Microparticulate systems for targeted drug delivery to phagocytes

Phagocytic cells are traditionally characterized as cells of the immune system (such as neutrophils, dendritic cells, monocytes and macrophages, among others) that actively take up apoptotic bodies, cellular debris and particulate matter.¹ Their ability to phagocytose allows them to play a central role in modulating immune responses. For example, uptake of pathogens leads to presentation of associated antigen on the cell surface as well as secretion of lymphocyte-activating chemokines and cytokines. Presentation of this combination of signals by a phagocytic cell typically triggers an inflammatory response against the pathogen. Conversely, uptake of harmless apoptotic bodies at a site of tissue remodeling rarely leads to the production of inflammatory mediators. Instead, this process promotes secretion of immunosuppressive cytokines and maintenance of immune homeostasis. Given their capacity to determine the outcome of an immune response, phagocytic cells have been common targets for the treatment of diseases with immune etiology.

Although, altering phagocytic cell phenotype can be difficult, new technologies that permit the targeting of therapeutic agents to these cells in vivo have enabled greater control over the explicit modulation of phagocyte function. One of the most widely used strategies involves passive targeting, in which the therapeutic agent is encapsulated into polymeric or lipid-based vesicles (such as microspheres) that are too large for non-phagocytic cells to envelop (0.5–5 µm).² These delivery vehicles have already been used for the delivery of antigens and also antigen-encoded DNA to professional antigen-presenting cells as a strategy for enhancing immune responses against tumors.^3–5 Further, small molecular drugs can also be delivered to these cells using polymeric microspheres.^6,7 In each of these cases, it is possible to achieve markedly higher potency with orders of magnitude less drug as compared to systemic delivery, or even local delivery, due to the capability for targeted and intracellular delivery of payload to phagocytes.⁸

Recent results suggest that using degradable polymeric microspheres for targeting phagocytic cells affords two distinct advantages: (1) fine control over the rate and duration of release of encapsulated agents^9–11 and (2) encapsulation and delivery of multiple agents inside the same phagocytic cell if desired. The latter may be particularly useful if two or more different cell functions (such as tissue homing capacity and secretion of cytokines) need to be influenced simultaneously or even sequentially (Fig. 1). For example, some of our work suggests that modulating dendritic cell (DC) function (as a potential treatment for inflammatory bowel diseases) requires the sustained delivery of certain agents that drive DC migration to the gut as well as other agents that induce DC to differentiate into a suppressive phenotype (unpublished data). Alternately, recent data also suggests that simultaneous presence of multiple therapeutic agents inside phagocytes may be required to overcome redundant intracellular pathways.

Figure 1.

Targeted intracellular delivery to phagocytes—polymeric microspheres can be used to target and deliver multiple therapeutic agents to the same phagocytic cell. Top part illustrates the capacity to simultaneously alter two discrete pathways, while bottom part illustrates the capacity to block redundant pathways in order to achieve a desired effect.

Further, use of these particulate systems need not be limited to phagocytic immune cells alone. For instance, cells of the osteogenic lineage (involved in a wide array of bone disorders) and synovial cells (which have been implicated in arthritis) have been shown to engulf large particulates as well. Using polymeric microspheres to target these cell types could not only obviate the need for systemic delivery of drugs (and the associated negative side effects), but could also serve as a platform to “program” new therapeutic strategies that can overcome multiple barriers to achieve a desired cell behavior.

Comment on: Jhunjhunwala S, et al. J Control Release. 2009;133:191–197. doi: 10.1016/j.jconrel.2008.10.011.