依克立达双重敏感纳米递药系统的构建及其逆转多药耐药的考察

Construction of a Dual Sensitive Nanocarrier Delivery System Loaded with Elacridar and Its Reversal Effect on Multidrug Resistance

将聚乙二醇(PEG)以二硫键连接到聚酰胺-胺(PAMAM)树状大分子表面构建还原-pH双重敏感纳米载体(PSSP),再用其包载多药耐药逆转剂依克立达(1)。所得载药纳米粒(PSSP/1)平均粒径(19.3±3.4)nm,z电位(+1.83±0.13)mV,载药量和包封率分别为(7.5±0.9)%和(82.3±3.5)%。体外释放试验表明,PSSP/1纳米粒的释放具有明显的还原和p H敏感性。通过体外毒性试验考察1或PSSP/1纳米粒与多柔比星(2)联合用药对乳腺癌耐药细胞系MCF-7/ADR多药耐药的逆转作用。结果表明,1和PSSP/1纳米粒均能显著增强2对MCF-7/ADR的细胞毒性,呈现出耐药逆转效果。逆转效率随PSSP/1纳米粒中1浓度的升高而增强,呈现剂量依赖关系。并且,PSSP/1纳米粒的耐药逆转效果优于游离1。

To entrap elacridar （1）, a reversal agent of multidrug resistance （MDR）, a redox and pH dual sensitive nanocarrier （PSSP） was constructed by introducing disulfide bonds to link the polyethylene glycol （PEG） and polyamidoamine （PAMAM） dendrimier. The average diameter, ζ potential, drug loading and encapsulation efficiency of the 1-loaded nanoparticles （PSSP/1） were （19.3±3.4） nm, （＋1.83±0.13） mV, （7.5±0.9） % and （82.3±3.5） %, respectively. The results of in vitro drug release test suggested that the release behavior of 1 from the PSSP/1 nanoparticles had an obvious sensitivity to redox and pH. Moreover, the reversal effects of free 1 and PSSP/1 nanoparticles in combination with doxorubicin （2） on the 2-resistant breast cancer cell line MCF-7/ADR were investigated by in vitro cytotoxicity test. The results showed that both 1 and PSSP/1 nanoparticles could significantly enhance the cell toxicity of 2 against MCF-7/ADR cells at different doses. Meanwhile, the reversal effect was promoted with the increasing of 1 concentration in PSSP/1 nanoparticles in a dose-dependent manner. Moreover, the reversal effect of PSSP/1 nanoparticles was superior to that of free 1.