Biomedical Engineering Reference
In-Depth Information
and infusion equipment supplies (Terwogt et al.
1999
), what makes it a “dominant
strategy” in pharmacoeconomic terms (Irshad
2010
).
However, despite the numerous advantages described above, the oral bioavail-
ability of current cancer drugs is limited by multiple factors such as rapid degradation,
low solubility, poor membrane permeability or extensive pre-systemic metabolism
(Schellens et al.
2000
). Their efflux by P-glycoprotein and/or intestinal and hepatic
metabolism by cytochrome P450 metabolizing enzyme system have recognized as
major determinants of oral bioavailability of common anticancer drugs (Zhang and
Benet
2001
).
Strategies to solve these handicaps are the synthesis of more soluble structural
analogs, prodrugs, the concomitant administration of cancer drugs with P-glycoprotein
or CYP inhibitors and the use of particulate carriers systems. In the literature, several
nanoparticle-based formulations developed for oral delivery applications have suc-
ceeded in protecting the encapsulated drugs, promoting their absorption through the
gastrointestinal mucosa and enhancing their oral bioavailability (Cai et al.
2010
).
This paper describes the major obstacles to cancer drugs gastrointestinal absor-
ption and strategies to circumvent them, with special attention to nanocarriers.
We also briefly analyse the factors affecting the interaction of these carriers with
the gut mucosa, their transport through and their final outcome. Finally, the possi-
bilities of oral administration of other modalities of cancer treatment, as immuno-
therapy, are also discussed.
There are several excellent recent reviews that describe the goodness of nanocar-
riers for enhancement of oral bioavailability of drugs (Roger et al.
2010a
) or as
adjuvants in mucosal vaccination with diverse therapeutic applications (Chadwick
et al.
2010
). This chapter is only focused in nanocarriers intended for oral adminis-
tration of cancer therapies.
2
Main Obstacles to Oral Delivery of Cancer Chemotherapy
Orally administered, most anticancer drugs are highly hampered to reach the target
cells. In fact, the bioavailability of these drugs may be limited by their solubility
and/or permeability through the gut epithelia. In the former a low aqueous solubility
and slow dissolution rate may decrease the amount of solubilised drug able to reach
the absorptive membrane (Pasquier et al.
2010
). The drug has to be sufficiently and
rapidly dissolved in the aqueous fluids of the gastrointestinal tract before absorption
through the epithelial cells. Poor dissolution properties, as observed for lipophilic
molecules may importantly limit the fraction of drug absorbed (Ganta et al.
2010
).
In the latter, the permeability of a molecule may be negatively affected when the
drug is substrate of the efflux transport systems or by the presence of hydrophilic
or ionisable groups in its chemical structure. Another important factor that can nega-
tively affect the bioavailability of a molecule is its sensibility to the harsh conditions
of the gastrointestinal tract (Roger et al.
2010a
) or its degradation by enzymatic
complex located in the enterocytes (pre-systemic metabolism) (Barrett et al.
1996
)
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