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586d

Recognition of the Size of Polymer Drug Carriers by Macrophages

Julie Champion and Samir Mitragotri. Chemical Engineering, University of California Santa Barbara, Engineering II Rm 3229, Santa Barbara, CA 93106

Polymeric particles are extensively used as carriers in targeted as well as systemic drug delivery applications. However, polymeric particles delivered in the body are rapidly cleared by macrophages by phagocytosis. Rate and extent of phagocytosis is known to depend on the size and surface chemistry of particles. While the dependence of phagocytosis on surface chemistry has been better studied and understood, the same cannot be said about the dependence on particle size. Previous studies on phagocytosis have suggested that macrophages recognize particle size but no explanation was presented for this peculiarity.

Using rat alveolar macrophages and polystyrene microspheres (1 to 9 um) possessing three different surface characteristics (unmodified polystyrene, IgG opsonized, and poloxamine coated) we investigated the dependence of phagocytosis on particle size. Dependence of two distinct steps of phagocytosis, particle attachment and internalization, on size and surface chemistry was separately assessed to elucidate the origins of size-recognition. Particle attachment to macrophages, quantified by flow cytometry, was found to depend on size and surface chemistry in a complex manner. Macrophages exhibited enhanced attachment to particles possessing diameters of 2-3 um. Further investigation, including manipulation of the physical structure of macrophage membranes and electron microscopy visualization, revealed that the ruffled topology of the membrane is responsible for size recognition and preferential attachment of 2-3 um particles to macrophages. Surprisingly, despite the intricate relationships between attachment and particle size and surface chemistry, the speed of particle internalization, measured with video microscopy, did not depend on either property.

Our studies show that particle attachment, orchestrated by the membrane topology, is solely responsible for recognition of particle size by macrophages. Several examples exist in biology of recognition at a molecular scale. However, the results presented here show a remarkable example of recognition on micron length scale. Such understanding of the interactions of polymeric particles with macrophages is essential in the design of particles to either reduce or enhance phagocytosis depending on drug delivery application.