| Encapsulation of therapeutic agents into polymeric carriers provides important benefits over traditional formulations, including controlled release of the therapeutic agents over days to months, protection of drug from degradation, and the ability to target therapy to a particular diseased site. These functions of drug delivery particles are dictated by physical properties such as polymer chemistry, surface chemistry, size and shape. Particles shape is, by far, the least studied of these properties, primarily due to the lack of techniques to produce polymer particles of non-spherical geometries. The goal of this work is to investigate the role of particle shape in drug delivery function and in particular, phagocytosis. Phagocytosis is a process by which foreign particles, such as those containing therapeutic drugs, are recognized and internalized by immune cells called macrophages. It is a significant obstacle of particulate delivery systems. Before the effect of particle shape could be studied, we first designed a technique by which to fabricate polymer particles with varied and controlled morphologies. By manipulating spherical poly(styrene) particles embedded in a film we created over twenty different shapes with features including low and high aspect ratios, convex and concave regions of varying curvature, and smooth and textured surfaces. Shape, size and surface chemistry of the particles can be independently controlled. Using these particles and a rat alveolar macrophage cell line, we investigated the role of shape in phagocytosis. Time-lapse video microscopy and actin staining revealed that the local particle shape at the point of macrophage attachment dictates whether or not internalization will occur. Only regions with high size-normalized curvature induce phagocytosis. Size only influences particle attachment to the membrane and, in the case of very large particles, the completion of phagocytosis. After establishing the role of shape in phagocytosis, we identified barrel and worm shaped particles as optimal for avoiding phagocytosis and demonstrated the generality of our shape manipulation method to biodegradable, drug encapsulating polymers. This work has broad implications not only in establishing shape as a new tool for drug delivery design, but also in fields as diverse as materials science and immunology. |
