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However, because nanoparticles are foreign bodies circulating in the bloodstream, the natural defense mechanisms of the body attempt to remove them. The way the body protects itself from nanoparticles or other foreign particulate matter circulating in the bloodstream is through the mononuclear phagocytic system (MPS), sometimes also called the reticuloendothelial system, in which phagocytic cells located primarily in the liver and spleen engulf the nanoparticles. High levels and fast rates of nanoparticle clearance by the MPS lead to an accumulation of nanoparticles in the liver and spleen, thus removing them from circulation before they are able to reach the site of disease and effectively deliver their therapeutic payloads. In addition, if the drug being delivered has potential specific toxicities in the liver or spleen, the clearance of nanoparticles by these organs may exacerbate those effects, making the drug less tolerable or more dangerous.

The optimization of nanoparticle properties, therefore, is critical to the development of a safe nanoparticle drug-delivery system. Particle-surface characteristics (e.g., chemical composition, charge) have a strong influence on the detection of nanoparticles by the MPS. Therefore, one way to minimize MPS clearance is to construct nanoparticles with poly(ethylene glycol) (PEG), a biocompatible polymer, on the surface, a technique that has been successfully used to increase the circulation time of biodegradable polymeric nanoparticles (Gref et al., 1994). The hydrophilic, uncharged nature of PEG can interfere with phagocytic recognition and the uptake of nanoparticles or proteins resulting in prolonged circulation times and more opportunity for the drug to reach the intended disease target.

DOXIL®, a liposomal formulation of the drug doxorubicin that uses a PEG surface to prolong circulation time,2 is approved for treatment of ovarian cancer, AIDS-related Kaposi’s sarcoma, and multiple myeloma. Doxorubicin, like many drugs, does not have a long circulation time in the bloodstream but instead can diffuse throughout the body in a way that can cause untoward side effects and that limits the amount of drug delivered to the tumor, thus decreasing its efficacy. By encapsulating doxorubicin in PEGylated liposome nanoparticles, DOXIL allows for longer circulation times than the drug has in its free, unencapsulated state, in fact long enough for the particles to diffuse into and deliver doxorubicin to the tumor vasculature.

A potential downside of nanoparticle-based drug-delivery systems is that they can deliver more drug to certain parts of the body than the free drug would normally deliver, which can result in either new side effects or an exacerbation of existing side effects. For DOXIL, the result is an increase in the incidence of hand-foot syndrome (a skin irritation that usually occurs on the hands and feet) compared to doxorubicin alone. The apparent cause is that the long-circulating nanoparticles eventually land in the capillary beds of the hands and feet where they deliver liposome-encapsulated doxorubicin in greater amounts than would be delivered by free, unencapsulated doxorubicin.

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