背景:甲氨蝶呤(MTX)是一种广泛用于治疗炎症性疾病和自身免疫性疾病的抗增殖药物。经皮给药的应用由于其较差的经皮渗透而受到阻碍。为了减少副作用并增强MTX的经皮给药,用两亲性阳离子材料制备的新型甲氨蝶呤(MTX)胶束,N,N-二甲基-(N',N'-二硬脂酰基-1-乙基)1,3-二氨基丙烷(DMSAP),是设计的。
方法:使用简单的化学试剂通过三个步骤合成DMSAP。使用H核磁共振和质谱来确认DMSAP的成功合成。一种安全无毒的磷脂酰胆碱,大豆磷脂酰胆碱(SPC),以不同比例添加到DMSAP中以形成P/D-胶束。然后,通过静电吸附制备了MTX包封的胶束(M/P/D-胶束)。彻底检查了胶束的理化性质和血液稳定性。此外,通过渗透实验评估胶束的透皮潜力。
结果:在水性环境中,DMSAP偶联物可以自发自组装成胶束,临界胶束浓度(CMC)低,为0.056mg/mL。稳定,制备了大小为100-120nm,高ζ电位为36.26mV的球形MTX包埋胶束(M/P/D-胶束)。体外渗透研究表明,与游离MTX相比,M/P/D胶束表现出优异的皮肤渗透性和MTX在表皮和真皮中的沉积。
结论:这些特殊的新型阳离子M/P/D胶束可以增强MTX的渗透性,有望成为治疗皮肤病的有前途的经皮给药系统。
BACKGROUND: Methotrexate (MTX) is an antiproliferative drug widely used to treat inflammatory diseases and autoimmune diseases. The application of percutaneous administration is hindered due to its poor transdermal penetration. To reduce side effects and enhanced percutaneous delivery of MTX, novel methotrexate (MTX)-loaded micelles prepared with a amphiphilic cationic material, N,N-dimethyl-(N\',N\'-di-stearoyl-1-ethyl)1,3-diaminopropane (DMSAP), was designed.
METHODS: DMSAP was synthesized via three steps using simple chemical agents. H nuclear magnetic resonance and mass spectroscopy were used to confirm the successful synthesis of DMSAP. A safe and non-toxic phosphatidylcholine, soybean phosphatidylcholine (SPC), was added to DMSAP at different ratios to form P/D-micelles. Then, MTX-entrapped micelles (M/P/D-micelles) were prepared by electrostatic adsorption. The physicochemical properties and blood stability of micelles were examined thoroughly. In addition, the transdermal potential of the micelles was evaluated by permeation experiments.
RESULTS: In aqueous environments, DMSAP conjugates could self-assemble spontaneously into micelles with a low critical micelle concentration (CMC) of 0.056 mg/mL. Stable, spherical MTX-entrapped micelles (M/P/D-micelles) with a size of 100-120 nm and high zeta potential of +36.26 mV were prepared. In vitro permeation studies showed that M/P/D-micelles exhibited superior skin permeability and deposition of MTX in the epidermis and dermis compared with that of free MTX.
CONCLUSIONS: These special novel cationic M/P/D-micelles can enhance the permeability of MTX and are expected to be a promising percutaneous delivery system for therapy skin diseases.