Mass Transport via Cellular Barriers and Endocytosis - Intracellular Delivery: Fundamentals and Applications - page 12

and particles from tumor interstitium, resulting in an enhanced permeability and
retention (EPR) effect that makes nanoparticles accumulate and be retained longer
at the tumor site (Iyer et al. 2006 ; Maeda et al. 2000 ). These tumor characteristics
have been successfully exploited in clinic for the delivery of doxorubicin-encapsu-
lated in liposomes, showing reduced cardiotoxicity while maintaining antitumor
efficacy (Batist et al. 2001 ). However, given the heterogeneous nature of cancer,
vessel permeability may vary significantly even within the same tumor, which
therefore leads to heterogeneous extravasation of therapeutic agents. An additional
result of the lack of permeability selectivity of the vasculature is the accumulation
of fluid and osmotic proteins from the blood in the interstitial space resulting in
increased osmotic pressure within the tumor interstitium (Cairns et al. 2006 ; Tredan
et al. 2007 ). Increased fluid pressure is high and relatively uniform in the center of
the tumor, but it drops to normal levels at the periphery and in the surrounding
normal tissues (Boucher et al. 1990 ). Consequently, transvasculature flow and con-
vective transport of therapeutic molecules in the tumor is greatly non-uniform,
resulting in low distribution of drugs at the tumor center. Poor vascular organization
also leads to hypoxia regions within the tumor which trigger the activation of cell
survival pathways and alternative energy sources, such as glycolytic energy produc-
tion. This generates the build-up of metabolic products that lower the extracellular
pH affecting protonation of drugs and therefore cellular uptake (Tredan et al. 2007 ).
All of these characteristics have to be taken into account in order to successfully
engineer novel therapeutics able to bypass the multiple barriers that oppose extrava-
sation of drugs into the tumor site.

2.3 Interstitial Transport in Solid Tumor: Stromal Barriers

Following extravasation, therapeutic agents still have to be transported across the
interstitial space by diffusion and convection in order to reach the targeted cells,
often far from the blood vessels. The ratio of non vascularized to well-perfused
regions, and tumor specific characteristics such as composition and structure of the
extracellular matrix, as well as cell density, are potential causes for the limited
delivery of therapeutics within the tissue (Tannock et al. 2002 ).
Various methods are available to characterize these barriers and to predict and
improve therapeutic agent penetration across tissues. Among the most common
methods are multi-cellular spheroids (Minchinton and Tannock 2006 ) and multi-
layered in vitro cell culture models (Tannock et al. 2002 ; Minchinton and
Tannock 2006 ), as well as in vivo analysis through magnetic resonance imaging
(MRI), positron emission tomography (PET), and fluorescent microscopy
(Reddy et al. 2006 ).
One barrier to drug transport in tumors is elevated interstitial fluid pressure,
which affects the convection flow of the extravasated molecules, slowing their
movement and causing them to move radially outward (Jain 1987 ). This leads to