Background: Therapeutic efficiency of ceragenins against cancers may be limited by lack of their hemocompatibility when high concentrations of molecules are required to reach a desired result. Synergistic effects observed upon administration of anticancer agents and metal nanoparticles may provide an opportunity to limit toxicity of immobilized ceragenins on the surface of metal nanoparticles and to improve their therapeutic efficiency at the same time. The aim of present work is to investigate the anticancer activities and hemocompatibility of nanoformulations consisting of ceragenin CSA-131 united with aminosilane-modified iron oxide-based magnetic nanoparticles (MNP) and prepared by 1) covalent bonding (MNP@CSA-131) or 2) by combining CSA-131 with MNP in 1:1 ratio (CSA-131 + MNP). Possible synergistic interactions between CSA-131 and magnetic nanoparticles were also quantified.
Methods: MNP@CSA-131 and CSA-131+MNP were tested in vitro against selected lung and colon cancer cells using colorimetric, fluorimetric and flow cytometry methods.
Results: Performed analysis demonstrates that MNP-based nanosystems significantly improve the killing efficiency of tested ceragenin, decreasing the viability of extra 1.37± 4.72% to 76.07± 15.30% cancer cells when compared to free CSA-131. Quantification of synergistic effects indicates the favorable interactions between CSA-131 and magnetic nanoparticles (CI < 1 for all tested doses), revealing at the same time a reduction in effective doses of ceragenin from 1.17 ± 0.61 to 34.57 ± 12.78 times when combined with MNP. We demonstrate that both MNP@CSA-131 and CSA-131+MNP induce significantly apoptosis of cancer cells and prevent the division of colon cancer cells even at relatively low doses of the active compound (10 μg/mL). Importantly, combining CSA-131 with MNP decreases the hemolytic activity of free ceragenin 4.72 to 7.88 times, which indicates a considerable improvement of hemotoxicity profile.
Conclusion: Comparative analyses have revealed that both developed CSA-containing nanoformulations due to the utility of synergistic interactions between MNP and CSA-131, which are effective against lung and colon cancer cells. This indicates the new directions in preparation of MNP-based therapeutics, which are relatively easy to synthetize, cost-effective and safe when intravenously administrated.



中文翻译：

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量化 Ceragenin CSA-131 与氧化铁磁性纳米颗粒联合抗癌细胞的协同作用。

背景：当需要高浓度的分子来达到预期的结果时，角质素对癌症的治疗效率可能会因缺乏血液相容性而受到限制。在施用抗癌剂和金属纳米颗粒时观察到的协同作用可能提供机会来限制固定化的角质素在金属纳米颗粒表面上的毒性并同时提高它们的治疗效率。本工作的目的是研究由 ceragenin CSA-131 与氨基硅烷修饰的氧化铁基磁性纳米粒子 (MNP) 结合并通过 1) 共价键合 (MNP@CSA-131) 或制备的纳米制剂的抗癌活​​性和血液相容性2) 通过将 CSA-131 与 MNP 以 1:1 的比例组合 (CSA-131 + MNP)。
方法： MNP@CSA-131 和 CSA-131+MNP 使用比色法、荧光法和流式细胞术方法在体外对选定的肺癌和结肠癌细胞进行了测试。
结果：进行的分析表明，与游离 CSA-131 相比，基于 MNP 的纳米系统显着提高了测试的 ceragenin 的杀伤效率，将额外的 1.37± 4.72% 癌细胞的生存能力降低至 76.07± 15.30%。协同效应的量化表明 CSA-131 与磁性纳米颗粒之间存在良好的相互作用（所有测试剂量的 CI < 1），同时表明当与 MNP 结合时，ceragenin 的有效剂量从 1.17 ± 0.61 减少到 34.57 ± 12.78 倍. 我们证明 MNP@CSA-131 和 CSA-131+MNP 均能显着诱导癌细胞凋亡并防止结肠癌细胞分裂，即使在相对低剂量的活性化合物（10 μg/mL）下也是如此。重要的是，将 CSA-131 与 MNP 结合使用可将游离角质素的溶血活性降低 4.72 至 7.88 倍，
结论：比较分析表明，由于 MNP 和 CSA-131 之间的协同相互作用，两者都开发了含有 CSA 的纳米制剂，这些纳米制剂对肺癌和结肠癌细胞有效。这表明了制备基于 MNP 的治疗药物的新方向，这些药物在静脉内给药时相对容易合成、具有成本效益且安全。