Duan Xiao, Wang Qiang, Wang Yue, Liu Xinping, Lu Manman, Li Zhifang, Jiang Xuelian, Ji Jingquan
Changzhi Key Laboratory of Drug Molecular Design and Innovative Pharmaceutics, Shanxi Provincial Department-Municipal Key Laboratory Cultivation Base for Quality Enhancement and Utilization of Shangdang Chinese Medicinal Materials, School of Pharmacy, Changzhi Medical College, Changzhi 046000, China.
The Stem Cell and Tissue Engineering Research Center, Changzhi Medical College, Changzhi 046000, China.
Pharmaceutics. 2024 Sep 6;16(9):1178. doi: 10.3390/pharmaceutics16091178.
Using an endogenous carrier is the best method to address the biocompatibility of carriers in the drug delivery field. Herein, we prepared a glutathione-responsive paclitaxel prodrug micelle based on an endogenous molecule of L-glutathione oxidized (GSSG) for cancer therapy using one-pot synthesis. The carboxyl groups in L-glutathione oxidized were reacted with the hydroxyl group in paclitaxel (PTX) using the catalysts dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). Then, the amino-polyethylene glycol monomethyl ether (mPEG-NH) was conjugated with GSSG to prepare PTX-GSSG-PEG. The structure of PTX-GSSG-PEG was characterized using infrared spectroscopy (FT-IR), nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry (MS). The drug release kinetics of PTX within PTX-GSSG-PEG were quantified using ultraviolet spectroscopy (UV-Vis). The size of the PTX-GSSG-PEG micelles was 83 nm, as evaluated using dynamic light scattering (DLS), and their particle size remained stable in a pH 7.4 PBS for 7 days. Moreover, the micelles could responsively degrade and release PTX in a reduced glutathione environment. The drug loading of PTX in PTX-GSSG-PEG was 13%, as determined using NMR. Furthermore, the cumulative drug release rate of PTX from the micelles reached 72.1% in a reduced glutathione environment of 5 mg/mL at 120 h. Cell viability experiments demonstrated that the PTX-GSSG-PEG micelles could induce the apoptosis of MCF-7 cells. Additionally, cell uptake showed that the micelles could distribute to the cell nuclei within 7 h. To sum up, with this glutathione-responsive paclitaxel prodrug micelle based on the endogenous molecule GSSG, it may be possible to develop novel nanomedicines in the future.
使用内源性载体是解决药物递送领域中载体生物相容性的最佳方法。在此，我们基于氧化型L-谷胱甘肽（GSSG）这一内源性分子，通过一锅法合成制备了用于癌症治疗的谷胱甘肽响应型紫杉醇前药胶束。使用二环己基碳二亚胺（DCC）和4-二甲氨基吡啶（DMAP）作为催化剂，使氧化型L-谷胱甘肽中的羧基与紫杉醇（PTX）中的羟基发生反应。然后，将氨基聚乙二醇单甲醚（mPEG-NH）与GSSG偶联以制备PTX-GSSG-PEG。使用红外光谱（FT-IR）、核磁共振光谱（NMR）和质谱（MS）对PTX-GSSG-PEG的结构进行了表征。使用紫外可见光谱（UV-Vis）对PTX在PTX-GSSG-PEG中的药物释放动力学进行了定量分析。通过动态光散射（DLS）评估，PTX-GSSG-PEG胶束的尺寸为83 nm，并且其粒径在pH 7.4的磷酸盐缓冲盐溶液（PBS）中7天内保持稳定。此外，胶束能够在还原型谷胱甘肽环境中响应性降解并释放PTX。使用NMR测定，PTX在PTX-GSSG-PEG中的载药量为13%。此外，在5 mg/mL的还原型谷胱甘肽环境中，120 h时PTX从胶束中的累积药物释放率达到72.1%。细胞活力实验表明，PTX-GSSG-PEG胶束可诱导MCF-7细胞凋亡。此外，细胞摄取实验表明，胶束可在7 h内分布到细胞核中。综上所述，基于内源性分子GSSG的这种谷胱甘肽响应型紫杉醇前药胶束，未来可能开发出新型纳米药物。
