Shi Xiangyang, Wang Suhe, Chen Xisui, Meshinchi Sasha, Baker James R
Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA.
Mol Pharm. 2006 Mar-Apr;3(2):144-51. doi: 10.1021/mp050078s.
A facile approach has been developed to encapsulate submicrometer-sized drug crystals into polymer multilayer capsules produced by sequential deposition of polymers onto the drug particle surfaces. 2-Methoxyestradiol (2-ME) is a hydrophobic metabolite of 17-beta estradiol, which has been demonstrated as a potential anticancer agent. It was selected as a model drug and was formulated into submicrometer-sized particles through fine milling followed by intense sonication in the presence of dipalmitoyl-dl-(R)-phosphatidylcholine (DPPC). The reserved positive charges on the 2-ME crystal surface by DPPC enhanced the water solubility of the particles and subsequent self-assembly of dextran sulfate (DS) and dextran (DN) multilayers through hydrogen bonding and physical adsorption. Upon the exposure of the drug capsules to ethanol, hollow DS/DN multilayer polymer shells can be formed. The encapsulation process and hollow polymer multilayer shell formation were confirmed by confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM), while the surface morphology of the formed drug capsules was investigated using scanning electron microscopy (SEM). In vitro studies show that the inhibitory effect of the formed 2-ME capsules is the same as that of the conventional formulation of 2-ME in a concentrated ethanol solution, as demonstrated by dramatic changes in cell morphology and significantly decreased viability of target cells. We also demonstrate that the change of the outermost layer of the drug capsules does not significantly influence its bioactivity. The presented strategy to encapsulate submicrometer-sized hydrophobic drug particles is expected to provide a general pathway to fabricate drug capsules for various biological applications.
已开发出一种简便方法，将亚微米级药物晶体封装到通过将聚合物依次沉积在药物颗粒表面而制备的聚合物多层胶囊中。2-甲氧基雌二醇（2-ME）是17-β雌二醇的疏水代谢物，已被证明是一种潜在的抗癌剂。它被选为模型药物，并通过精细研磨，然后在二棕榈酰-dl-(R)-磷脂酰胆碱（DPPC）存在下进行强力超声处理，制成亚微米级颗粒。DPPC在2-ME晶体表面保留的正电荷增强了颗粒的水溶性，并通过氢键和物理吸附促进了硫酸葡聚糖（DS）和葡聚糖（DN）多层膜的后续自组装。将药物胶囊暴露于乙醇中时，可形成中空的DS/DN多层聚合物壳。通过共聚焦激光扫描显微镜（CLSM）和透射电子显微镜（TEM）确认了包封过程和中空聚合物多层壳的形成，同时使用扫描电子显微镜（SEM）研究了形成的药物胶囊的表面形态。体外研究表明，在浓乙醇溶液中，形成的2-ME胶囊的抑制作用与2-ME的传统制剂相同，这通过细胞形态的显著变化和靶细胞活力的显著降低得以证明。我们还证明，药物胶囊最外层的变化不会显著影响其生物活性。所提出的封装亚微米级疏水药物颗粒的策略有望为制造用于各种生物应用的药物胶囊提供一条通用途径。
