Qin Benkai, Liu Lei, Wu Xiaohe, Liang Fengguang, Hou Tian, Pan Yangyang, Song Shiyong
Institute of Pharmacy, Pharmaceutical College of Henan University, North Jinming Road, Kaifeng 475004, China.
Huaihe Hospital of Henan University, No. 1 Baobei Street, Kaifeng 475000, China.
Acta Biomater. 2017 Dec;64:211-222. doi: 10.1016/j.actbio.2017.09.040. Epub 2017 Sep 27.
We prepared an amphiphilic redox-responsive conjugate based on mPEGylated solanesol, solanesyl poly(ethylene glycol) dithiodipropionate (SPDP), along with its inert counterpart solanesyl poly(ethylene glycol) succinate (SPGS), which self-assembled in aqueous solution to form redox-responsive micelles. Used as efficient drug carriers for doxorubicin (DOX), the micelles acted as synergistic agents for cancer therapy. Dynamic light scattering (DLS) measurements showed that the SPDP micelles had average diameters of 111nm, which decreased to 88nm after the encapsulation of DOX. The mean diameters and size distribution of the disulfide-containing micelles changed obviously in the presence of the reducing agent glutathione (GSH), whereas no changes occurred in the case of redox-insensitive SPGS micelles. DOX could be loaded into both types of micelles, with drug loading content of about 4.0%. A significantly accelerated release of DOX was triggered by GSH for DOX-loaded SPDP micelles, compared with DOX-loaded SPGS micelles. Blank SPGS and SPDP micelles displayed higher inhibition of HeLa and MCF-7 cell proliferation but less cytotoxicity to normal L-02 cells at similar concentrations. Confocal microscopic observation indicated that a greater amount of DOX was delivered into the nuclei of cells following 9 or 12h incubation with DOX-loaded micelles. In vivo studies on H22-bearing Swiss mice demonstrated the superior anticancer activity of DOX-loaded SPDP micelles over free DOX and DOX-loaded SPGS micelles. All of the data presented here suggested that these SPDP micelles may have a dual function, as they are preferentially toxic for tumor cells alone and are efficient and safe carriers for anticancer drugs.
Various nanoscale drug carriers were used to enhance therapeutic effect of many drugs. While, the metabolites of high quantities of carriers may cause additional short- or long-term toxicities. In this study, a new systems based on solanesol derivatives was developed for anticancer drug delivery. There are two features for this system. One is solanesol originated bioactivity of the carrier, which will synergistically facilitate therapeutic effect of the encapsulated drug. The other is the redox-responsive drug release behavior adaptable to the glutathione-rich atmosphere of tumor cell. All the hypothesis have been elucidated in this work through in vitro and in vivo studies. It was found that this drug delivery system may have a dual function, as they are preferentially toxic for tumor cells alone and are efficient and safe carriers for anticancer drugs.
我们基于甲氧基聚乙二醇化的茄尼醇制备了一种两亲性氧化还原响应性共轭物，即茄尼醇聚（乙二醇）二硫代二丙酸酯（SPDP），以及其惰性对应物茄尼醇聚（乙二醇）琥珀酸酯（SPGS），它们在水溶液中自组装形成氧化还原响应性胶束。用作阿霉素（DOX）的高效药物载体时，这些胶束可作为癌症治疗的协同剂。动态光散射（DLS）测量表明，SPDP胶束的平均直径为111nm，在包封DOX后降至88nm。在还原剂谷胱甘肽（GSH）存在下，含二硫键的胶束的平均直径和尺寸分布发生明显变化，而对氧化还原不敏感的SPGS胶束则没有变化。DOX可负载到两种类型的胶束中，载药含量约为4.0%。与负载DOX的SPGS胶束相比，GSH可显著加速负载DOX的SPDP胶束中DOX的释放。空白SPGS和SPDP胶束在相似浓度下对HeLa和MCF-7细胞增殖的抑制作用较高，但对正常L-02细胞的细胞毒性较小。共聚焦显微镜观察表明，与负载DOX的胶束孵育9或12小时后，有更多的DOX被递送至细胞核。对荷H22的瑞士小鼠的体内研究表明，负载DOX的SPDP胶束的抗癌活性优于游离DOX和负载DOX的SPGS胶束。本文提供的所有数据表明，这些SPDP胶束可能具有双重功能，因为它们仅对肿瘤细胞具有优先毒性，并且是抗癌药物的高效且安全的载体。
各种纳米级药物载体被用于增强许多药物的治疗效果。然而，大量载体的代谢产物可能会引起额外的短期或长期毒性。在本研究中，开发了一种基于茄尼醇衍生物的新系统用于抗癌药物递送。该系统有两个特点。一是载体源自茄尼醇的生物活性，这将协同促进包封药物的治疗效果。另一个是氧化还原响应性药物释放行为，可适应肿瘤细胞富含谷胱甘肽的环境。所有这些假设均已在本研究中通过体外和体内研究得以阐明。结果发现，这种药物递送系统可能具有双重功能，因为它们仅对肿瘤细胞具有优先毒性，并且是抗癌药物的高效且安全的载体。
