Synthetic carriers such as polymer and lipid particles often struggle to meet clinical expectations. Natural particulates - that range from pathogens to mammalian cells - are therefore worth examining in more depth, as they are highly optimized for their specific functions in vivo and possess features that are often desired in drug delivery carriers. With a better understanding of these biological systems, in conjunction with the availability of advanced biotechnology tools that are useful for re-engineering the various natural systems, researchers have started to exploit natural particulates for multiple applications in the delivery of proteins, small interfering RNA and other therapeutic agents. Here, we review the natural drug delivery carriers that have provided the basis and inspiration for new drug delivery systems.

Monoclonal antibodies are used in numerous therapeutic and diagnostic applications; however, their efficacy is contingent on specificity and avidity. Here, we show that presentation of antibodies on the surface of nonspherical particles enhances antibody specificity as well as avidity toward their targets. Using spherical, rod-, and disk-shaped polystyrene nano-and microparticles and trastuzumab as the targeting antibody, we studied specific and nonspecific uptake in three breast cancer cell lines: BT-474, SK-BR-3, and MDA-MB-231. Rods exhibited higher specific uptake and lower nonspecific uptake in all cells compared with spheres. This surprising interplay between particle shape and antibodies originates from the unique role of shape in determining binding and unbinding of particles to cell surface. In addition to exhibiting higher binding and internalization, trastuzumab-coated rods also exhibited greater inhibition of BT-474 breast cancer cell growth in vitro to a level that could not be attained by soluble forms of the antibody. The effect of trastuzumab-coated rods on cells was enhanced further by replacing polystyrene particles with pure chemotherapeutic drug nanoparticles of comparable dimensions made from camptothecin. Trastuzumab-coated camptothecin nanoparticles inhibited cell growth at a dose 1,000-fold lower than that required for comparable inhibition of growth using soluble trastuzumab and 10-fold lower than that using BSA-coated camptothecin. These results open unique opportunities for particulate forms of antibodies in therapeutics and diagnostics.morphology | nanomedicine | nanotechnology | drug delivery A ntibodies are used routinely in various analytical, diagnostic, and therapeutic applications, including cell and protein sorting (1), in vitro assays (2), in vivo imaging (3), and targeted delivery of therapeutics for the treatment of various diseases, including cancer (4), arthritis (5), and allergies (6). Significant attention has been given to understanding the molecular basis of antibody-antigen interactions (7) as well as to molecular engineering of antibodies to enhance their functions (8). An increasingly larger number of emerging applications of antibodies, however, are based on particulate systems in which antibodies are chemically or physically immobilized on the surface of microor nanoparticles (9-11). Such particulate antibodies are being pursued for targeted drug delivery or imaging. Although the benefits of antibodies in delivering therapeutic carriers to tissues have long been recognized, the effect of carriers themselves on antibody function has been relatively less studied. The function of antibodies that are immobilized on particles depends on the physicochemical properties of underlying particles, including the choice of material, size, surface modification, and shape. Commonly used nanoparticles for immobilizing antibodies include gold (9), iron oxide (12), quantum dots (13, 14), silica (15), polymers including poly(lactide-coglycolic acid) (PLGA) (11, 16) and polystyrene (...

Numerous types of nanoparticles are being designed for systemic and targeted drug delivery. However, keeping nanoparticles in blood for sufficiently long times so as to allow them to reach their therapeutic target is a major challenge. Upon administration into blood, nanoparticles are quickly opsonized and cleared by the macrophages, thereby limiting their circulation times. Surface-modification of nanoparticles by PEG was developed as the first strategy to prolong nanoparticles circulation. While PEGylation has helped prolong particle circulation, it has several limitations including transient nature of the effect and compromised particle-target interactions. Accordingly, several other approaches have been developed to prolong nanoparticle circulation in blood. These include modification with CD47, modulation of mechanical properties, engineering particle morphology and hitchhiking on red blood cells. In this review, we discuss the factors that affect nanoparticles circulation time and discuss recent progress in development of strategies to prolong circulation time.

Particle engineering for biomedical applications has unfolded the roles of attributes such as size, surface chemistry, and shape for modulating particle interactions with cells. Recently, dynamic manipulation of such key properties has gained attention in view of the need to precisely control particle interaction with cells. With increasing recognition of the pivotal role of particle shape in determining their biomedical applications, we report on polymeric particles that are able to switch their shape in real time in a stimulusresponsive manner. The shape-switching behavior was driven by a subtle balance between polymer viscosity and interfacial tension. The balance between the two forces was modulated by application of an external stimulus chosen from temperature, pH, or chemical additives. The dynamics of shape switch was precisely controlled over minutes to days under physiological conditions. Shapeswitching particles exhibited unique interactions with cells. Elliptical disk-shaped particles that are not phagocytosed by macrophages were made to internalize through shape switch, demonstrating the ability of shape-switchable particles in modulating interaction with cells.drug delivery | carrier | geometry | nanotechnology | phagocytosis I nteractions of polymeric particles with various cells, including macrophages, in the form of endocytosis and phagocytosis determine the effectiveness of carriers used for drug delivery and medical imaging (1, 2). The outcome of these interactions relies on optimal selection of key particle properties including surface chemistry, size, and shape (3, 4). Accordingly, numerous studies have reported on methods to synthesize materials with precisely engineered functional attributes such as size, surface chemistry, mechanical properties, and shape to facilitate or mitigate interactions with various cell types (3-5).For a given application, particle properties are optimized through extensive experimentation, and a set of fixed values are then chosen for further development. In reality, however, the optimal values of parameters may vary with time depending on the application. This variation has motivated the need to gain dynamic control over key particle properties so as to achieve an interactive interface between the particles and the complex biological milieu. For example, studies have reported on stimulusresponsive type control over the size of particles, and such particles have been used for the triggered release of encapsulated drugs (6-8). In another study, the surface chemistry of polymeric micelles has been controlled by using the environmental pH of solid tumors so as to enhance the cellular uptake and release of anticancer agents (9). Studies have also reported on achieving dynamic control of surface properties through the use of electric fields (10). Relatively little attention, however, has been devoted to switching particle's shape.Here we report poly(lactide-co-glycolide) (PLGA) particles whose shape can be switched in real time from an elliptical disk to a sphere in re...

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