Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
Int J Pharm. 2011 Feb 14;404(1-2):238-49. doi: 10.1016/j.ijpharm.2010.11.010. Epub 2010 Nov 17.
In this study we report the development and in vitro characterization of paclitaxel (PTX) and docetaxel (DTX) loaded into hydrophobically derivatized hyperbranched polyglycerols (HPGs). Several HPGs derivatized with hydrophobic groups (C(8/10) alkyl chains) (HPG-C(8/10)-OH) and/or methoxy polyethylene glycol (MePEG) chains (HPG-C(8/10)-MePEG) were synthesized. PTX or DTX were loaded into these polymers by a solvent evaporation method and the resulting nanoparticle formulations were characterized in terms of size, drug loading, stability, release profiles, cytotoxicity, and cellular uptake. PTX and DTX were found to be chemically unstable in unpurified HPGs and large fractions (∼80%) of the drugs were degraded during the preparation of the formulations. However, both PTX and DTX were found to be chemically stable in purified HPGs. HPGs possessed hydrodynamic radii of less than 10nm and incorporation of PTX or DTX did not affect their size. The release profiles for both PTX and DTX from HPG-C(8/10)-MePEG nanoparticles were characterized by a continuous controlled release with little or no burst phase of release. In vitro cytotoxicity evaluations of PTX and DTX formulations demonstrated a concentration-dependent inhibition of proliferation in KU7 cell line. Cellular uptake studies of rhodamine-labeled HPG (HPG-C(8/10)-MePEG(13)-TMRCA) showed that these nanoparticles were rapidly taken up into cells, and reside in the cytoplasm without entering the nuclear compartment and were highly biocompatible with the KU7 cells.
在这项研究中，我们报告了紫杉醇（PTX）和多西紫杉醇（DTX）负载到疏水性衍生的超支化聚甘油（HPG）中的开发和体外表征。几种用疏水性基团（C（8/10）烷基链）（HPG-C（8/10）-OH）和/或甲氧基聚乙二醇（MePEG）链（HPG-C（8/10）-MePEG）衍生的 HPG 被合成。通过溶剂蒸发法将 PTX 或 DTX 载入这些聚合物中，并根据粒径、药物负载、稳定性、释放曲线、细胞毒性和细胞摄取对所得纳米颗粒制剂进行了表征。PTX 和 DTX 在未纯化的 HPG 中化学不稳定，在制剂制备过程中，药物的大部分（约 80%）发生降解。然而，PTX 和 DTX 在纯化的 HPG 中均发现化学稳定。HPG 的流体力学半径小于 10nm，并且 PTX 或 DTX 的掺入不会影响其大小。HPG-C（8/10）-MePEG 纳米颗粒中 PTX 和 DTX 的释放曲线表现为连续控制释放，几乎没有或没有释放的初始突释阶段。PTX 和 DTX 制剂的体外细胞毒性评估表明，KU7 细胞系的增殖受到浓度依赖性抑制。罗丹明标记的 HPG（HPG-C（8/10）-MePEG（13）-TMRCA）的细胞摄取研究表明，这些纳米颗粒被迅速摄取到细胞中，并存在于细胞质中，而不会进入核区室，并且与 KU7 细胞高度相容。
