Zhao Xubo, Jia Xu, Liu Lei, Zeng Jin, Tian Kun, Zhou Tingting, Liu Peng
State Key Laboratory of Applied Organic Chemistry and Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, College of Chemistry and Chemical Engineering, Lanzhou University , Lanzhou 730000, China.
Biomacromolecules. 2016 Apr 11;17(4):1496-505. doi: 10.1021/acs.biomac.6b00102. Epub 2016 Mar 31.
A versatile folate-receptor-mediated targeting tumor theranostics has been designed for pH/reduction dual-responsive controlled anticancer drug release and pH-modulated fluorescent tumor imaging via facile ionic (pH sensitive) and covalent (reduction responsive) double-cross-linking (DCL) of the folic acid (FA) and Rhodamine 6G modified hyaluronic acid (HA) (FA-HA-Rh 6G). After optimizing the morphology and diameter of the resultant nanoparticles (DCL FA-HA-Rh 6G NPs) via modulating the concentration of the ionic and covalent cross-linking agents, the one with Ca and S contents of 1.70 and 2.84 wt % and an average hydrodynamic diameter of 154 nm was chosen as the desired drug delivery system (DDS) for DOX. They not only had high drug loading capacity and drug encapsulation efficiency (716 ± 34 mg/g and 71.6 ± 3.4%) but also possessed perfect triggered release and strong fluorescence intensity in the stimulated tumor microenvironment. The MTT assay and CLSM analysis revealed that the proposed double-cross-linked HA-based DDS had favorable cytocompatibility and folate-receptor-mediated targeting functionality to the HeLa cells and could obviously enhance the anticancer efficiency of DOX. The integration of the pH and reduction dual-responsiveness, folate-receptor-mediated targeting functionality, and pH-dependent fluorescence intensity into the biodegradable and biocompatible HA nanoparticles make the DCL FA-HA-Rh 6G NPs significant potential for future visualized chemotherapy of cancers.
一种多功能的叶酸受体介导的肿瘤诊疗试剂已被设计出来，用于通过叶酸（FA）和罗丹明6G修饰的透明质酸（HA）（FA-HA-Rh 6G）的简便离子（pH敏感）和共价（还原响应）双交联（DCL）实现pH/还原双重响应控制的抗癌药物释放以及pH调节的荧光肿瘤成像。通过调节离子和共价交联剂的浓度优化所得纳米颗粒（DCL FA-HA-Rh 6G NPs）的形态和直径后，选择钙和硫含量分别为1.70和2.84 wt%且平均流体动力学直径为154 nm的纳米颗粒作为用于阿霉素（DOX）的理想药物递送系统（DDS）。它们不仅具有高载药量和药物包封率（分别为716±34 mg/g和71.6±3.4%），而且在受刺激的肿瘤微环境中具有完美的触发释放和强荧光强度。MTT法和共聚焦激光扫描显微镜（CLSM）分析表明，所提出的基于HA的双交联DDS对HeLa细胞具有良好的细胞相容性和叶酸受体介导的靶向功能，并且可以显著提高DOX的抗癌效率。将pH和还原双重响应性、叶酸受体介导的靶向功能以及pH依赖性荧光强度整合到可生物降解且生物相容的HA纳米颗粒中，使得DCL FA-HA-Rh 6G NPs在未来癌症可视化化疗方面具有巨大潜力。
