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Factors affecting the clearance and biodistribution of polymeric nanoparticles.

Alexis F, Pridgen E, Molnar LK, Farokhzad OC - Mol. Pharm. (2008)

Bottom Line: Rapid clearance of circulating nanoparticles during systemic delivery is a critical issue for these systems and has made it necessary to understand the factors affecting particle biodistribution and blood circulation half-life.These factors include interactions with biological barriers and tunable nanoparticle parameters, such as composition, size, core properties, surface modifications (pegylation and surface charge), and finally, targeting ligand functionalization.All these factors have been shown to substantially affect the biodistribution and blood circulation half-life of circulating nanoparticles by reducing the level of nonspecific uptake, delaying opsonization, and increasing the extent of tissue specific accumulation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. falexis@zeus.bwh.harvard.edu

ABSTRACT
Nanoparticle (NP) drug delivery systems (5-250 nm) have the potential to improve current disease therapies because of their ability to overcome multiple biological barriers and releasing a therapeutic load in the optimal dosage range. Rapid clearance of circulating nanoparticles during systemic delivery is a critical issue for these systems and has made it necessary to understand the factors affecting particle biodistribution and blood circulation half-life. In this review, we discuss the factors which can influence nanoparticle blood residence time and organ specific accumulation. These factors include interactions with biological barriers and tunable nanoparticle parameters, such as composition, size, core properties, surface modifications (pegylation and surface charge), and finally, targeting ligand functionalization. All these factors have been shown to substantially affect the biodistribution and blood circulation half-life of circulating nanoparticles by reducing the level of nonspecific uptake, delaying opsonization, and increasing the extent of tissue specific accumulation.

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Nanoparticle platforms for drug delivery. Polymeric nanoparticle platforms are characterized by their physicochemical structures, including polymerosome, solid polymeric nanoparticle, nanoshell, dendrimer, polymeric micelle, and polymer−drug conjugates.
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fig1: Nanoparticle platforms for drug delivery. Polymeric nanoparticle platforms are characterized by their physicochemical structures, including polymerosome, solid polymeric nanoparticle, nanoshell, dendrimer, polymeric micelle, and polymer−drug conjugates.

Mentions: Nanoparticles have drawn increasing interest from every branch of medicine1–5 for their ability to deliver drugs in the optimum dosage range, often resulting in increased therapeutic efficacy of the drug, weakened side effects,6,7 and improved patient compliance. Today, there are several examples of nontargeted NPs currently used in clinical practice (Doxil8–11 and Daunoxome(12)) and in clinical development (Cyclosert).(13) Early success of these lipid-based vesicular drug delivery nanoparticles has led to the investigation and development of many different compositions of polymeric nanoparticles, including polymeric micelles, dendrimers, drug conjugates, and polypeptide- and polysaccharide-based nanoparticles. Among these, Genexol-PM [methoxy-PEG-poly(d,l-lactide)Taxol] is the first polymeric micellar nanoparticle in phase II clinical trials in the United States.14,15 Generally, clinical success correlates well with pharmacological and toxicological parameters. Blood circulation residence, maximal tolerated dose (MTD), and selectivity are the most important factors for achieving a high therapeutical index and corresponding clinical success. Polymeric nanoparticles are defined by their morphology and polymer composition in the core and corona (Figure 1). The therapeutic load is typically conjugated to the surface of the nanoparticle, or encapsulated and protected inside the core. The delivery systems can be designed to provide either controlled release or a triggered release of the therapeutic molecule.16,17 The nanoparticle surface can then be functionalized by various methods to form the corona. Surface functionalization can be utilized to increase residence time in the blood, reduce nonspecific distribution, and, in some cases, target tissues or specific cell surface antigens with a targeting ligand (peptide, aptamer, antibody/antibody fragment, small molecule). For instance, it is well established that hydrophilic polymers, most notably poly(ethylene glycol) (PEG), can be grafted, conjugated, or absorbed to the surface of nanoparticles to form the corona, which provides steric stabilization and confers “stealth” properties such as prevention of protein absorption.18,19 Surface functionalization can address the major limiting factor for long-circulating nanoparticle systems, which is protein absorption. Proteins adsorbed on the surface of the nanoparticle promote opsonization, leading to aggregation and rapid clearance from the bloodstream.20–23 The resultant rapid clearance is due to phagocytosis by the mononuclear phagocyte system (MPS) in the liver and splenic filtration. Typically, the majority of opsonized particles are cleared by a receptor-mediated mechanism in fewer than a few minutes due to the high concentration of phagocytic cells in the liver and spleen, or they are excreted.(21) Thus, over the past 20 years, numerous approaches to improving nanoparticle blood residence and accumulation in specific tissues for the treatment of disease have been developed. In this review, we will discuss the effects of physiological tissue defects (high permeability) and polymeric nanoparticle physicochemical properties on their biodistribution and clearance. Specifically, polymeric composition, nanoparticle size, pegylation, surface charge, and targeting functionality will be discussed.


Factors affecting the clearance and biodistribution of polymeric nanoparticles.

Alexis F, Pridgen E, Molnar LK, Farokhzad OC - Mol. Pharm. (2008)

Nanoparticle platforms for drug delivery. Polymeric nanoparticle platforms are characterized by their physicochemical structures, including polymerosome, solid polymeric nanoparticle, nanoshell, dendrimer, polymeric micelle, and polymer−drug conjugates.
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2663893&req=5

fig1: Nanoparticle platforms for drug delivery. Polymeric nanoparticle platforms are characterized by their physicochemical structures, including polymerosome, solid polymeric nanoparticle, nanoshell, dendrimer, polymeric micelle, and polymer−drug conjugates.
Mentions: Nanoparticles have drawn increasing interest from every branch of medicine1–5 for their ability to deliver drugs in the optimum dosage range, often resulting in increased therapeutic efficacy of the drug, weakened side effects,6,7 and improved patient compliance. Today, there are several examples of nontargeted NPs currently used in clinical practice (Doxil8–11 and Daunoxome(12)) and in clinical development (Cyclosert).(13) Early success of these lipid-based vesicular drug delivery nanoparticles has led to the investigation and development of many different compositions of polymeric nanoparticles, including polymeric micelles, dendrimers, drug conjugates, and polypeptide- and polysaccharide-based nanoparticles. Among these, Genexol-PM [methoxy-PEG-poly(d,l-lactide)Taxol] is the first polymeric micellar nanoparticle in phase II clinical trials in the United States.14,15 Generally, clinical success correlates well with pharmacological and toxicological parameters. Blood circulation residence, maximal tolerated dose (MTD), and selectivity are the most important factors for achieving a high therapeutical index and corresponding clinical success. Polymeric nanoparticles are defined by their morphology and polymer composition in the core and corona (Figure 1). The therapeutic load is typically conjugated to the surface of the nanoparticle, or encapsulated and protected inside the core. The delivery systems can be designed to provide either controlled release or a triggered release of the therapeutic molecule.16,17 The nanoparticle surface can then be functionalized by various methods to form the corona. Surface functionalization can be utilized to increase residence time in the blood, reduce nonspecific distribution, and, in some cases, target tissues or specific cell surface antigens with a targeting ligand (peptide, aptamer, antibody/antibody fragment, small molecule). For instance, it is well established that hydrophilic polymers, most notably poly(ethylene glycol) (PEG), can be grafted, conjugated, or absorbed to the surface of nanoparticles to form the corona, which provides steric stabilization and confers “stealth” properties such as prevention of protein absorption.18,19 Surface functionalization can address the major limiting factor for long-circulating nanoparticle systems, which is protein absorption. Proteins adsorbed on the surface of the nanoparticle promote opsonization, leading to aggregation and rapid clearance from the bloodstream.20–23 The resultant rapid clearance is due to phagocytosis by the mononuclear phagocyte system (MPS) in the liver and splenic filtration. Typically, the majority of opsonized particles are cleared by a receptor-mediated mechanism in fewer than a few minutes due to the high concentration of phagocytic cells in the liver and spleen, or they are excreted.(21) Thus, over the past 20 years, numerous approaches to improving nanoparticle blood residence and accumulation in specific tissues for the treatment of disease have been developed. In this review, we will discuss the effects of physiological tissue defects (high permeability) and polymeric nanoparticle physicochemical properties on their biodistribution and clearance. Specifically, polymeric composition, nanoparticle size, pegylation, surface charge, and targeting functionality will be discussed.

Bottom Line: Rapid clearance of circulating nanoparticles during systemic delivery is a critical issue for these systems and has made it necessary to understand the factors affecting particle biodistribution and blood circulation half-life.These factors include interactions with biological barriers and tunable nanoparticle parameters, such as composition, size, core properties, surface modifications (pegylation and surface charge), and finally, targeting ligand functionalization.All these factors have been shown to substantially affect the biodistribution and blood circulation half-life of circulating nanoparticles by reducing the level of nonspecific uptake, delaying opsonization, and increasing the extent of tissue specific accumulation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. falexis@zeus.bwh.harvard.edu

ABSTRACT
Nanoparticle (NP) drug delivery systems (5-250 nm) have the potential to improve current disease therapies because of their ability to overcome multiple biological barriers and releasing a therapeutic load in the optimal dosage range. Rapid clearance of circulating nanoparticles during systemic delivery is a critical issue for these systems and has made it necessary to understand the factors affecting particle biodistribution and blood circulation half-life. In this review, we discuss the factors which can influence nanoparticle blood residence time and organ specific accumulation. These factors include interactions with biological barriers and tunable nanoparticle parameters, such as composition, size, core properties, surface modifications (pegylation and surface charge), and finally, targeting ligand functionalization. All these factors have been shown to substantially affect the biodistribution and blood circulation half-life of circulating nanoparticles by reducing the level of nonspecific uptake, delaying opsonization, and increasing the extent of tissue specific accumulation.

Show MeSH