Gao Zhiguo, Li Yaojia, You Chaoqun, Sun Kai, An Peijing, Sun Chen, Wang Mingxin, Zhu Xiaoli, Sun Baiwang
School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210089, PR China.
Department of Respiratory Medicine, The Affiliated Zhongda Hospital of Southeast University, Nanjing 210096, PR China.
ACS Appl Bio Mater. 2018 Aug 20;1(2):270-280. doi: 10.1021/acsabm.8b00056. Epub 2018 Jul 20.
Combination therapy with multiple drugs through a multi-pronged assault as a strategy to combat cisplatin resistance shows great potential in biochemical therapy for cancer. However, inherent issues such as low drug loading and the poor synergistic effects of multiple drugs partially limit the further application of combination therapy. Here, we synthesized a new compound, ART-Chol, by coupling artemisinin and cholesterol as a base material combined with cyclic (Arg-Gly-Asp-d-Phe-Lys)]-poly(ethylene glycol) distearoylphosphatidylcholine (cRGD-PEG-DSPE) and phospholipids to form a magnetic liposome cRGD-AFePt@NPs encapsulating superparamagnetic ferric oxide nanoparticles and cisplatin for achieving high drug loading and a better synergistic effect. The cRGD-AFePt@NPs could be effectively internalized and responsively release loading cargos under alternating magnetic field irradiation due to local hyperthermia generated from magnetic nanoparticles by hysteresis loss and Néel relaxation. The generated Fe/Fe from FeO NPs in the acid lysosomes motivated cisplatin and catalyzed the Fe-dependent anticancer drug artemisinin (ART) to generate highly toxic ROS through the Fenton reaction, which greatly enhances the anticancer effect of cisplatin with minimized side effects. In vitro cytotoxicity tests demonstrated that the cRGD-AFePt@NPs exhibited a 15.17-fold lower IC value of free cisplatin (IC = 32.47 μM) against A549/R cells. Further flow-cytometry tests also showed obviously increased intracellular ROS generation and cell apoptosis rates. We highlight the potential for Fe/Fe-mediated combination therapy of cisplatin and ART for circumventing cisplatin drug resistance.
通过多管齐下的联合多种药物的治疗策略来对抗顺铂耐药性，在癌症的生化治疗中显示出巨大潜力。然而，诸如药物负载量低和多种药物协同效果差等固有问题在一定程度上限制了联合治疗的进一步应用。在此，我们合成了一种新化合物ART-Chol，它是通过将青蒿素与胆固醇偶联作为基础材料，再与环（精氨酸-甘氨酸-天冬氨酸-d-苯丙氨酸-赖氨酸）-聚乙二醇二硬脂酰磷脂酰胆碱（cRGD-PEG-DSPE）和磷脂结合，形成一种磁性脂质体cRGD-AFePt@NPs，其包裹超顺磁性氧化铁纳米颗粒和顺铂，以实现高药物负载量和更好的协同效果。由于磁滞损耗和奈尔弛豫导致磁性纳米颗粒产生局部热疗，cRGD-AFePt@NPs能够在交变磁场照射下有效地被内化并响应性地释放负载的货物。酸性溶酶体中FeO NPs产生的Fe/Fe促使顺铂并催化铁依赖性抗癌药物青蒿素（ART）通过芬顿反应产生高毒性的ROS，这极大地增强了顺铂的抗癌效果，同时副作用最小化。体外细胞毒性测试表明，cRGD-AFePt@NPs对A549/R细胞的半数抑制浓度（IC）值比游离顺铂（IC = 32.47 μM）低15.17倍。进一步的流式细胞术测试还显示细胞内ROS生成和细胞凋亡率明显增加。我们强调了Fe/Fe介导的顺铂和ART联合治疗规避顺铂耐药性的潜力。
