Nanoparticles for the Oral Administration of Cancer Therapies - Intracellular Delivery: Fundamentals and Applications - page 495

P-glycoprotein inhibitors also affected the activity of CYP3A4, limiting their clinical
applicability (Fischer et al. 1998 ). More recently, a third-generation of compounds
was synthetised in order to specifically interact with the P-glycoprotein transporter
(Breedveld et al. 2006 ; Hyafil et al. 1993 ; Dantzig et al. 1996 ). In this context, some
agents such as elacridar (GF120918), zosuquidar (LY335979) and tariquidar
(XR9576) have been developed (Breedveld et al. 2006 ; Hyafil et al. 1993 ; Dantzig
et al. 1996 ). Nevertheless, their usefulness in vivo is limited due to toxicological issues
such as cardiotoxicity or immunosuppressive effects (Bardelmeijer et al. 2000b ;
Woo et al. 2003 ).
Therefore, several authors are focused in the identification of more effective and
safe P-gp inhibitors without pharmacological activity (Bansal et al. 2009b ). In this
context, recently, it has been reported that some pharmaceutical excipients could
inhibit the function of intestinal P-gp. These excipients offer a number of advan-
tages including their well-known use in the formulation of parenteral and enteral
medicines, safety and regulatory acceptance (Buggins et al. 2007 ). Among others,
surfactants (i.e. Pluronic derivatives), co-solvents (i.e. polyethylenglycols) and solu-
bilising agents (i.e. cyclodextrins) have been proposed. Under specific circumstances,
these compounds may interact with the polar head of the lipid bilayers modifying
the membrane structure by inserting themselves between the lipophilic tails of the
bilayers. These membrane perturbations would induce a certain degree of fluidiza-
tion of the lipid membrane affecting, as a consequence, the activity of the P-gp
(Lo 2003 ). In the specific case of Pluronics, Batrakova and Kabanov showed that
these surfactants would modulate the P-gp by inhibiting the ATPase activity resulting
in ATP depletion (Batrakova and Kabanov 2008 ). In any case, it appears that moderate
lipophilicity of surfactants (with HLB <20) is a key factor which determines the
inhibitory potency (Lo 2003 ; Batrakova et al. 2003 ).
Ishiwaka and Arima, also reported the inhibitory effect of dimethyl-b-cyclodextrin,
hydroxypropyl-b-cyclodextrin and other b-cyclodextrin derivatives in the activity
of the CYP3A complex (Ishikawa et al. 2005 ) and the P-gp (Arima et al. 2001 ).
The mechanism by which these oligosaccharides inhibit P-gp activity would be
due to a modulation of the membrane microenvironment, mediated by a removal
process of cholesterol and phospholipids in the P-gp's immediate environment
(Arima et al. 2001 ), leading to a transient impairment of the transmembrane pro-
tein activity (Lo 2003 ).
Other pharmaceutical excipients, such as poly(ethylene glycol)s (PEG) and
some thiolated polymers (i.e. thiolated chitosan and thiolated carbomer) also display
a specific ability to inhibit P-gp activity (Foger et al. 2006 ).

3.3 Nanocarriers

Nanocarriers offer several advantages for oral drug delivery. They can protect the
drug against degradation and promote its absorption through the gut mucosa.
According to their physico-chemical properties, nanoparticles can diffuse within