Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology and Biopharmacy, University of Freiburg, Sonnenstraße 5, 79104 Freiburg, Germany.
Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology and Biopharmacy, University of Freiburg, Sonnenstraße 5, 79104 Freiburg, Germany.
Eur J Pharm Biopharm. 2019 Jul;140:20-28. doi: 10.1016/j.ejpb.2019.04.013. Epub 2019 Apr 20.
Liposomes are a popular formulation strategy for the delivery of anticancer drugs. While their benefits for formulating hydrophilic anticancer drugs have been clearly shown during the last decades, the suitability of liposomes for the delivery of hydrophobic drugs is questionable. Curcumin is a diphenolic plant compound that is extensively researched for its anticancer properties. It was chosen as a hydrophobic model drug in this study. Due to its low bioavailability, poor solubility and instability in aqueous media it is a highly problematic compound and requires particular formulation techniques. Curcumin liposomes with lipids of different rigidities were comprehensively investigated in respect to their physicochemical properties, their storage and serum stability. In vitro experiments were conducted with common 2D cell models and additionally with multicellular tumor spheroids (MCTS) as a more sophisticated tool to represent the physiology of avascular solid tumors. Our results indicate that liposomes containing the fluid phospholipid dioleoylphosphatidylcholine (DOPC) represent an excellent formulation to enhance the solubility and stability of curcumin. However, in presence of serum or cells, curcumin is rapidly released from the protecting and stabilizing lipid bilayer. Thus, improvement of the in vivo efficacy of curcumin is probably not achieved by using liposomes. Cytotoxicity and uptake experiments showed clearly a reduced effectivity of curcumin liposomes in the 3D cell model in comparison to the 2D model. This not only illustrates the limitations of monolayer cultures in predicting drug and nanocarrier interactions with solid tumors, but also further questions the use of liposomes as a formulation strategy in the treatment of solid tumors with curcumin.
脂质体是一种常用于递呈抗癌药物的制剂策略。尽管在过去几十年中，脂质体在递呈亲水性抗癌药物方面的优势已经得到了充分证明，但脂质体递呈疏水性药物的适用性仍存在争议。姜黄素是一种二酚类植物化合物，因其抗癌特性而受到广泛研究。在本研究中，它被选为疏水性模型药物。由于其生物利用度低、在水介质中的溶解度差和不稳定性，它是一种极具挑战性的化合物，需要特殊的制剂技术。本研究全面研究了不同刚性脂质的姜黄素脂质体的理化性质、储存稳定性和血清稳定性。进行了体外实验，使用常见的 2D 细胞模型，另外还使用了多细胞肿瘤球体（MCTS）作为更复杂的工具来模拟无血管实体瘤的生理学。我们的研究结果表明，含有流体磷脂二油酰基磷脂酰胆碱（DOPC）的脂质体是一种增强姜黄素溶解度和稳定性的优秀制剂。然而，在存在血清或细胞的情况下，姜黄素会迅速从保护和稳定的脂质双层中释放出来。因此，通过使用脂质体来提高姜黄素的体内疗效可能无法实现。细胞毒性和摄取实验清楚地表明，与 2D 模型相比，3D 细胞模型中姜黄素脂质体的效果明显降低。这不仅说明了单层培养在预测药物和纳米载体与实体瘤相互作用方面的局限性，也进一步质疑了使用脂质体作为姜黄素治疗实体瘤的制剂策略的适用性。
