Biomedical Engineering Reference
In-Depth Information
5-6 nm are freely filtered by the glomerulus, while larger solutes are retained. For globular proteins,
this size is equivalent to a molecular weight around 60 kDa. The molecular weight limit can be lower
for nonglobular proteins (Maack et al. 1979). Grafting polymer chains to drugs is now a common
method of circumventing renal filtration and increasing the biological half-life (Kopecek et al. 2001).
Until today, PEG remains the most frequently utilized polymer to augment the D H of therapeutic
molecules (Harris and Chess 2003; Gao et al. 2010), but other hydrosoluble polymers (Seymour et al.
1987; Li et al. 1999, Gauthier and Klok 2010) as well as synthetic linear polypeptides (Schellenberger
et al. 2009, Zalevsky et al. 2010) have also been employed for this purpose. Several soluble CDCs
based on non-PEG polymers are currently in the preclinical and clinical stages of development.
Macromolecules with sizes around the filtration threshold must distort through the pores in order
to be filtered. Factors affecting their deformability, such as hydration, flexibility, as well as intra- and
intermolecular architecture, also highly influence their glomerular filtration (Bertrand et al. 2009;
Fox et  al. 2009; Nasongkla et  al. 2009). Most particulate CDCs are too large to be filtered with-
out prior biodegradation. Exceptions include QDs, shown to be filtered for diameters up to 5.5 nm
(Choi et al. 2007, 2010a,b), and CNTs (Liu et al. 2008; Schipper et al. 2008). The unique shape of
CNTs might promote their renal clearance by a favorable blood flow orientation (Lacerda et al. 2008;
Ruggiero et al. 2010) or distinctive transcellular transport mechanisms (Kostarelos et al. 2007).
Nevertheless, additional studies are still needed to confirm that their renal filtration is sufficiently
fast to prevent accumulations and toxicities in a clinical context. Recently, an interesting study
has shown that the renal mesangium could be targeted by particulate CDCs with a defined size of
~75 nm (Choi et al. 2011). Compared to similar particles of larger and smaller sizes, colloids of this
diameter are small enough to permeate the endothelial fenestrae and sufficiently large to interact
with mesangial cells. The particles were trapped in the collagen network of the GBM for at least
24 h and were cleared by the residing macrophages.
However, compared to the organs of the mononuclear phagocyte system (MPS), the total amount
found in the kidneys remained low (≤5% ID), and complementary investigations are required to
determine whether this size-dependent passive targeting can be exploited for imaging or drug deliv-
ery purposes.
14.3.3 t uBular r eaBsorptIoN
Once a solute is filtered in Bowman's capsule and reaches the proximal and distal tubules, it
can be reabsorbed by the epithelial cells. Tubular reabsorption regulates the elimination of ions
and proteins. It occurs through receptor-mediated and fluid-phase endocytosis. After internaliza-
tion, protein-containing vesicles can transcytose back to peritubular circulation (e.g., via FcRn)
(Anderson and Sandlie 2009) or can be catabolized in lysosomes. In the latter case, catabolic
products are subsequently released into systemic circulation (Maack et al. 1979). Soluble CDCs
filtered through the glomerulus can also be reabsorbed. The accumulation of PEG-protein con-
jugates in intracellular vacuoles inside tubular epithelial cells has been reported (Bendele et al.
1998). In this case, the protein moiety seems essential for endocytosis by tubular cells. It is
believed that the incomplete catabolism of nonbiodegradable polymers leads to a sequestration
in intracellular organelles. Although the vacuolization process appears to be transient and no
signs of toxicity were witnessed, one should be aware that data remain limited and the risk could
increase upon chronic exposure.
14.3.4 p oteNtIal r Isk of N aNoMaterIals oN the k IdNey
The most common route for the excretion of xenobiotics is via the kidneys into the urine. This pro-
cess involves the filtration of the blood through a complex filtration membrane in the glomerulus
of kidney nephrons. The size of the fenestrae within the glomerular filter is limited to allow the
passage of small molecular weight substances while preventing the filtration of larger molecules. It
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