Drug Design and Discovery Research Group, College of Pharmacy and Nutrition.
Department of Chemistry, University of Saskatchewan, Saskatoon, SK, Canada.
Int J Nanomedicine. 2016 Dec 12;11:6703-6712. doi: 10.2147/IJN.S121156. eCollection 2016.
Novel drug delivery systems are developed to improve the biological behavior of poorly soluble drugs and to improve therapeutic outcomes. In melanoma therapy, the goal is efficient drug delivery and mitigation of drug resistance. Melphalan (Mel), a currently used therapeutic agent for melanoma, requires solvent system for solubilization, leading to poor chemical stability. Moreover, drug resistance often renders the drug inefficient in clinical setting. A novel β-cyclodextrin-modified gemini surfactant (CDgemini) delivery system was developed to incorporate Mel in order to improve its physicochemical and biological behavior. Melphalan nanoparticles (Mel-NP) showed optimal particle size in the 200-250 nm range for endocytosis and induced significantly higher cell death compared with Mel (50% of inhibitory concentration [IC] of 36 µM for the complexes vs 82 µM for Mel). The CDgemini delivery system did not alter the pathway of the cellular death triggered by Mel and caused no intrinsic toxicity to the cells. The Mel-NP complexes induced significant cell death in melanoma cells that were rendered resistant to Mel. These findings demonstrate in principle the applicability of the CDgemini delivery system as safe and efficient alternative to the current melanoma therapy, especially in chemoresistant cases.
新型药物传递系统旨在改善难溶性药物的生物学行为，并提高治疗效果。在黑色素瘤治疗中，目标是实现有效的药物传递和减轻药物耐药性。美法仑（Mel）是目前用于黑色素瘤的治疗药物，需要溶剂系统来溶解，导致化学稳定性差。此外，药物耐药性常常使药物在临床应用中无效。为了改善其物理化学和生物学行为，开发了一种新型β-环糊精修饰的双子表面活性剂（CDgemini）传递系统来包载美法仑。美法仑纳米粒（Mel-NP）的最佳粒径范围在 200-250nm 之间，有利于内吞作用，并与美法仑相比诱导更高的细胞死亡（复合物的 50%抑制浓度 [IC] 为 36µM，而美法仑为 82µM）。CDgemini 传递系统不改变 Mel 触发的细胞死亡途径，对细胞没有内在毒性。Mel-NP 复合物在对 Mel 耐药的黑色素瘤细胞中诱导了显著的细胞死亡。这些发现原则上证明了 CDgemini 传递系统作为当前黑色素瘤治疗的安全有效替代方案的适用性，特别是在化疗耐药的情况下。
