Longcirculating Nanoparticles

Long-circulating nanoparticles can be created through surface modification of conventional nanoparticles with water-soluble polymers such as polyethylene glycol (PEG) or polyethylene oxide (PEO) (Figure 13.2). The hydrophilic nature of these surface modifiers minimizes the interactions between the nanoparticles and plasma proteins (opsonins), resulting in reduced uptake by the reticulo-endothelial system (RES). The major outcome of modification with PEG or other hydrophilic flexible polymers is a significant increase in circulation time, the advantages of which include maintenance of optimal therapeutic concentration of the drug in the blood after a single administration of the drug carrier, increased probability of extravasation and retention of the colloidal carrier in areas of discontinuous endothelium, and enhancement in targetability of the system by use of a target-specific ligand.39

The protective action (Stealth® property) of PEG is mainly due to the formation of a dense, hydrophilic cloud of long polyethylene chains on the surface of the colloidal particle that reduces the hydrophobic interactions with the RES. The tethered or chemically anchored PEG chains can

FIGURE 13.2 Schematic of long-circulating polymeric nanoparticles. The polymeric nanoparticles are made long-circulating by surface modification. The nanoparticles prepared from a hydrophilic polymer are modified using poly(ethylene glycol) (a), and the nanoparticles prepared from hydrophobic polymers are modified using Pluronic®, a triblock co-polymer of poly(ethylene oxide) and poly(propylene oxide) (b).

FIGURE 13.2 Schematic of long-circulating polymeric nanoparticles. The polymeric nanoparticles are made long-circulating by surface modification. The nanoparticles prepared from a hydrophilic polymer are modified using poly(ethylene glycol) (a), and the nanoparticles prepared from hydrophobic polymers are modified using Pluronic®, a triblock co-polymer of poly(ethylene oxide) and poly(propylene oxide) (b).

undergo spatial conformations, thereby preventing the opsonization of particles by the RES of the liver and spleen and improving the circulation time of molecules and particles in the blood. The greater the flexibility of the polymer, the greater the total number of possible conformations and transitions from one conformation to another.40-43 Water molecules form a structured shell through hydrogen bonding to the ether oxygens of PEG. The tightly bound water around PEG chains forms a hydrated film around the particle and prevents protein interactions.44 Furthermore, PEGylation may also increase the hydrodynamic size of the particles, decreasing their clearance through the kidneys, renal filtration being dependent on molecular mass and volume. This would ultimately result in an increase in the circulation half-life of the particles.45,46

The size, molecular weight, and shape of the PEG fraction and the linkage used to connect it to the entity of interest determine the consequences of PEGylation in relation to protein adsorption and pharmacokinetics such as volume of distribution, circulation time, and renal clearance. When formulated into colloidal particles, the PEG density on the colloidal surface can be changed by using PEG of appropriate molecular weight (PEG chain length) and molar ratio (the grafting efficiency). Longer PEG chains offer greater steric influence around the colloidal entity, similar to increased grafting density with shorter PEG chains. Longer PEG chains may also collapse onto the nanoparticle surface, providing a hydrophilic shield.40

Besides PEG, other hydrophilic polymers, including polyvinyl alcohol, polyacryl amide, polyvinyl pyrrolidone, poly-[N-(2-hydroxypropyl)methacrylamide], polysorbate-80, and block co-polymers such as poloxomer (Pluronic®) and poloxamine (Tetronic®), are also being used to

32 47 48

modify the physicochemical properties of the colloidal carriers. , ,

The polymeric nanoparticles modified with PEG or PEO are mainly used to passively target tumors through the EPR effect. The surface-modified long-circulating polymeric nanoparticles are used to deliver both genes and drugs to the tumor tissues. Some of the polymeric nanoparticulate systems that were developed by this group will be discussed in the sections that follow.

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