Yu Junxian, Li Zhe, Wang Wei, Zhang Yang, Li Dandan, Liu Yi, Shen Su, Zhang Ruiwen
Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Jun 1;1022:13-20. doi: 10.1016/j.jchromb.2016.03.045. Epub 2016 Apr 1.
Polymeric micelles are effective drug-loading sites and often used to formulate poorly water-soluble agents. In the present study, the amphiphilic copolymer methoxy-capped poly(ethyleneglycol)-block-poly(Ɛ-caprolactone) (mPEG-b-PCL) was successfully developed for the delivery of 20(R)-dammarane-3β,12β,20,25-tetrol (25-OH-PPD), a natural anticancer product from Panax notoginseng. The 25-OH-PPD-loaded micelles were characterized by morphological observation and thermodynamic stability testing. The concentrations of 25-OH-PPD was determined by HPLC-MS/MS. The optimum MRM transition of 25-OH-PPD was selected at m/z 479.4.0→461.4. The chromatographic separation was achieved on a SB-C18 column (1.8μm, 2.1×50mm) with an optimized gradient mobile phase system. The extraction recoveries of plasma and various tissue homogenates were within the range of 81.1%-110.4% and the matrix effects ranged from 81.9% to 106.7%. The intra- and inter- day precision values (RSD%) were less than 12.0%, with accuracies ranging from 85.2% to 114.2%. In addition, 25-OH-PPD was found to be stable in different biological matrix after three freeze-thaw cycles, at room temperature and at -70°C for 4 weeks. The pharmacokinetics of 25-OH-PPD-loaded micelles was evaluated in rats. The micelles appeared as transparent liquid, stable and uniform spheres with an average particle size of 35.4±4.2nm. The maximum concentration of 25-OH-PPD in micelles was much lower than in free drug preparation. However, the drug in the micelles was released steadily, with a t1/2 of 9.1±4.0h, significantly longer than in free drug (3.3±1.4h). However, the drug concentrations in tissues after the micelle administration were lower than the levels after administration of the free drugs. In summary, the micelles were characterized by long circulation and sustained release, with an ability to avoid uptake by the reticuloendothelial system, providing a promising approach to deliver intravenous 25-OH-PPD for therapy.
聚合物胶束是有效的药物负载部位，常用于配制水溶性差的药物。在本研究中，成功开发了两亲性共聚物甲氧基封端的聚乙二醇 - 聚己内酯（mPEG-b-PCL），用于递送三七中的天然抗癌产物20（R）-达玛烷-3β，12β，20，25-四醇（25-OH-PPD）。通过形态观察和热力学稳定性测试对负载25-OH-PPD的胶束进行了表征。采用HPLC-MS/MS测定25-OH-PPD的浓度。选择25-OH-PPD的最佳多反应监测（MRM）跃迁为m/z 479.4→461.4。在SB-C18柱（1.8μm，2.1×50mm）上，采用优化的梯度流动相系统实现了色谱分离。血浆和各种组织匀浆的提取回收率在81.1% - 110.4%范围内，基质效应在81.9%至106.7%之间。日内和日间精密度值（RSD%）小于12.0%，准确度在85.2%至114.2%之间。此外，发现25-OH-PPD在经历三次冻融循环后，在室温及-70°C下保存4周时，在不同生物基质中均稳定。在大鼠中评估了负载25-OH-PPD胶束的药代动力学。胶束呈现为透明液体，是稳定且均匀的球体，平均粒径为35.4±4.2nm。胶束中25-OH-PPD的最大浓度远低于游离药物制剂中的浓度。然而，胶束中的药物释放稳定，t1/2为9.1±4.0h，明显长于游离药物（3.3±1.4h）。然而，胶束给药后组织中的药物浓度低于游离药物给药后的水平。总之，该胶束具有长循环和缓释的特点，能够避免被网状内皮系统摄取，为静脉注射25-OH-PPD进行治疗提供了一种有前景的方法。
