Xue Weiming, Liu Xiao-Li, Ma Heping, Xie Wensheng, Huang Saipeng, Wen Huiyun, Jing Guangyin, Zhao Lingyun, Liang Xing-Jie, Fan Hai Ming
School of Chemical Engineering, Northwest University, Xi'an, Shaanxi 710069, People's Republic of China.
J Mater Chem B. 2018 Apr 21;6(15):2289-2303. doi: 10.1039/c7tb03206d. Epub 2018 Apr 3.
DOX-loaded magnetic alginate-chitosan microspheres (DM-ACMSs) were developed as a model system to evaluate alternating magnetic field (AMF)-responsive, chemo-thermal synergistic therapy for multimodality postsurgical treatment of breast cancer. This multimodality function can be achieved by the combination of DOX for chemotherapy, with superparamagnetic iron oxide nanoparticles (SPIONs) as magnetic hyperthermia agents and drug release trigger. Both moieties are encapsulated in ACMSs which also allow on-demand drug release. It is demonstrated that the optimized SPION content in DM-ACMSs is about 0.29 mg Fe, at which DM-ACMSs could exhibit the best hyperthermia performance. Under a remote AMF, DM-ACMs can quickly reach a 22.5% cumulative drug release in the tumor site within 10 min upon exposure under AMF, whereas only 0.2% DOX is released in the absence of AMF. Furthermore, a comparison study of AMF and water bath as heating source indicates that the cumulative drug release amount upon AMF exposure is twice that by water bath heating. Further analysis revealed that the AMF stimulated drug release is driven by both thermal and concentration gradient from inside to outside, which can be well-described by the coupling mechanism of mass and heat transfer using the Soret diffusion model. In vitro cytotoxicity tests on MCF-7 breast cancer cells show that the combined therapy based on DM-ACMSs leads to 95.5% cell death, about 1.5-fold and 1.1-fold higher than that of single magnetic hyperthermia or chemotherapy, respectively. The in vivo anti-tumor effect on tumor-bearing mice demonstrates that the residual tumor disappears in 12 days after chemo-thermal synergistic treatment using DM-ACMSs, and there is no recurrence in the entire experiment period (40 days) as compared to 25 days recurrence for single-modality treatment. Our results not only provide an innovative DM-ACMSs system as a stimuli-responsive, synergistic chemo-thermal therapy platform for efficient reduction in the recurrence of breast cancer, but also provide insight into the intricate interplay of the functional components in magnetic hydrogel microspheres.
负载阿霉素的磁性海藻酸钠-壳聚糖微球（DM-ACMSs）被开发为一种模型系统，用于评估交变磁场（AMF）响应的化学热协同疗法，用于乳腺癌的多模态术后治疗。这种多模态功能可以通过将用于化疗的阿霉素与作为磁热疗剂和药物释放触发剂的超顺磁性氧化铁纳米颗粒（SPIONs）相结合来实现。这两种成分都包裹在ACMSs中，ACMSs还能实现按需药物释放。结果表明，DM-ACMSs中优化的SPION含量约为0.29 mg Fe，此时DM-ACMSs可表现出最佳的热疗性能。在远程AMF作用下，DM-ACMs在AMF作用下暴露10分钟内可在肿瘤部位迅速达到22.5%的累积药物释放，而在无AMF时仅释放0.2%的阿霉素。此外，以AMF和水浴作为加热源的比较研究表明，AMF作用下的累积药物释放量是水浴加热的两倍。进一步分析表明，AMF刺激的药物释放是由从内到外的热梯度和浓度梯度驱动的，这可以用索雷特扩散模型通过质量和热传递的耦合机制很好地描述。对MCF-7乳腺癌细胞的体外细胞毒性试验表明，基于DM-ACMSs的联合疗法导致95.5%的细胞死亡，分别比单一磁热疗或化疗高约1.5倍和1.1倍。对荷瘤小鼠的体内抗肿瘤作用表明，使用DM-ACMSs进行化学热协同治疗后12天残余肿瘤消失，与单模态治疗25天复发相比，在整个实验期（40天）内无复发。我们的结果不仅提供了一种创新的DM-ACMSs系统，作为一种刺激响应性、协同化学热疗法平台，用于有效降低乳腺癌的复发率，还深入了解了磁性水凝胶微球中功能成分的复杂相互作用。
