摘要
基于β-环糊精和胆固醇之间的主客体识别作用,通过对主客体分子的设计,构筑模块化的组装基元;通过主客体分子组装,将具有靶向功能的乳糖酸、成像功能的异硫氰酸荧光素和治疗作用的阿霉素引入同一超分子聚合物前药胶束中,制备得到多功能的纳米药物传递系统.研究结果表明,具有不同功能的模块基元可通过超分子主客体组装在水中自组装成一定尺寸的前药胶束,并通过二维1H NOESY谱证明了主客体作用的发生.该前药胶束具有p H值响应的药物释放行为,在细胞内涵体/溶酶体酸性环境下药物释放速率显著加快.用荧光显微镜和流式细胞仪对此聚合物前药胶束的细胞内吞行为进行了研究.在乳糖酸受体介导作用下,聚合物前药胶束能在肿瘤细胞内有效富集,并同时观察到阿霉素和异硫氰酸荧光素的荧光,用以跟踪载体在细胞内的位置.MTT的结果进一步表明,该前药胶束能有效地抑制癌细胞的增殖.
Unlike the crude study conducted at the beginning of nanomedicine, researchers have devoted more efforts to developing nanosystems with elaborated structures and multifunctions owing to the fact that the tumor microenvironment is complicated. However, it is still a great challenge to prepare these nanoplatforms for drug delivery. In this study, multifunctional prodrug nanocarriers were fabricated by the modularized host-vip self- assembly between cholesterol and fl-cyclodextrin. The targeted ligand lactobionic acid （LBA）, fluorescent probe fluoresceine isothiocyanate （FITC）, and chemtherapeutic drug doxorubicin （DOX） were integrated into the multifunctional supramolecualr drug nanocarriers. The host-vip interaction between Chol-PEG and fl-CD- hydrazone-DOX was confirmed by 2D 1H NOESY spectrum. The modularized functional building blocks could self-assemble into micelles with a diameter of 20 nm. The supramolecular nanocarriers showed pH-sensitive drug release behavior. The release of DOX can be greatly accelerated in acidic endo/lysosomal pH. The internalization of the supramolecular drug nanocarriers by HepG2 cells was studied by fluorescence microscopy and flow cytometry. The nanocarriers can be well taken up by cancer cells. Due to the targeting ability of LBA, the internalization of the nanocarriers can be greatly inhibited if the cells are pre-treated by free LBA. At the same time, the fluorescence of FITC can be clearly observed intracellularly, which can be used to track the sub-cellular location of the drug nanocarriers. Finally, the cytotoxicity of the drug nanocarriers was investigaed by MTT assay. With the HepG2 cells pre-treated with free LBA, the cytotoxicity of the drug nanocarriers was significantly reduced, most probably owing to the unsatisfactory cell uptake. The concentration-dependent cytotoxicity toward HepG2 cells was also observed. Therefore, the integration of target ligand and imaging ligand have endowed the nanocarriers with targeted theranostic property. More importantly, since the modularized host-vip self-assembly is dynamically tunable, the percentage of functional ligands could be easily optimized to achieve a better outcome. Such multifunctional prodrug nanocarriers fabricated by modularized host-vip self-assembly may have great potential in drug delivery.
作者
王寅
王海波
韩海杰
贾凡
金桥
计剑
Yin Wang;Hai-bo Wang;Hai-jie Han;Fan Jia;Qiao Jin;Jian Ji(Ministry of Education Key Laboratory of Macromoleeular Synthesis and Functionalization,Department of Polymer Science and Engineering,Zhejiang University,Hangzhou 310027)
出处
《高分子学报》
SCIE
CAS
CSCD
北大核心
2018年第8期1089-1096,共8页
Acta Polymerica Sinica
基金
国家自然科学基金(基金号21574114)
浙江省科技计划(项目号2016C04002)资助
关键词
主客体作用
超分子
药物传递
成像
Host-vip interactions
Supramolecule
Drug delivery
Imaging
