Institution of Nanochemistry and Nanobiology, School of Environmental and Chemical Engineering, Shanghai University, Shanghai, 200444, China.
School of Medicine, Shanghai University, Shanghai, 200444, China.
Drug Deliv Transl Res. 2023 Nov;13(11):2885-2902. doi: 10.1007/s13346-023-01357-0. Epub 2023 May 6.
Kaempferol (KAE) is a naturally occurring flavonoid compound with antitumor activity. However, the low aqueous solubility, poor chemical stability, and suboptimal bioavailability greatly restrict its clinical application in cancer therapy. To address the aforementioned limitations and augment the antitumor efficacy of KAE, we developed a kaempferol nanosuspensions (KAE-NSps) utilizing D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) as a stabilizing agent, screened the optimal preparation process, and conducted a comprehensive investigation of their fundamental properties as well as the antitumor effects in the study. The findings indicated that the particle size was 186.6 ± 2.6 nm of the TPGS-KAE-NSps optimized, the shape of which was fusiform under the transmission electron microscope. The 2% (w/v) glucose was used as the cryoprotectant for TPGS-KAE-NSps, whose drug loading content was 70.31 ± 2.11%, and the solubility was prominently improved compared to KAE. The stability and biocompatibility of TPGS-KAE-NSps were favorable and had a certain sustained release effect. Moreover, TPGS-KAE-NSps clearly seen to be taken in the cytoplasm exhibited a stronger cytotoxicity and suppression of cell migration, along with increased intracellular ROS production and higher apoptosis rates compared to KAE in vitro cell experiments. In addition, TPGS-KAE-NSps had a longer duration of action in mice, significantly improved bioavailability, and showed a stronger inhibition of tumor growth (the tumor inhibition rate of high dose intravenous injection group was 68.9 ± 1.46%) than KAE with no obvious toxicity in 4T1 tumor-bearing mice. Overall, TPGS-KAE-NSps prepared notably improved the defect and the antitumor effects of KAE, making it a promising nanodrug delivery system for KAE with potential applications as a clinical antitumor drug.
山奈酚（KAE）是一种具有抗肿瘤活性的天然黄酮类化合物。然而，其低水溶性、差的化学稳定性和不理想的生物利用度极大地限制了其在癌症治疗中的临床应用。为了解决上述限制并增强 KAE 的抗肿瘤功效，我们利用 D-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）作为稳定剂开发了山奈酚纳米混悬剂（KAE-NSps），筛选了最佳的制备工艺，并对其基本性质以及抗肿瘤作用进行了全面研究。结果表明，优化后的 TPGS-KAE-NSps 的粒径为 186.6±2.6nm，在透射电子显微镜下呈梭形。2%（w/v）葡萄糖被用作 TPGS-KAE-NSps 的冷冻保护剂，其载药量为 70.31±2.11%，与 KAE 相比，溶解度显著提高。TPGS-KAE-NSps 的稳定性和生物相容性良好，具有一定的缓释效果。此外，在体外细胞实验中，与 KAE 相比，TPGS-KAE-NSps 明显被细胞摄取到细胞质中，表现出更强的细胞毒性和抑制细胞迁移作用，同时增加了细胞内 ROS 的产生和更高的细胞凋亡率。此外，与 KAE 相比，在 4T1 荷瘤小鼠中，TPGS-KAE-NSps 的作用持续时间更长，生物利用度显著提高，且对肿瘤生长的抑制作用更强（高剂量静脉注射组的肿瘤抑制率为 68.9±1.46%），无明显毒性。总的来说，制备的 TPGS-KAE-NSps 显著改善了 KAE 的缺陷和抗肿瘤效果，使其成为 KAE 的一种有前途的纳米药物递送系统，有望作为临床抗肿瘤药物应用。
