Peek Laura J, Roberts Lydia, Berkland Cory
Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, Kansas 66047, USA.
Langmuir. 2008 Sep 2;24(17):9775-83. doi: 10.1021/la8012014. Epub 2008 Aug 5.
A dry powder aerosol drug delivery system was designed with both nano- and microstructure to maximize the protein loading via surface adsorption and to facilitate delivery to the deep lung, respectively. Ovalbumin was employed as a model protein to adsorb to and controllably flocculate DOTAP-coated PLG nanoparticles into "nanoclusters" possessing low density microstructure. The mechanism of nanoparticle flocculation was probed by evaluating the effects of ionic strength, shear force, and protein concentration on the geometric and aerodynamic diameters of the nanoclusters as well as the protein adsorption efficiency. Salt ions were found to compete with ovalbumin adsorption to nanoparticles and facilitate flocculation; therefore, formulation of nanoclusters for inhaled drug delivery may require the lowest possible ionic strength to maximize protein adsorption. Additional factors, such as shear force and total protein-particle concentration can be altered to optimize nanocluster size, suggesting the possibility of regional lung delivery. Immediate release of ovalbumin was observed, and native protein structure upon release was confirmed by circular dichroism and fluorescence spectroscopy studies. Controlled flocculation of nanoparticles may provide a useful alternative to spray drying when formulating dry powders for pulmonary or nasal administration of protein therapeutics or antigens.
设计了一种具有纳米和微观结构的干粉气溶胶药物递送系统，分别通过表面吸附最大化蛋白质负载量，并促进向深部肺部的递送。采用卵清蛋白作为模型蛋白，使其吸附到DOTAP包被的聚乳酸-羟基乙酸共聚物（PLG）纳米颗粒上，并可控地使其絮凝成具有低密度微观结构的“纳米簇”。通过评估离子强度、剪切力和蛋白质浓度对纳米簇的几何直径和空气动力学直径以及蛋白质吸附效率的影响，探究了纳米颗粒絮凝的机制。发现盐离子与卵清蛋白竞争吸附到纳米颗粒上并促进絮凝；因此，用于吸入药物递送的纳米簇制剂可能需要尽可能低的离子强度以最大化蛋白质吸附。可以改变其他因素，如剪切力和蛋白质-颗粒总浓度，以优化纳米簇大小，这表明有可能实现肺部区域递送。观察到卵清蛋白的立即释放，并通过圆二色性和荧光光谱研究证实了释放后天然蛋白质结构。在为蛋白质治疗剂或抗原的肺部或鼻腔给药制备干粉时，纳米颗粒的可控絮凝可能为喷雾干燥提供一种有用的替代方法。
