Review
Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles

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Abstract

The process of opsonization is one of the most important biological barriers to controlled drug delivery. Injectable polymeric nanoparticle carriers have the ability to revolutionize disease treatment via spatially and temporally controlled drug delivery. However, opsonin proteins present in the blood serum quickly bind to conventional non-stealth nanoparticles, allowing macrophages of the mononuclear phagocytic system (MPS) to easily recognize and remove these drug delivery devices before they can perform their designed therapeutic function. To address these limitations, several methods have been developed to mask or camouflage nanoparticles from the MPS. Of these methods, the most preferred is the adsorption or grafting of poly(ethylene glycol) (PEG) to the surface of nanoparticles. Addition of PEG and PEG-containing copolymers to the surface of nanoparticles results in an increase in the blood circulation half-life of the particles by several orders of magnitude. This method creates a hydrophilic protective layer around the nanoparticles that is able to repel the absorption of opsonin proteins via steric repulsion forces, thereby blocking and delaying the first step in the opsonization process.

Introduction

Through spatial and temporal controlled drug delivery, injectable nanoparticle carriers have the ability to revolutionize disease treatment. Spatially localizing the release of toxic and other potent drugs only at specific therapeutic sites can lower the overall systemic dose and damage that these drugs would otherwise produce. Temporally controlling the release of a drug can also help decrease unwanted side effects that might otherwise occur due to the natural circadian fluctuations of chemical levels throughout the body (Hermida et al., 2001). The overall benefit of these improvements in disease treatment would be an increase in patient compliance and quality of life. In order for a drug delivery device to achieve these desired benefits it must be present in the bloodstream long enough to reach or recognize its therapeutic site of action. However, the opsonization or removal of nanoparticulate drug carriers from the body by the mononuclear phagocytic system (MPS), also known as the reticuloendothelial system (RES), is a major obstacle to the realization of these goals.

The macrophages of the MPS have the ability to remove unprotected nanoparticles from the bloodstream within seconds of intravenous administration, rendering them ineffective as site-specific drug delivery devices (Gref et al., 1994). These macrophages, which are typically Kupffer cells, or macrophages of the liver, cannot directly identify the nanoparticles themselves, but rather recognize specific opsonin proteins bound to the surface of the particles (Frank and Fries, 1991). Broadly speaking, opsonins are any blood serum component that aids in the process of phagocytic recognition, but complement proteins such as C3, C4, and C5 and immunoglobulins are typically the most common. Several methods of camouflaging or masking nanoparticles have been developed, which allow them to temporarily bypass recognition by the MPS and increase their blood circulation half-life (Illum and Davis, 1984, Gref et al., 1994, Kaul and Amiji, 2002). Many of these systems make use of surface treatments that interfere with the binding of opsonin proteins to the particle surface as a means of imparting stealth, or MPS-avoidance characteristics to nanoparticles. This review focuses on those systems that utilize poly(ethylene glycol) and PEG-containing surface treatments because these systems seem to hold the most promise and show the lowest occurrence of harmful effects in vivo.

Section snippets

Opsonization and phagocytosis

Opsonization is the process by which a foreign organism or particle becomes covered with opsonin proteins, thereby making it more visible to phagocytic cells. After opsonization, phagocytosis can occur, which is the engulfing and eventual destruction or removal of foreign materials from the bloodstream. Together these two processes form the main clearance mechanism for the removal of undesirable components larger than the renal threshold limit from the blood. In the case of polymeric

PEGylation

As previously mentioned, the preferred method of imparting stealth, or sterically stabilized properties to nanoparticles is through the PEGylation of these particles. PEGylation simply refers to the decoration of a particle surface by the covalently grafting, entrapping, or adsorbing of PEG chains. Also, in the case of biodegradable nanoparticles, PEG chains can be incorporated as copolymers throughout the particle so that some surface PEG chains are always available even after the degradation

Biodistribution and pharmacokinetics

Typically once a polymeric nanoparticle is opsonized and removed from the bloodstream, it is sequestered in one of the MPS organs. In the case of “naked” nanoparticles, or nanoparticles that have not been PEGylated and lack stealth properties, sequestration in the MPS organs is very rapid, typically a matter of minutes, and usually concentrates in the liver and spleen (Illum et al., 1987a, Gref et al., 1995, Panagi et al., 2001). However, for PEGylated stealth nanoparticles the speed of

Conclusions

The summarized work above demonstrates that the study of stealth nanoparticles and their opsonization by the mononuclear phagocytic system remains a very active and developing area of research. Although the proteins and blood serum components involved in this process are fairly well known, the mechanism by which they activate specific cellular responses and interact with stealth nanoparticles is still not fully understood. Also, the lack of a comprehensive study of these responses across

Acknowledgements

This work was supported in part by grant no. DGE-0333080 from the US National Science Foundation through the IGERT Program on Cellular and Molecular Imaging for Diagnostics and Therapeutics.

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