Department of Obstetrics and Gynecology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, People's Republic of China.
Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, Nanjing, 210009, People's Republic of China.
Drug Deliv Transl Res. 2021 Oct;11(5):1969-1982. doi: 10.1007/s13346-020-00859-5. Epub 2020 Oct 2.
Balancing the antitumor activity and systemic toxicity of tripterine still faces a big challenge due to the narrow therapeutic window. To address this issue, we report a microemulsion system based on tripterine, brucea oil, and glycyrrhizin, and dual modified with both transferrin and cell-penetrating peptide SA-RH (Tf/SA-RH-TBG-MEs) for combinational and tumor-targeted cancer therapy. Such a microemulsion exhibited a spherical shape with a size of ~50 nm and a mildly-negative charge. The half-maximal inhibitory concentration (IC) of Tf/SA-RH-TBG-MEs against ovarian cancer SKOV3 cells was 0.27 ± 0.43 μg tripterine/mL, which was 5.85 times lower than that of free tripterine. The cellular uptake of tripterine after treatment with Tf/SA-RH-TBG-MEs was 1.56 times higher than that of TBG-MEs (non-modified microemulsion). In pharmacokinetics studies, the area under the curve of Tf/SA-RH-TBG-MEs increased by 1.97 times compared with that of the physical mixture group. The tumoral accumulation of tripterine was significantly improved in Tf/SA-RH-TBG-MEs group than TBG-MEs-treated group. In antitumor efficacy in vivo, Tf/SA-RH-TBG-MEs exhibited the strongest inhibition of tumor growth and the longest survival period among all the groups, which is associated with the rational combination, microemulsion system, and dual modification with tumor-targeted ligands. Importantly, Tf/SA-RH-TBG-MEs significantly reduced the toxicity of tripterine against the liver and kidney. Our design provides a new approach for efficient and safe ovarian cancer therapy based on a multicomponent combination.
由于治疗窗口较窄，平衡汉防己甲素的抗肿瘤活性和全身毒性仍然面临巨大挑战。为了解决这个问题，我们报告了一种基于汉防己甲素、鸦胆子油和甘草酸的微乳液系统，并通过转铁蛋白和细胞穿透肽 SA-RH（Tf/SA-RH-TBG-MEs）进行双重修饰，用于联合和肿瘤靶向癌症治疗。这种微乳液呈球形，大小约为 50nm，带轻微负电荷。Tf/SA-RH-TBG-MEs 对卵巢癌 SKOV3 细胞的半最大抑制浓度（IC）为 0.27±0.43μg 汉防己甲素/mL，比游离汉防己甲素低 5.85 倍。Tf/SA-RH-TBG-MEs 处理后汉防己甲素的细胞摄取量比 TBG-MEs（未修饰的微乳液）高 1.56 倍。在药代动力学研究中，Tf/SA-RH-TBG-MEs 的曲线下面积与物理混合物组相比增加了 1.97 倍。与 TBG-MEs 处理组相比，Tf/SA-RH-TBG-MEs 组汉防己甲素在肿瘤中的积累明显增加。在体内抗肿瘤功效中，Tf/SA-RH-TBG-MEs 组表现出最强的肿瘤生长抑制作用和最长的生存时间，这与合理的组合、微乳液系统以及与肿瘤靶向配体的双重修饰有关。重要的是，Tf/SA-RH-TBG-MEs 显著降低了汉防己甲素对肝和肾的毒性。我们的设计为基于多组分组合的高效和安全卵巢癌治疗提供了一种新方法。
