Department of Chemical & Biomolecular Engineering, Faculty of Engineering, National University of Singapore, Block E5 02-11, 4 Engineering Drive 4, Singapore 117576, Singapore.
Int J Pharm. 2012 Nov 15;438(1-2):98-106. doi: 10.1016/j.ijpharm.2012.08.038. Epub 2012 Aug 29.
Double emulsion has been used most often in formulation of hydrophilic drugs by nanoparticles of biodegradable polymers, which has disadvantages such as low drug loading and low drug encapsulation efficiency due to the drug loss in the process. The drug release may be too fast for sustained chemotherapy. We developed in this research a D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) prodrug micelle system with cisplatin as a model hydrophilic drug. We demonstrated that such a system can successfully deliver the model hydrophilic drug with a low critical micelle concentration (CMC) of only 5.01 mg/L, a high drug load of 4.95% (w/w) and a pH-responsive drug release kinetics and higher cellular uptake in comparison with the original drug and the TPGS-cisplatin prodrug itself. The cell viability experiment showed great enhancement of the cisplatin chemotherapy, which is demonstrated by the IC50 value reduced from 3.95, 0.98, 0.19 for cisplatin to 1.36, 0.51, 0.08 μg/mL for the TPGS prodrug micelle formulation after 24, 48, 72 h culture with the HepG2 hepatocarcinoma cells, respectively. Furthermore, such a TPGS prodrug micellar formulation showed significant neuroprotective effects for the cisplatin chemotherapy, which is demonstrated by the greatly increased IC50 value for the SH-SY5Y neuroblast-like cells in comparison between cisplatin and the TPGS prodrug micelle formulation. The TPGS prodrug micelles can also be generalized to become a new strategy for codelivery of hydrophilic and hydrophobic drugs and/or imaging agents.
双乳液最常用于通过可生物降解聚合物的纳米粒子来制备亲水性药物的制剂，但由于药物在该过程中的损失，存在载药量低和药物包封效率低等缺点。对于持续的化学疗法，药物释放可能过快。我们在这项研究中开发了一种 D-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）前药胶束系统，以顺铂为模型亲水性药物。我们证明，与原始药物和 TPGS-顺铂前药本身相比，这种系统可以成功地递送电镜亲水性药物，其临界胶束浓度（CMC）低至 5.01mg/L，药物载药量高至 4.95%（w/w），且具有 pH 响应性药物释放动力学和更高的细胞摄取率。细胞活力实验表明，顺铂化疗效果大大增强，这表现为 HepG2 肝癌细胞培养 24、48 和 72 h 后，IC50 值分别从顺铂的 3.95、0.98 和 0.19μg/mL 降低到 TPGS 前药胶束制剂的 1.36、0.51 和 0.08μg/mL。此外，与顺铂相比，TPGS 前药胶束制剂对顺铂化疗具有显著的神经保护作用，SH-SY5Y 神经母细胞瘤样细胞的 IC50 值大大增加。TPGS 前药胶束还可以推广成为亲水性和疏水性药物和/或成像剂共递送的新策略。
