[论文解读] Superparamagnetic iron oxide nanoparticles conjugated with doxorubicin for targeting breast cancer

Enrico Catalano|arXiv (Cornell University)|Nov 13, 2019

Nanoparticle-Based Drug Delivery被引用 6

一句话总结

本研究开发了与多柔比星（DOX）结合的超顺磁性铁氧化 nanoparticle（SPIONs），用于靶向乳腺癌治疗。DOX-SPIONs 通过增强的细胞摄取和磁力 hyperthermia 实现双重作用，显著抑制了 MCF-7 和 MDA-MB-231 细胞的增殖，表现出协同细胞毒性，显示出作为化疗热疗剂的潜力。

ABSTRACT

Development of the next generations of cancer therapy modalities is currently a crucial requirement of oncology. Advances in nanotechnology are bringing us closer to the development of dual and multifunctional nanoparticles that are challenging the traditional distinction between diagnostic and treatment agents. The chase of innovative, multifunctional, more efficient, and safer treatments is a major challenge in preclinical nanoparticle-mediated thermotherapeutic research for breast cancer. Here, we report that iron oxide nanoparticles have the dual capacity to act as both magnetic and drug delivery agents. The aim of this work was to investigate the in vitro effect of the loading of doxorubicin (DOX) on negatively charged polycarboxylic iron-oxide nanoparticles (SPIONs) and Rhodamine B functionalized SPIONs on breast carcinoma cell lines. For proper analysis and understanding of cell behavior after administration of DOX-SPIONs compared with free DOX, a complex set of in vitro tests, including production of MTT assay, cell cycle determination, and cellular uptake, were utilized. In summary, we have developed a magnetic nanoparticle-based drug delivery system that sequentially delivers the cytotoxic drug doxorubicin to breast cancer cells (MCF-7 and MDA-MB-231). The drug-coated nanoparticles, DOX-NPs, were assembled stepwise, with doxorubicin adsorbed to bare iron oxide nanoparticles first, by electrostatic reaction and allowed for the complexation of doxorubicin. In contrast, they were internalized to a much greater extent in MCF-7 and MDA-MB-231 cells and were cytotoxic due to the synergistic action of the two drugs and the effects of hyperthermia. The drug-coated particles were able to inhibit growth and proliferation of breast cancer cells in vitro, indicating that the system has potential to act as an antimetastatic chemothermotherapeutic agent.

研究动机与目标

• 开发一种结合磁力靶向与药物递送的多功能 nanoparticle 系统，用于乳腺癌治疗。
• 研究负载 DOX 的 SPIONs 在乳腺癌细胞系中的体外疗效。
• 评估多柔比星与磁力 hyperthermia 在抑制癌细胞增殖方面的协同效应。
• 比较 DOX-SPIONs 与游离多柔比星在细胞摄取和细胞毒性方面的差异。
• 评估 DOX-SPIONs 作为抗转移性化疗热疗剂的潜力。

提出的方法

• 合成带负电荷的聚羧酸超顺磁性铁氧化 nanoparticle（SPIONs）。
• 通过静电相互作用分步将多柔比星（DOX）偶联至 SPIONs。
• 使用罗丹明 B 对 SPIONs 进行功能化，以实现细胞摄取的荧光追踪。
• 通过 MTT 检测评估细胞毒性和细胞活力。
• 进行细胞周期分析，以评估药物诱导的细胞周期阻滞。
• 利用荧光显微镜和流式细胞术定量 DOX-SPIONs 的细胞摄取。

实验结果

研究问题

• RQ1 与游离 DOX 相比，DOX-SPIONs 是否能显著增强 MCF-7 和 MDA-MB-231 乳腺癌细胞的细胞摄取和细胞毒性？
• RQ2 DOX 与磁力 hyperthermia 对癌细胞增殖的协同效应如何？
• RQ3 SPIONs 的表面电荷如何影响 DOX 的负载和递送效率？
• RQ4 DOX-SPIONs 在多大程度上抑制乳腺癌细胞的细胞周期进展？
• RQ5 DOX-SPIONs 是否可作为兼具成像与靶向治疗功能的双重功能剂？

主要发现

• 与游离多柔比星相比，DOX-SPIONs 在 MCF-7 和 MDA-MB-231 细胞中的内化程度显著更高。
• 由于多柔比星与磁力 hyperthermia 的协同作用，DOX-SPIONs 展现出增强的细胞毒性。
• DOX-SPIONs 处理后，两种细胞系的细胞活力均显著降低，表明有效抑制了细胞生长。
• 细胞周期分析显示，DOX-SPIONs 诱导细胞周期阻滞于 G2/M 期，与多柔比星的作用机制一致。
• 荧光追踪证实 DOX-SPIONs 实现了高效的细胞内递送，支持其作为靶向治疗的潜力。
• 该系统在体外表现出作为双重功能抗转移性化疗热疗剂的潜力。