Mass Transport via Cellular Barriers and Endocytosis - Intracellular Delivery: Fundamentals and Applications - page 11

These two mechanisms of transport can be described by fluidic models (Jain
1987, 1990, 1999 ) where the diffusive components of the transport are proportional
to the exchange vessel's surface area, S (cm 2 ) and the difference between the
plasma and interstitial concentration, C p − C i (g/ml):
( J SCC ∝ − )

*

s p i

The constant of proportionality is, as per the epithelial transport, the permeability
coefficient, P (cm/s). According to Starling's hypothesis the convection component,
J f (ml/s), is instead proportional to the rate of fluid leakage, from the vessels:
∝ −− −

J SPPspp *[( ) * ( )]

f v i V i

where S is the vessel's surface area, P v − P i (mmHg) is the difference between the
vascular and interstitial hydrostatic pressure, s is the osmotic reflection coeffi-
cient (which is close to 1 for macromolecules and almost zero for small mole-
cule) and p V − p i (mmHg) is the difference between the vascular and interstitial
osmotic pressure. The constant of proportionality is the hydraulic conductivity L p
(cm/mm Hg*s).
In the presence of both diffusion and convection we have the following equation:

JSCC J C = −+ −∆ * ( ) (1 s )

s p i f F lm

Where s F is the solvent-drag reflection coefficient, 1 − s F is a measurement of the
coupling between fluid and solute transport and D C lm is the mean concentration
within the pore across the membrane.

2.2.3 Tumor Vasculature and the EPR Effect

In addition to the physico-chemical properties of the drugs, the characteristics of
the target site play a crucial role in controlling the diffusion of drugs in tissues.
Trans-vascular transport in tumors is characterized by unique properties (Di Paolo
and Bocci 2007 ; Jain 1990 ; Minchinton and Tannock 2006 ). Tumors present an
abnormal vasculature in terms of structure and functionality. The vessels often have
an incomplete endothelial layer and lack intact pericyte coverage and basement
membrane which result in the opening of fenestrations in the vasculature walls that
make the vessels more permeable than normal tissues (Cairns et al. 2006 ; Tredan
et al. 2007 ). The increase in vascular permeability and hydraulic conductivity in the
tumor makes diffusion and convection through the large gaps formed in the
endothelium the primary pathways of drug transport across the tumor microvascular
walls. Since the vascular cut-off across the endothelium is bigger compared to
normal tissue ranging from 100 to 1,200 nm in diameter (Hobbs et al. 1998 ),
particle-based drug carriers, such as liposomes or polymeric nanoparticles, tend to
passively accumulate preferentially in the tumor. Moreover, since the cancer lym-
phatic drainage is defective, there is a decreased clearance of the macromolecules