The Reticuloendothelial System and Clearance of Foreign Materials

Physical properties such as surface chemistry and particle size can drive targeting of nanomaterials (and presumably nanodevices containing them) to some tissues. For instance, the pharmacokinetic (Pk) and biodistribution (Bd) properties [10.32] of many drugs and nanomaterials are driven by their clearance in urine, which is in turn governed by the filtration preferences of the kidney. Most molecules making transit into urine have masses of less than 25 to 50 kilodaltons (kDa; 25-50 kDa particles corresponding loosely to effective diameters of about 5 nm or less) and are preferably positively charged; these parameters are routinely modulated to control clearance rates of administered drugs. Clearance of low molecular weight (nano)materials in urine can be suppressed by tuning their molecular weights and effective diameters, typically accomplished by chemical conjugation, to polymers such as poly(ethylene glycol) [10.19]. Polymer conjugation (pegylation) has been applied to many different materials and may provide some degree of charge shielding. Pegylation also increases effective molecular weights of small materials above the kidney exclusion limit, diverting them from rapid clearance in urine.

Coating foreign particles with serum proteins (op-sonization [10.61]) is the first step in the clearance of foreign materials. Opsonized particles are recognized and taken up by tissue dendritic cells (DCs) and specific clearance organs. These tissues (thymus, liver, and spleen, constituting the organs of the retic-uloendothelial system or RES) extract materials from circulation by both passive diffusion and active processes (receptor-mediated endocytosis). Charge-driven, receptor-mediated uptake of synthetic nanomaterials occurs in the RES and can result in partition of positively charged nanoparticles into the RES. For instance, PAMAM dendritic polymers exhibit high positive charge densities related to the large number of primary amines on their surfaces [10.28-30]. In experimental animals, biodistribution of unmodified PAMAM dendrimers is limited nearly exclusively to RES organs [10.62]. This unfavorable biodistribution can be modulated by "capping" the dendrimers (i. e., derivatiz-ing the dendrimer to another chemical specificity, such as carboxy or hydroxyl functionalities [10.15,62]).

Despite legitimate applications of targeting to the kidney and the RES (for instance in glomerular disease [10.63]), intrinsic targeting to clearance sites is of interest primarily as a technical problem that impedes therapeutic delivery to other sites. In such cases, numerous targeting strategies are available, some of which depend on synthetic nanomaterial properties (for instance, see discussion of the enhanced permeability and retention or EPR effect in the context of oncology, below) to minimize uptake of nanotherapeutic devices by clearance systems and maximize delivery to desired sites. Targeting via biological affinity reagents decorating the surfaces of therapeutic nanodevices may be the most direct approach.

CGFECVRQCPERC CDCGRDCFC SMS IARL Identify consensus sequences

CGFECVRQCPERC CDCGRDCFC SMS IARL Identify consensus sequences

Propagate

Propagate

Tissue A

Tissue B

Tissue A

Tissue B

Sacrifice

Harvest organ(s)

Sacrifice

Harvest organ(s)

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