Zhang Min, Liu Jia, Kuang Ying, Li Qilin, Chen Hongyu, Ye Haifeng, Guo Li, Xu Yanglin, Chen Xueqin, Li Cao, Jiang Bingbing
Hubei Collaborative Innovation Center for Advanced Organic Chemical Materials, Key Laboratory for the Green Preparation and Application of Functional Materials of Ministry of Education, Hubei University, Wuhan, Hubei 430062, P. R. China.
J Mater Chem B. 2016 May 21;4(19):3387-3397. doi: 10.1039/c5tb02548f. Epub 2016 May 3.
Suitable protection strategies utilized in anticancer drug delivery systems enable carriers to reach their targeted positions and release drugs intracellularly more effectively. In this study, a novel "stealthy" chitosan (CHI)/mesoporous silica nanoparticle (MSN) based complex system, named DOX@MSN-SS-CHI-PEG, was developed for tumor-triggered intracellular drug release. CHI was applied to block the pores of MSNs to prevent premature drug release, whereas mPEG was grafted on the surface of the nanoparticles via a pH-sensitive benzoic imine linker to protect the carriers. As the pH of solid tumor tissues is slightly lower than that of normal tissues, mPEG could leave the nanoparticles to expose positively charged CHI at the surface, which enabled the nanoparticles to enter cancer cells more easily. The MSNs were covered by CHI via redox-sensitive disulfide bonds. As a result, the carriers could release the drug intercellularly to kill cancer cells owing to the high concentration of glutathione (GSH) in the cytosol. In vitro drug release studies at different GSH concentrations proved the redox-sensitivity of DOX@MSN-SS-CHI-PEG. mPEG leaving studies demonstrated that mPEG could leave the nanoparticles effectively at pH 6.0. The cytotoxicity and cell internalization behavior were also investigated in detail. In conclusion, the novel DOX@MSN-SS-CHI-PEG drug delivery system, which was "stealthy" in the physiological environment at pH 7.4 because of the protection of mPEG, was "activated" in weakly acidic tumor tissues to achieve tumor-triggered intracellular drug release; this system has great potential for cancer therapy.
抗癌药物递送系统中采用的合适保护策略可使载体到达其靶向位置并更有效地在细胞内释放药物。在本研究中，开发了一种新型的基于“隐形”壳聚糖（CHI）/介孔二氧化硅纳米颗粒（MSN）的复合系统，命名为DOX@MSN-SS-CHI-PEG，用于肿瘤触发的细胞内药物释放。应用CHI来封堵MSN的孔以防止药物过早释放，而通过pH敏感的苯甲酰亚胺连接子将甲氧基聚乙二醇（mPEG）接枝到纳米颗粒表面以保护载体。由于实体瘤组织的pH略低于正常组织，mPEG可离开纳米颗粒，使表面暴露出带正电荷的CHI，从而使纳米颗粒更容易进入癌细胞。MSN通过氧化还原敏感的二硫键被CHI覆盖。因此，由于胞质溶胶中谷胱甘肽（GSH）浓度高，载体可在细胞内释放药物以杀死癌细胞。在不同GSH浓度下的体外药物释放研究证明了DOX@MSN-SS-CHI-PEG的氧化还原敏感性。mPEG离去研究表明，mPEG在pH 6.0时可有效离开纳米颗粒。还详细研究了细胞毒性和细胞内化行为。总之，新型DOX@MSN-SS-CHI-PEG药物递送系统由于mPEG的保护在pH 7.4的生理环境中是“隐形”的，在弱酸性肿瘤组织中被“激活”以实现肿瘤触发的细胞内药物释放；该系统在癌症治疗方面具有巨大潜力。
