Functional Polymer Materials, Department of Chemistry and Pharmacy and Bavarian Polymer Institute, Würzburg University, Röntgenring 11, 97070 Würzburg, Germany.
University Hospital Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
J Control Release. 2019 Jun 10;303:162-180. doi: 10.1016/j.jconrel.2019.04.014. Epub 2019 Apr 11.
Curcumin (CUR) is a natural extract from the plant Curcuma longa and part of turmeric, a spice and herbal remedy in traditional medicine. Thousands of papers claim a plethora of health benefits by CUR, but a growing number of reports and contributions caution that many experimental data may be artifacts or outright deny any suitability of CUR due to its problematic physicochemical properties. Two major issues often encountered with CUR are its extraordinarily low solubility in water and its limited chemical stability. Here, we report on a novel nanoformulation of CUR that enables CUR concentrations in water of at least 50 g/L with relative drug loadings of >50 wt% and high dose efficacy testing in 3D tumor models. Despite this high loading and concentration, the CUR nanoformulation comprises polymer-drug aggregates with a size <50 nm. Most interestingly, this is achieved using an amphiphilic block copolymer, that by itself does not form micelles due to its limited hydrophilic/lipophilic contrast. The ultra-high loaded nanoformulations exhibit a very good stability, reproducibility and redispersibility. In order to test effects of CUR in conditions closer to an in vivo situation, we utilized a 3D tumor test system based on a biological decellularized tissue matrix that better correlates to clinical results concerning drug testing. We found that in comparison to 2D culture, the invasively growing breast cancer cell line MDA-MB-231 requires high concentrations of CUR for tumor cell eradication in 3D. In addition, we supplemented a 3D colorectal cancer model of the malignant cell line SW480 with fibroblasts and observed also in this invasive tumor model with stroma components a decreased tumor cell growth after CUR application accompanied by a loss of cell-cell contacts within tumor cell clusters. In a flow bioreactor simulating cancer cell dissemination, nanoformulated CUR prevented SW480 cells from adhering to a collagen scaffold, suggesting an anti-metastatic potential of CUR. This offers a rationale that the presented ultra-high CUR-loaded nanoformulation may be considered a tool to harness the full therapeutic potential of CUR.
姜黄素（CUR）是从植物姜黄中提取的天然提取物，也是传统医学中香料和草药疗法的一部分。数以千计的论文声称 CUR 具有多种健康益处，但越来越多的报告和贡献警告说，许多实验数据可能是假象，或者由于其有问题的物理化学性质而完全否认 CUR 的适用性。CUR 通常遇到的两个主要问题是其在水中的溶解度极低和化学稳定性有限。在这里，我们报告了一种 CUR 的新型纳米制剂，该制剂可使 CUR 在水中的浓度至少为 50g/L，相对药物载药量>50wt%，并在 3D 肿瘤模型中进行高剂量功效测试。尽管载药量和浓度如此之高，但 CUR 纳米制剂仍由聚合物-药物聚集体组成，其粒径<50nm。最有趣的是，这是使用一种两亲嵌段共聚物实现的，由于其亲水/亲脂性对比有限，该共聚物本身不会形成胶束。超负载纳米制剂表现出非常好的稳定性、重现性和再分散性。为了在更接近体内情况的条件下测试 CUR 的效果，我们利用了基于生物去细胞组织基质的 3D 肿瘤测试系统，该系统与药物测试的临床结果更相关。我们发现，与 2D 培养相比，侵袭性生长的乳腺癌细胞系 MDA-MB-231 需要高浓度的 CUR 才能在 3D 中消除肿瘤细胞。此外，我们在恶性细胞系 SW480 的 3D 结直肠癌模型中补充了成纤维细胞，并在具有基质成分的侵袭性肿瘤模型中也观察到，CUR 应用后肿瘤细胞生长减少，肿瘤细胞簇内的细胞-细胞接触丧失。在模拟癌细胞扩散的流动生物反应器中，纳米制剂 CUR 阻止了 SW480 细胞附着在胶原支架上，表明 CUR 具有抗转移潜力。这为以下观点提供了依据，即所提出的超高 CUR 负载纳米制剂可被视为利用 CUR 全部治疗潜力的工具。
