Möller Karin, Macaulay Beth, Bein Thomas
Department of Chemistry and Center for NanoScience, University of Munich (LMU), Butenandtstrasse 5-13, 81377 Munich, Germany.
Nanomaterials (Basel). 2021 Feb 15;11(2):489. doi: 10.3390/nano11020489.
The efficiency of anti-cancer drugs is commonly determined by endpoint assays after extended incubation times, often after days. Here we demonstrate that curcumin encapsulated in crosslinked cyclodextrin nanoparticles (CD-NP) acts extremely rapidly on cell metabolism resulting in an immediate and complete inhibition of cell growth and in efficient cancer-cell killing only few hours after incubation. This early onset of anti-cancer action was discovered by live-cell high-throughput fluorescence microscopy using an environmental stage. To date, only very few examples of covalently crosslinked nanoscale CD-based (CD-NP) drug carriers exist. Crosslinking cyclodextrins enables the adsorption of unusually high payloads of hydrophobic curcumin (762 µg CC/mg CD-NP) reflecting a molar ratio of 2.3:1 curcumin to cyclodextrin. We have investigated the effect of CD-NP encapsulated curcumin (CD-CC-NP) in comparison to free, DMSO-derived curcumin nanoparticles (CC-NP) on 4 different cell lines. Very short incubations times as low as 1 h were applied and cell responses after medium change were subsequently followed over two days. We show that cell proliferation is inhibited nearly immediately in all cell lines and that a cell- and concentration dependent cancer-cell killing occurs. Anti-cancer effects were similar with free and encapsulated curcumin, however, encapsulation in CD-NP drastically extends the long-term photostability and anti-cancer activity of curcumin. Curcumin-sensitivity is highest in HeLa cells reaching up to 90% cell death under these conditions. Sensitivity decreased from HeLa to T24 to MDA MB-231 cells. Strikingly, the immortalized non-cancerous cell line MCF-10A was robust against curcumin concentrations that were highly toxic to the other cell lines. Our results underline the potential of curcumin as gentle and yet effective natural anti-cancer agent when delivered solvent-free in stabilizing and biocompatible drug carriers such as CD-NP that enable efficient cellular delivery.
抗癌药物的疗效通常是在延长培养时间后，往往是数天之后，通过终点检测来确定的。在此，我们证明，包裹在交联环糊精纳米颗粒（CD-NP）中的姜黄素对细胞代谢作用极快，孵育仅数小时后就能立即且完全抑制细胞生长，并有效杀死癌细胞。这种抗癌作用的早期起效是通过使用环境载物台的活细胞高通量荧光显微镜发现的。迄今为止，共价交联的基于环糊精的纳米级（CD-NP）药物载体的例子非常少。交联环糊精能够吸附异常高含量的疏水性姜黄素（762 µg姜黄素/毫克CD-NP），这反映出姜黄素与环糊精的摩尔比为2.3:1。我们研究了与游离的、二甲基亚砜衍生的姜黄素纳米颗粒（CC-NP）相比，包裹在CD-NP中的姜黄素（CD-CC-NP）对4种不同细胞系的影响。应用了低至1小时的极短孵育时间，随后在更换培养基后跟踪细胞反应两天。我们表明，所有细胞系中的细胞增殖几乎立即受到抑制，并且发生了细胞和浓度依赖性的癌细胞杀伤。游离姜黄素和包裹姜黄素的抗癌效果相似，然而，包裹在CD-NP中极大地延长了姜黄素的长期光稳定性和抗癌活性。在这些条件下，HeLa细胞对姜黄素最为敏感，细胞死亡率高达90%。敏感性从HeLa细胞到T24细胞再到MDA MB-231细胞逐渐降低。引人注目的是，永生化的非癌细胞系MCF-10A对其他细胞系具有高毒性的姜黄素浓度具有抗性。我们的结果强调了姜黄素在以无溶剂方式递送至稳定且生物相容的药物载体（如CD-NP）中时，作为温和而有效的天然抗癌剂的潜力，这种载体能够实现高效的细胞递送。
