具有改善的水溶性和肿瘤治疗潜力的含二茂铁的樟脑磺酰胺胶束形态。
Micellar Form of a Ferrocene-Containing Camphor Sulfonamide with Improved Aqueous Solubility and Tumor Curing Potential.
发表日期:2023 Feb 27
作者:
Maria Schröder, Maria Petrova, Georgi M Dobrikov, Georgy Grancharov, Denitsa Momekova, Petar D Petrov, Iva Ugrinova
来源:
Cell Death & Disease
摘要:
发现新型抗癌药物,比传统的化疗药物具有更高的特异性和减少了副作用,是当代医学研究和开发的巨大挑战。为了达到显著的疗效,抗肿瘤药物的设计可以将不同的生物活性亚基结合在一种分子中,它可以影响癌细胞中不同的调节途径。我们最近证明了一种新合成的有机金属化合物,一种含有二茂铁的樟脑磺酰胺(DK164),对乳腺和肺癌细胞具有良好的抑制增殖活性。然而,它仍然在生物液中遇到可溶性问题。在这项工作中,我们描述了一种新型的DK164胶束形式,在水介质中具有显著提高的溶解度。DK164被嵌入基于聚(乙二醇)-b-聚(α-肉桂基-ε-己内酯-co-ε-己内酯)-b-聚(乙二醇)三嵌段共聚物(PEO113-b-P(CyCL3-co-CL46)-b-PEO113)的可生物降解胶束中,并研究了所得到的体系的物理化学参数(大小、大小分布、ζ电位、封装效率)和生物活性。我们使用细胞毒性测定和流式细胞术来确定细胞死亡的类型,以及免疫细胞化学来评估封装药物对细胞关键蛋白(p53和NFkB)和自噬过程动力学的影响。根据我们的结果,有机金属二茂铁衍生物(DK164-NP)的胶束形式相比于游离物具有更高的代谢稳定性、更好的细胞摄取能力、改善的生物利用度和长期活性,保持了近乎相同的生物活性和抗癌性能。
The discovery of new anticancer drugs with а higher, more specific activity and diminished side effects than the conventional chemotherapeutic agents is a tremendous challenge to contemporary medical research and development. To achieve a pronounced efficacy, the design of antitumor agents can combine various biologically active subunits in one molecule, which can affect different regulatory pathways in cancer cells. We recently demonstrated that a newly synthesized organometallic compound, a ferrocene-containing camphor sulfonamide (DK164), possesses promising antiproliferative activity against breast and lung cancer cells. However, it still encounters the problem of solubility in biological fluids. In this work, we describe a novel micellar form of DK164 with significantly improved solubility in aqueous medium. DK164 was embedded in biodegradable micelles based on a poly(ethylene oxide)-b-poly(α-cinnamyl-ε-caprolactone-co-ε-caprolactone)-b-poly(ethylene oxide) triblock copolymer (PEO113-b-P(CyCL3-co-CL46)-b-PEO113), and the physicochemical parameters (size, size distribution, zeta potential, encapsulation efficiency) and biological activity of the obtained system were studied. We used cytotoxicity assays and flow cytometry to determine the type of cell death, as well as immunocytochemistry to assess the influence of the encapsulated drug on the dynamics of cellular key proteins (p53 and NFkB) and the process of autophagy. According to our results, the micellar form of the organometallic ferrocene derivate (DK164-NP) exhibited several advantages compared to the free substance, such as higher metabolic stability, better cellular uptake, improved bioavailability, and long-term activity, maintaining nearly the same biological activity and anticancer properties of the drug.