Huang Wenzhe, Wang Xu, Shi Changying, Guo Dandan, Xu Gaofei, Wang Lili, Bodman Alexa, Luo Juntao
†Department of Pharmacology and §Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York 13078, United States.
Mol Pharm. 2015 Apr 6;12(4):1216-29. doi: 10.1021/acs.molpharmaceut.5b00051. Epub 2015 Mar 2.
Certain natural products such as gambogic acid (GA) exhibit potent antitumor effects. Unfortunately, administration of these natural products is limited by their poor solubility in conventional pharmaceutical solvents. In this study, a series of telodendrimers, composed of linear polyethylene glycol (PEG)-blocking-dendritic oligomer of cholic acid (CA) and vitamin E (VE), have been designed with architectures optimized for efficient delivery of GA and other natural anticancer compounds. Two of the telodendrimers with segregated CA and VE domains self-assembled into stable cylindrical and/or spherical nanoparticles (NPs) after being loaded with GA as observed under transmission electron microscopy (TEM), which correlated with the dynamic light scattering (DLS) analysis of sub-30 nm particle sizes. A very high GA loading capacity (3:10 drug/polymer w/w) and sustained drug release were achieved with the optimized telodendrimers. These novel nanoformulations of GA were found to exhibit similar in vitro cytotoxic activity against colon cancer cells as the free drug. Near-infrared fluorescence small animal imaging revealed preferential accumulation of GA-loaded NPs into tumor tissue. The optimized nanoformulation of GA achieved superior antitumor efficacy compared to GA-Cremophor EL formulation at equivalent doses in HT-29 human colon cancer xenograft mouse models. Given the mild adverse effects associated with this natural compound and the enhanced anticancer effects via tumor targeted telodendrimer delivery, the optimized GA nanoformulation is a promising alternative to the traditional chemotherapy in colon cancer treatment.
某些天然产物，如藤黄酸（GA），具有强大的抗肿瘤作用。不幸的是，这些天然产物的给药受到其在传统药用溶剂中溶解度差的限制。在本研究中，设计了一系列由线性聚乙二醇（PEG）-封端-胆酸（CA）和维生素E（VE）的树枝状低聚物组成的端接树枝状聚合物，其结构经过优化，可有效递送GA和其他天然抗癌化合物。如在透射电子显微镜（TEM）下观察到的，其中两个具有分离的CA和VE结构域的端接树枝状聚合物在负载GA后自组装成稳定的圆柱形和/或球形纳米颗粒（NPs），这与小于30nm粒径的动态光散射（DLS）分析结果相关。通过优化的端接树枝状聚合物实现了非常高的GA负载量（药物/聚合物重量比为3:10）和持续的药物释放。发现这些GA的新型纳米制剂对结肠癌细胞表现出与游离药物相似的体外细胞毒性活性。近红外荧光小动物成像显示负载GA的NPs优先在肿瘤组织中积累。在HT-29人结肠癌异种移植小鼠模型中，在等效剂量下，GA的优化纳米制剂比GA-聚氧乙烯蓖麻油EL制剂具有更高的抗肿瘤疗效。鉴于这种天然化合物具有轻微的不良反应，并且通过肿瘤靶向的端接树枝状聚合物递送增强了抗癌效果，优化的GA纳米制剂是结肠癌治疗中传统化疗的一个有前途的替代方案。
