摘要
唑来膦酸（ZA）是第三代含氮双膦酸盐，是最有效的双膦酸盐之一，是一种高效的骨吸收抑制剂，对骨矿化无不良影响。它还可用于治疗多种癌症，如肺癌、骨癌、乳腺癌和前列腺癌。微流体系统可以在多个具有所需形状和尺寸的通道内产生可调节的流速和压力，这些通道通常由 PDMS 聚合物制成。这些系统的优点包括精确控制环境条件、减少用户干预、缩短时间和减少试剂用量。微流控方法是一种简单、经济、高效的工艺，可实现纳米粒子的粒度控制、窄粒度分布和球形形状。随着微流控技术的快速发展，用这种方法制备尺寸、形态和成分可控的颗粒将成为可能。据我们所知，本研究首次研究了微流控合成壳聚糖-唑来膦酸（CS-ZA）纳米粒子的细胞毒性活性，以期利用医药纳米技术开发新的癌症治疗策略。上一篇文章（Khayati et al., Int J Biol Macromol 234, 2023）详细介绍了通过壳聚糖（CS）与唑来膦酸（ZA）的离子凝胶化作用微流控合成具有窄尺寸分布和均匀形态的纳米粒子的方法。本研究旨在通过 MTT 细胞活力检测和流式细胞凋亡检测，评估以 ZA 溶液为核心流、CS 为鞘流，以及 ZA/CS = 0.5 的流量比（以 MFCSZA0.5 表示）合成的最佳微流控合成纳米粒子与合成的散装纳米粒子（BCSZA）对 A549 肺癌细胞系的细胞毒性效果。结果表明，MFCSZA0.5 的抗肿瘤活性明显高于 BCSZA 和游离ZA。与在散装条件下合成的 BCSZA 相比，MFCSZA0.5 微流体合成纳米粒子的体外药物释放呈现出渐进、持续的释放特征。不过，这两种纳米粒子都是很有前景的细胞内输送ZA分子的载体，而ZA分子最终会影响癌细胞的活力。与散装方法相比，微流控方法具有更高的药物夹带效率，而且药物的体外释放更可控。无论是微流控方法还是散装方法合成的纳米粒子，其抗癌效果都与游离ZA药物相当。Zoledronic acid (ZA), the third-generation nitrogen-containing bisphosphonate, is one of the most effective bisphosphonates and is used as a highly potent inhibitor of bone resorption with no adverse effects on bone mineralization. It is also used to treat multiple cancers, such as lung cancer, bone cancer, breast cancer, and prostate cancer. A microfluidic system can generate an adjustable flow rate and pressure inside multiple channels with the desired shape and dimensions, which are often fabricated from PDMS polymer. Among the advantages of these systems are precise control of environmental conditions, reduction of user intervention, and reduced time and reagent volumes. The microfluidic method, as a simple and cost-effective process with high capability, leads to particle size control, narrow size distribution, and the spherical shape of nanoparticles. With the rapid development of microfluidic technology, the preparation of particles with controlled size, morphology, and composition would be possible with this approach. In this study, to the best of our knowledge, the evaluation of the cytotoxic activity of microfluidic synthesized chitosan-zoledronic acid (CS-ZA) nanoparticles has been investigated for the first time in order to develop new cancer therapy strategies by using pharmaceutical nanotechnology. A microfluidic synthesis of nanoparticles with a narrow size distribution and uniform morphology through the ionic gelation of chitosan (CS) with ZA without a crosslinker was explained in detail in the previous article (Khayati et al., Int J Biol Macromol 234, 2023). This study aimed to evaluate the cytotoxic effect of the best microfluidic synthesized nanoparticles with ZA solution as core flow, CS as sheath flow, and flow ratios of ZA/CS = 0.5 (denoted by MFCSZA0.5) along with synthesized bulk nanoparticles (BCSZA) on the A549 lung cancer cell line through an MTT cell viability assay and a flow cytometric apoptosis assay. The results indicate that MFCSZA0.5 demonstrated significantly greater antitumor activity compared to BCSZA and free ZA. The in vitro drug release from MFCSZA0.5 microfluidic synthesized nanoparticles depicted a gradual, sustained release profile compared to BCSZA synthesized in bulk conditions. However, both of these nanoparticles exhibit promising carriers for intracellular delivery of ZA molecules, which ultimately affect cancer cell viability. The microfluidic method demonstrated a high drug entrapment efficiency compared to the bulk method, and it showed a more controlled in-vitro release of the drug. The synthesized nanoparticles in both microfluidic and bulk methods were found to have an anticancer effect comparable to the free ZA drug.
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