酚/IR825 | 78.64±1.35 | 0.193±0.026 |
| 盐酸苯达莫司汀/花青素/IR820 | 90.25±2.56 | 0.269±0.039 |
| 盐酸伊立替康/花青素/IR1045 | 85.67±2.39 | 0.312±0.015 |
| 长春碱/茶黄素/IR908 | 96.87±3.89 | 0.176±0.024 |
| 盐酸米托蒽醌/茶黄素/IR825 | 117.96±4.75 | 0.135±0.064 |
| 丝裂霉素C/白藜芦醇/IR1045 | 87.43±1.96 | 0.287±0.031 |
| 盐酸吡柔比星/白藜芦醇/磺化Cy3 | 105.35±4.65 | 0.191±0.023 |
| 盐酸氨柔比星/儿茶素/磺化Cy5 | 98.87±3.64 | 0.183±0.021 |
| 盐酸表阿霉素/没食子酸/磺化Cy7 | 110.68±2.48 | 0.281±0.045 |
| 长春碱/没食子酚儿茶素/IR908 | 87.26±3.46 | 0.279±0.074 |
| 硼替佐米/木酚素/IR783 | 135.73±2.98 | 0.218±0.056 |
| 舒尼替尼/大豆黄素/IR1045 | 127.83±3.65 | 0.173±0.082 |
| 甲磺酸伊马替尼/苹果多酚/MHI-148 | 93.46±1.28 | 0.092±0.003 |
| 多西他赛/木酚素/IR1045 | 115.64±3.87 | 0.139±0.043 |
实施例18：基于质子触发的亲疏水-尺寸双转换纳米药物体系的载药量
基于质子触发的亲疏水-尺寸双转换纳米药物体系的载药量测定方法：利用紫外分光光度法，测定不同浓度的每种物质在其最大吸收波长处的吸光度值，绘制浓度-吸光值标准曲线。对载药后的亲疏水转换体系在最大吸收波长处测其吸光度值，根据公式(1)(2)计算载药量。根据表2所示含苯环的芳香族小分子药物载药量均在23％左右，吲哚菁类衍生物载药量在35％左右。证明该体系载药量比较高，提高药物在肿瘤部位浓度。
注：M1(mg)为含苯环的芳香族小分子抗肿瘤活性药物投入质量；M2(mg)为上清中含苯环的芳香族小分子抗肿瘤活性药物的质量；M3(mg)为吲哚菁类衍生物投入质量；M4(mg)为上清中含吲哚菁类衍生物的质量；M5(mg)为多酚类化合物的投入质量。
表2基于质子触发的亲疏水-尺寸双转换纳米药物体系的载药量
相比于传统聚合物胶束或脂质体作为药物的载体的纳米制剂，载药量仅在10％左右，如聚(环氧乙烷)-嵌段-聚(β-苄基-1-天冬氨酸)(PEO-PBLA)装载阿霉素的载药量在5％-12％。而负载吲哚菁类衍生物的载药量小于10％，如负载吲哚菁绿(ICG)的聚乳酸-乙醇酸(PLGA)-卵磷脂-聚乙二醇(PEG)核壳纳米粒的载药量仅为6％-7％。负载Cy系列荧光染料的载体载药量亦较低，如壳聚糖胶束负载Cy7荧光染料的载药量仅为0.5％，远低于本专利发明的基于质子触发的亲疏水-尺寸双转换纳米药物体系的相关载药量。
实施例19：基于质子触发的亲疏水-尺寸双转换纳米药物体系经质子触发的粒径变化
在各组基于质子触发的亲疏水-尺寸双转换纳米药物体系中加入pH4.5及pH6.5的磷酸盐-柠檬酸缓冲液，如图1所示，各体系表现为在pH4.5和pH6.5环境下迅速发生疏水转换而聚集，而重新置于细胞质溶液中会发生亲水转换而复溶。证明该质子触发亲疏水转换纳米体系可发生在肿瘤弱酸性环境下及溶酶体中聚集，而在细胞质中重新组装进而靶向细胞核释放药物的行为。粒径变化过程利用电位粒度测定仪测定。
Claims (9)
1.一种基于质子触发的具有亲疏水-尺寸双转换特性的纳米药物体系，其特征在于：其成分由含苯环的芳香族小分子抗肿瘤活性药物、多酚类化合物及吲哚菁类衍生物或CY系列荧光染料组成，所述含苯环的芳香族小分子抗肿瘤活性药物、多酚类化合物以及吲哚菁类衍生物或CY系列荧光染料的质量比为1-9：1-15：2-20。
2.根据权利要求1所述的基于质子触发的具有亲疏水-尺寸双转换特性的纳米药物体系，其特征在于：所述含苯环的芳香族小分子抗肿瘤活性药物为盐酸阿霉素、盐酸表阿霉素、盐酸柔红霉素、盐酸阿柔比星、盐酸伊达比星、盐酸氨柔比星、盐酸吡柔比星、盐酸苯达莫司汀、长春碱、盐酸米托蒽醌、丝裂霉素C、盐酸伊立替康中、硼替佐米、舒尼替尼、甲磺酸伊马替尼或多西他赛。
3.根据权利要求1所述的基于质子触发的具有亲疏水-尺寸双转换特性的纳米药物体系，其特征在于：所述多酚类化合物为鞣酸、儿茶素、表儿茶素、没食子酚儿茶素、表没食子酚儿茶素、白藜芦醇、茶多酚、花青素、木酚素、大豆黄素、苹果多酚或茶黄素。
4.根据权利要求1所述的基于质子触发的具有亲疏水-尺寸双转换特性的纳米药物体系，其特征在于：所述吲哚菁类衍生物或CY系列荧光染料为吲哚菁绿、新吲哚菁绿、IR780、IR783、IR808、IR820、IR825、IR908、IR1045、MHI-148、磺化Cy3、磺化Cy5或磺化Cy7。
5.根据权利要求1所述的基于质子触发的具有亲疏水-尺寸双转换特性的纳米药物体系，其特征在于：其尺寸为10nm-1000nm。
6.如权利要求1所述的基于质子触发的具有亲疏水-尺寸双转换特性的纳米药物体系的制备方法，其特征在于：包括如下步骤：
（1）将含苯环的芳香族小分子抗肿瘤活性药物、多酚类化合物及吲哚菁类衍生物或CY系列荧光染料分别溶于超纯水、醇或醇与水的混合溶剂，制备得到相应的溶液，所述水与醇的体积比为1:1~200:1；
（2）混合含苯环的芳香族小分子抗肿瘤活性药物水溶液和多酚类化合物水溶液，混合过程中注入水、醇或水和醇的混合物；
（3）向步骤（2）的混合体系中匀速加入吲哚菁类衍生物或CY系列荧光染料水溶液，继续混合搅拌，经离心、复溶、超声后收集产物，即可。
7.根据权利要求6所述的基于质子触发的具有亲疏水-尺寸双转换特性的纳米药物体系的制备方法，其特征在于：所述步骤（2）中水、醇或水和醇的混合物的体积是步骤（1）中三种水溶液体积的5-25倍。
8.如权利要求1所述的基于质子触发的具有亲疏水-尺寸双转换特性的纳米药物体系在制备抗肿瘤药物或生物成像产品中的用途。
9.根据权利要求8所述的用途，所述抗肿瘤药物的给药类型为注射、口服、外用或非经胃肠道给药。
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