The reticuloendothelial system RES

The above approach has been investigated both for nonbiodegradable polymer particles (such as polystyrene or cyanoacrylate) and biodegradable particles (such as poly(lactic acid)/poly(lactic acid-co-glycolic acid) [39,40]. 

The phagocytic cells (macrophages of the liver and spleen) of the RES remove particulate systems (considered as foreign bodies). This process is facilitated by adsorption of proteins at the solid/liquid interlace, a process that is referred to as opsonization. Suppression of phagocytosis by other components of the blood, such as immunoglobin 

IgA and secretory IgA is referred to as dysopsonosis and is sometimes attributed to the hydrophilicity of IgA. However, it was shown that coating polystyrene nanoparticles with IgA had little effect on liver uptake. 

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Polyanionic polymers can enter into biological functions by distribution throughout the host and they behave similar to proteins, glycoproteins and polynucleotides which modulate a number of biological responses related to the host defense mechanism. These are enhanced immune responses, and activation of the reticuloendothelial system (RES) macrophages. 

Several types of dmg carriers such as microspheres, liposomes, and polymer have been investigated to achieve targetable drug delivery, especially for anticancer drugs. However, nonselective scavenging of such carriers by the reticuloendothelial system (RES) is a serious problem even when monoclonal antibodies are used to carry the dmg [15,16]. 

We have shown that polymeric micelles constmcted of block copolymers of poly(ethylene oxide) (PEG) and poly(L-asparate) containing the anticancer dmg (adriamycin, ADR) selectively accumulate at solid tumor sites by a passive targeting mechanism. This is likely due to the hydrophilicity of the outer PEG chains and micellar size (<100 nm) that allow selective tissue interactions [17,18]. Polymeric micelle size ranges are tailored during polymer synthesis steps. Carefully selection of block polymer chemistry and block lengths can produce micelles that inhibit nonselective scavenging by the reticuloendothelial system (RES) and can be utilized as targetable dmg... 

Depending on their size and surface charge, parenterally administered liposomes interact with the reticuloendothelial system (RES) and provoke an immune response. 

It is well established that size, charge, and chemical composition of liposomes affect their fate in vivo [306], To manipulate their biodistribution and/or drug release, liposomes of different structures have been prepared, including those sensitive to changes in pH [307, 308] or temperature [309,310]. Compared to soluble polymers discussed in previous chapters, liposomes, when applied i.v., are captured by a substantially greater extent by the specialized cells (macrophages) of the reticuloendothelial system (RES) [311]. The removal of liposomes from the bloodstream takes place by nonspecific endocytosis (phagocytosis) [312],... 

When HES is infused, the smaller molecules are excreted by the kidneys, while the larger molecules are metabolised by o-amylase, and taken up by the reticuloendothelial system (RES) and the skin. Even though HES molecules disappear from the blood within 10-72 hours, dependent on their molecular weight, they can be detected in the RES for at least one month. Anaphylactic reactions to HES are lower than with other colloids and they have minimal effects on coagulation. Controversy exists regarding the use of HES in patients with renal insufficiency, and dose recommendations are based on the risk of renal tubular overload and the influence on haemostasis (possible decrease in factor Vll/von Willebrand factor). The risk is greater with the higher MW solutions, and appears to be lower with the new HES 130/0.4. 

The size of polymeric micelles, with an approximate diameter range of 20 to 60 nm, is smaller than achievable by liposomes and micro(nano)spheres. The smaller carrier systems are expected to show higher vascular permeability at target sites by a diffusion mechanism. Furthermore, the diameter range of the polymeric micelle systems is considered to be appropriate to evade renal excretion and nonspeciLc capture by the reticuloendothelial systems (RES). 

USPIO contrast agents are eliminated from the circulation by the reticuloendothelial system (RES), and often become sequestered in liver cells. Half-life in the circulation depends on the chemistry of preparation, and can range from... 

Particles introduced into the bloodstream are covered rapidly by components of the circulation, such as plasma proteins, in a process called opsonization. Opsonization makes the particles recognizable to the body s major defense system, the reticuloendothelial system (RES). The RES comprises a diffuse system of phagocytic cells (which engulf inert material) that are primarily associated with the connective tissues in the liver, spleen, and lymph nodes. Macrophage (Kupffer) cells in the liver and macrophages of the spleen and circulation are important in removing particles identified by opsonization. A significant fraction of nanoparticles can be cleared from the circulation system in as little as 15 minutes [48, 49],... 

Besides curcuminoids and oils, C. longa also contains some polysaccharides. Three acidic polysaccharides were isolated from turmeric ( Ukon ) by hot water extraction, followed by precipitation with ethanol, with remarkable activity on the reticuloendothelial system (RES) (Gonda et al., 1990). The components were purified on a column of DEAE Sephadex A-25 and named as Ukon A, Ukon B and Ukon C. 

In addition to the issue of endothelial permeability, the effect of macrophages in direct contact with the blood circulation (e.g. Kupffer cells in the liver) on the disposition of carrier systems must be considered. Unless precautions are taken, particulate carrier systems are readily phagocytosed by these macrophages and tend to accumulate in these cells. Phagocytic uptake by the cells of the mononuclear phagocyte systems (MPS also sometimes known as the reticuloendothelial system, RES) has been described in Chapter 1 (Section 1.3.3.2). The MPS comprises both ... 

The clinical applications of liposomes are well known (Table 4). The initial success achieved with many liposome-based drugs has fueled further clinical investigations. One of the drawbacks of the use of liposomes is the fast elimination from the blood and capture of liposomal preparations by the cells of the reticuloendothelial system (RES), primarily in the liver. 

Adverse effects on the reticuloendothelial system (RES) can be shown by impaired ability to produce antibody protein or by the development of hypersensitivity. 

Biodistribution of liposomes is a very important parameter from the clinical point of view. Liposomes can alter both the tissue distribution and the rate of clearance of the drug by making the drug take on the pharmacokinetic characteristics of the carrier (10, 11). The pharmacokinetic variables of the liposomes depend on the physiochemical characteristics of the liposomes, such as size, surface charge, membrane lipid packing, steric stabilization, dose, and route of administration. As with other microparticulate delivery systems, conventional liposomes are vulnerable to elimination from systemic circulation by the cells of the reticuloendothelial system (RES) (12). The primary sites of accumulation of conventional liposomes are the tumor, liver, and spleen compared with non-liposomal formulations (13). Many studies have shown that within the first 15-30 min after intravenous administration of liposomes between 50 and 80% of the dose is adsorbed by the cells of the RES, primarily by the Kupffer cells of the liver (14-16). 

Dalmo, R.A., K. Ingebrigste and J. Bogwald. Non-specific defence mechanisms in fish, with particular reference to the reticuloendothelial system (RES). J. Fish Dis. 20 241 -273, 1997. 

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