Zhu Jing-Jing, Zhang Xin-Xin, Miao Yun-Qiu, He Shu-Fang, Tian Dan-Mei, Yao Xin-Sheng, Tang Jin-Shan, Gan Yong
Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Ji-nan University, Guangzhou 510632, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Acta Pharmacol Sin. 2017 Feb;38(2):290-300. doi: 10.1038/aps.2016.113. Epub 2016 Dec 5.
Acetylthevetin B (ATB), a cardiac glycoside from the seed of Thevetia peruviana (Pers) K Schum (yellow oleander), exhibits not only antitumor activity but also potential cardiac toxicity. In the present study, we attempted to enhance its antitumor action and decrease its adverse effects via chitosan-Pluronic P123 (CP) micelle encapsulation. Two ATB-loaded CP micelles (ATB-CP1, ATB-CP2) were prepared using an emulsion/solvent evaporation technique. They were spherical in shape with a particle size of 40-50 nm, showed a neutral zeta potential, and had acceptable encapsulation efficiency (>90%). Compared to the free ATB (IC=2.94 μmol/L), ATB-loaded CP micelles exerted much stronger cytotoxicity against human lung cancer A549 cells with lower IC values (0.76 and 1.44 μmol/L for ATB-CP1 and ATB-CP2, respectively). After administration of a single dose in mice, the accumulation of ATB-loaded CP1 micelles in the tumor and lungs, respectively, was 15.31-fold and 9.49-fold as high as that of free ATB. A549 xenograft tumor mice treated with ATB-loaded CP1 micelles for 21 d showed the smallest tumor volume (one-fourth of that in the control group) and the highest inhibition rate (85.6%) among all the treatment groups. After 21-d treatment, no significant pathological changes were observed in hearts and other main tissues. In summary, ATB may serve as a promising antitumor chemotherapeutic agent for lung cancer, and its antitumor efficacy was significantly improved by CP micelles, with lower adverse effects.
乙酰黄夹次苷B（ATB）是一种从黄花夹竹桃（Thevetia peruviana (Pers) K Schum）种子中提取的强心苷，不仅具有抗肿瘤活性，还具有潜在的心脏毒性。在本研究中，我们试图通过壳聚糖-普朗尼克P123（CP）胶束包封来增强其抗肿瘤作用并降低其不良反应。采用乳化/溶剂蒸发技术制备了两种载ATB的CP胶束（ATB-CP1、ATB-CP2）。它们呈球形，粒径为40-50nm，zeta电位呈中性，包封率可接受（>90%）。与游离ATB（IC=2.94μmol/L）相比，载ATB的CP胶束对人肺癌A549细胞具有更强的细胞毒性，IC值更低（ATB-CP1和ATB-CP2分别为0.76和1.44μmol/L）。在小鼠单次给药后，载ATB的CP1胶束在肿瘤和肺中的蓄积量分别是游离ATB的15.31倍和9.49倍。用载ATB的CP1胶束治疗21天的A549异种移植瘤小鼠在所有治疗组中肿瘤体积最小（为对照组的四分之一），抑制率最高（85.6%）。治疗21天后，心脏和其他主要组织未观察到明显的病理变化。综上所述，ATB可能是一种有前景的肺癌抗肿瘤化疗药物，CP胶束显著提高了其抗肿瘤疗效，且不良反应较低。
