Nanoparticles for the Oral Administration of Cancer Therapies - Intracellular Delivery: Fundamentals and Applications - page 500

After the oral administration of these nanoparticles to laboratory animals, the
paclitaxel plasma levels were characterized by a plateau close to the C max spanning
from T max till 24 h post-administration. These sustained levels of the anticancer drug
corresponded with a relative oral bioavailability of about 80% (Agueros et al.
2010 ). This fact would be due to the combination of both bioadhesive and inhibi-
tory properties of these cyclodextrin-poly(anhydride) nanoparticles. In fact, the
nanoparticles would be capable to approach the paclitaxel-cyclodextrin complex till
the surface of the mucosa where these carriers would remain immobilised in intimate
contact with the absorptive membrane. Then, nanoparticles would progressively release
their content to the gut environment. At this moment, the paclitaxel-cyclodextrin
complex would dissociate yielding the free drug and the oligosaccharide molecules.
Under these conditions, the anticancer drug would be rapidly absorbed whereas the
cyclodextrins would interact with lipidic components of the membrane disturbing
the activity of the efflux pump and cytochrome P450.

4 Cancer Immunotherapy: Implications of Gut and Tumor

Immunology in the Design of Oral Cancer Vaccines

Cancer immunotherapy is an attractive alternative, or addition, to conventional cancer
chemotherapy treatments and their study has increased significantly in the past
two decades. The idea behind them focused primarily on manipulating the patient's
own immune system to destroy cancer cells. Significant advantages to this modality
of cancer treatment are its ability to (i) induce specific killing of tumor cells (with
minimal detriment to healthy, non-tumor cells), (ii) systemically stimulate antitumor
immune responses that can target primary and secondary metastasis and (iii) result
in immunological memory that would provide long-term protection against possible
future tumor recurrences (Blattman and Greenberg 2004 ; Higgins et al. 2009 ).
There are several modalities of cancer immunotherapy as the administration
of tumor-cell targeting monoclonal antibodies, adjuvant cytokine treatment and
vaccines. These strategies of antitumor therapy are unlikely to be effective when
orally administered. First, monoclonal antibodies, cytokines or Tumor-Associated
Antigen (TAA) as cancer vaccines are labile proteins that are easily degraded in the
gastrointestinal tract by the low pH or digestive enzymes. Furthermore, what
immune response concerns, intestinal mucosa is characterized by the constitutive
and abundant presence of prostaglandine E2, TGF-b and IL-10 that favour the dif-
ferentiation of DCs and T-cells towards a regulatory phenotype (producing IL-4,
IL-10 and TGF-b). This fact leads to systemic tolerance (Malik et al. 2010 ).
Furthermore, cancer vaccines must also be effective in overcoming tumor- associ-
ated immune dysfunction/suppression and may need to adopt the role of proin-
flammatory cytokines and chemokines in inducing tumoricidal effector functions
and homing (Lasaro and Ertl 2010 ; Mocellin and Nitti 2008 ).
The tendency of oral vaccination to induce tolerance with immunosuppressive
environment that frequently surrounded tumors could explain that few cancer vac-
cines have been orally administered. The exceptions are the recombinant bacteria