Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago 8380453, Chile.
Nanoscale. 2018 Dec 21;10(47):22612-22622. doi: 10.1039/c8nr06173d. Epub 2018 Nov 28.
Curcumin is widely considered beneficial to human health, but insolubility and instability greatly hamper reproducible exploitation of the advantageous traits. Here we report on the development, characterization and evaluation of a curcumin-loaded nanoemulsion (CUR-NEM) that is highly effective in preventing post-surgery tumor reincidence and metastasis. The method of fabrication utilized safe excipients and generated particles of 200 nm (PDI ≤ 0.2) with negative zeta potential (-30 mV) and a high yield of curcumin (95%), which can be converted by lyophilization to a dry powder. In vitro assays showed that CUR-NEM is safe in non-cancerous human cells (HEK-293T) and preferentially cytotoxic in gastric (AGS), colon (HT29-ATCC, HT29-US), breast (MDA-MB-231) and melanoma (B16F10) cells. In addition, in melanoma cells the nanoformulation increases intracellular curcumin accumulation and reactive oxygen species (ROS) formation, while preventing cell-migration and invasion. In vivo studies in C57BL/6 mice demonstrated that a single dose, applied topically to the wounded area after surgical excision of primary tumors formed upon subcutaneous injection of syngeneic B16F10 cells, was sufficient to completely prevent reincident tumor growth and spontaneous lung metastasis, while in untreated animals 70% reincidence and metastasis were observed. In vivo experiments also showed that the fluorescence signal due to curcumin was maintained at least 15 days after topical application of CUR-NEM, while when administered in DMSO the curcumin signal disappeared within 4 days. Importantly, the administration of a dose 22 times larger than that applied topically to animals after tumor surgery did not alter biochemical parameters. Due to the safety and efficacy of the formulation, we envisage it as ideal for topical application in cancer patients following surgery, to prevent tumor reincidence and metastasis. In addition, other routes of administration/protocols could also be proposed to treat/prevent malignant tumors in patients.
姜黄素被广泛认为对人类健康有益，但不溶性和不稳定性极大地阻碍了其有利特性的可重复开发。在这里，我们报告了一种姜黄素负载的纳米乳液（CUR-NEM）的开发、表征和评估，该纳米乳液在预防手术后肿瘤复发和转移方面非常有效。所采用的制备方法利用了安全的赋形剂，生成了粒径为 200nm（PDI≤0.2）、带负电荷（-30mV）的颗粒，姜黄素的产率很高（95%），可以通过冷冻干燥转化为干粉。体外试验表明，CUR-NEM 在非癌细胞（HEK-293T）中是安全的，并且在胃（AGS）、结肠（HT29-ATCC、HT29-US）、乳腺（MDA-MB-231）和黑色素瘤（B16F10）细胞中具有优先的细胞毒性。此外，在黑色素瘤细胞中，该纳米制剂增加了细胞内姜黄素的积累和活性氧（ROS）的形成，同时阻止了细胞迁移和侵袭。在 C57BL/6 小鼠体内研究中，单次剂量，在皮下注射同源 B16F10 细胞形成的原发性肿瘤切除后，局部应用于伤口部位，足以完全阻止复发肿瘤的生长和自发性肺转移，而在未治疗的动物中，70%观察到复发和转移。体内实验还表明，在局部应用 CUR-NEM 后，姜黄素的荧光信号至少可以维持 15 天，而在以 DMSO 给药时，姜黄素信号在 4 天内消失。重要的是，在肿瘤手术后给动物局部应用的剂量的 22 倍大时，不会改变生化参数。由于该制剂的安全性和有效性，我们设想它非常适合在癌症患者手术后局部应用，以预防肿瘤复发和转移。此外，还可以提出其他给药途径/方案来治疗/预防患者的恶性肿瘤。
