Nanoparticles for the Oral Administration of Cancer Therapies - Intracellular Delivery: Fundamentals and Applications - page 493

Only drugs that are absorbed via the intestinal lymphatic system are essentially
protected from hepatic first pass metabolism since the mesenteric lymph, in contrast
to portal blood, enters the systemic circulation directly without first passing through
the liver (Trevaskis et al. 2008 ; Hussain et al. 2001 ). Another advantage of this route
of delivery is the lymphatic exposure to drug concentrations orders of magnitude higher
than that attained in systemic blood (Trevaskis et al. 2008 ; Hussain et al. 2001 ).

3 Strategies to Improve Oral Bioavailability

of Anticancer Drugs

In spite of the different developments in progress, to date, the majority of anticancer
drugs have to be administered via parenteral routes. A common strategy to overcome
solubility and permeability limitations of anticancer drugs consist on chemical
modification in order to make the drug more hydrophilic and/or stable face to
enzymatic attack. On the other hand, the encapsulation of the drug in nanocarriers
can be applied in order to protect the loaded drug and try to promote its permeability
across the mucosal membrane. They include lipid nanospheres, nanoemulsions or
polymer nanoparticles.

3.1 Prodrugs

Prodrugs are compounds that need to be transformed before exhibiting their phar-
macological activity. The term prodrug was introduced in the late 1950s by Albert
who defined it as a pharmacologically inactive derivative of a parent drug molecule
that requires spontaneous or enzymatic transformation within the body to convert
to the active drug molecule (Albert 1958 ). Prodrug strategies are typically employed to
reduce toxicity, enhance the solubility or the stability, modify lipophilicity, perme-
ability, and tissue specificity of the parent drug (Singh et al. 2008 ).
In general, for those prodrugs designed to increase the bioavailability, it is
preferred a relatively low activation of the prodrug into the antitumor agent in the
blood or liver, thereby preventing acute toxic effects (Connors 1986 ). Ideally, after
absorption, the drug should be slowly released and activated only in the tumor site
where the parent drug can execute its mode of action. However, due to the reactivity
of most antitumor drugs, a limitation of this slow-releasing prodrug concept is that
frequently “healthy” tissues are also affected. Another drawback of prodrugs activated
by enzymes with low catalytic efficiencies, may be the metabolism of these prodrugs
by competing enzymes into inactive metabolites (Boddy and Yule 2000 ).
5-fluorouracil (5-FU) is a good example of anticancer drug for which a relatively
wide variety of prodrug systems have been evaluated. Among others, 5-FU prodrugs
that have been studied include 5-Fluoro-Pyrimidinone (5-FP) (Guo et al. 1995 ),