Lessons Learned from Pharmaceutical Nanomaterials - Safety of Nanomaterials along Their Lifecycle - page 122

technology. Reformulation also leads to less variability in the fasted and fed states of
patients, thus food effect decreased compared to conventional formulations (Bawa
2009; Moschwitzer 2013).
Another aspect of nanopharmaceuticals is the improved safety profile compared
to traditional formulations. Size and surface properties largely dictate the in vivo
behavior of nanopharmaceuticals. Bawa showed that tuning size and surface of
nanocarrier systems alters the pharmacokinetic profile compared to their parent
counterpart (Bawa 2009), so that adverse effects occurring with traditional formula-
tions are reduced, according to their adjustable release kinetics, as can be seen for
AmBisome ® (Adler-moore and Proffitt 1993; Bekersky et al. 2002; Boswell et al.
1998).
The importance of carrier systems for pharmaceutical applications is also based on
their targeting potential and potential to overcome biological barriers. Although the
structure of the blood brain barrier (BBB) makes most of the small-molecule drugs
and practically all of macromolecules not suitable for traversing it, some nanoparticu-
late therapeutics, however, are able to cross this barrier without the need for opening it
beforehand (Pardridge 2003; Tosi et al. 2008). Tosi et al. showed various strategies for
crossing the BBB using modified nanoparticles, such as magnetic nanoparticles, the
use of surfactants for coating of the nanoparticles, or the covalent conjugation of the
particles with specific ligands. They offer a more specific and selective drug delivery
to the central nervous system. If ligands are chosen, they have to show appropriate
characteristics for taking advantage of receptor-mediated transcytosis or endocyto-
sis. Molecules such as transferrin, insulin, or thiamin and also small peptides have
been tested successfully (Tosi et al. 2008). Maeda and Matsumura described a pas-
sive tumor-targeting mechanism, which is known as the EPR effect (Matsumura et al.
1986): tumor capillaries show higher endothelial fenestrations and architectural anar-
chy compared to healthy tissue. Yuan et al. found liposomes of up to 400 nm in diameter
to be able to permeate tumor vessels, suggesting the cutoff size of pores to be between
400 and 600 nm in diameter (Yuan et al. 1995). Consequently, injected agents with
the “right size” are able to accumulate at tumor sites, if not previously cleared by the
immune system. Further, surface characteristics are important to escape mononuclear
phagocyte system (MPS) capture, which represents one part of immune response.
Nanoparticles with hydrophilic surface (e.g., via PEGylation) have a higher chance of
escaping macrophage clearance (Moghimi and Szebeni 2003). Once a particle fulfills
size and surface characteristics requirements, it will circulate for a longer period of
time in the bloodstream reaching and accumulating in tumor tissue. An example of
such a marketed formulation is Doxil ® /Caelyx ® . A comparable effect, which could
be applicable to passive targeting via nanoparticulate formulations, was observed for
rheumatoid arthritis: Results of various studies suggest that retention of prodrugs at
inflamed joints occurs due to similar effects, shown for the EPR effect. A prolonged
half-life of prodrugs, in combination with leaky vasculature, leads to accumulation
at the site of action (Quan et al. 2010; Wang et al. 2004; Wunder et al. 2003). Hence,
enhanced endocytic capacity is exhibited in synoviocytes and explains the sustained
suppression of inflammation (Wunder et al. 2003; Wang and Goldring 2011; Quan
et al. 2010). This effect was recently termed ELVIS “Extravasation through Leaky
Vasculature and the subsequent Inflammatory cell-mediated Sequestration” by Yuan