Encapsulation of Submicrometer-Sized 2-Methoxyestradiol Crystals into Polymer Multilayer Capsules for Biological Applications

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Abstract
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 submicrometersized hydrophobic drug particles is expected to provide a general pathway to fabricate drug capsules for various biological applications.