Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
J Drug Target. 2013 Aug;21(7):675-83. doi: 10.3109/1061186X.2013.796955. Epub 2013 May 16.
Triple negative breast cancer (TNBC) is a subtype of breast cancer characterized by its poor outcome and a lack of targeted therapies. Recently, our laboratory has developed a second generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidine-4-one (RL71) that shows potent in vitro cytotoxicity. RL71 is hydrophobic with poor bioavailability which limits its clinical development.
We have designed styrene-co-maleic acid (SMA) micelles encapsulating 5, 10 or 15% RL71 by weight/weight ratio to improve its solubility and pharmacokinetic profile.
The micelles charge, size and release rate were characterized. We evaluated their cytotoxicity against TNBC cell lines. The internalization of the drug inside the cells was measured by HPLC and the efficiency of the micelles was tested using a tumor spheroid model.
The micelles exhibited mean diameters of 125-185 nm and had a neutral charge. SMA-RL71 micelles have a cytotoxicity profile comparable to the free drug against several TNBC cell lines. Moreover, the 15% loaded micelles increased the stability of RL71 and demonstrated higher activity in a tumor spheroid model.
The current study demonstrates the efficiency of SMA for drug delivery, the influence of physicochemical characteristics on cytotoxicity, and provides the basis for preclinical testing in vivo.
三阴性乳腺癌（TNBC）是一种乳腺癌亚型，其预后较差，缺乏靶向治疗方法。最近，我们实验室开发了一种第二代姜黄素衍生物，3,5-双（3,4,5-三甲氧基苄叉基）-1-甲基哌啶-4-酮（RL71），具有很强的体外细胞毒性。RL71 具有疏水性和较差的生物利用度，这限制了它的临床开发。
我们设计了苯乙烯-马来酸共聚物（SMA）胶束，通过重量/重量比包封 5%、10%或 15%的 RL71，以提高其溶解度和药代动力学特性。
对胶束的电荷、粒径和释放率进行了表征。我们评估了它们对 TNBC 细胞系的细胞毒性。通过 HPLC 测量药物在细胞内的内化情况，并使用肿瘤球体模型测试胶束的效率。
胶束的平均粒径为 125-185nm，带中性电荷。SMA-RL71 胶束对几种 TNBC 细胞系的细胞毒性与游离药物相当。此外，负载 15%的胶束增加了 RL71 的稳定性，并在肿瘤球体模型中表现出更高的活性。
本研究证明了 SMA 在药物传递方面的效率、物理化学特性对细胞毒性的影响，并为体内临床前测试提供了依据。
