Mass Transport via Cellular Barriers and Endocytosis - Intracellular Delivery: Fundamentals and Applications - page 13

diffusion-dominated interstitial transport, which is very slow for particles and
macromolecules (Jain 1987 ), as well as to a possible clearance of the drugs.
Another barrier is the extracellular matrix (Netti et al. 2000 ). The major compo-
nents of extracellular matrix are fibrous proteins (collagen and fibronectin) and
polysaccharides (hyaluronan and proteoglycans). In vitro models used to study
transport include gels with immobilized cells and collagen (Ramanujan et al. 2002 ).
As an example, these systems are used to study the impact of cell density and col-
lagen concentration on drug movement. Studies have shown that drug transport is
inhibited by high cell density and over-expression of ECM components (Netti et al.
2000 ; Jain 1987 ).
Due to these barriers, only tumor cells close to the vasculature are exposed to an
effective drug concentration. In addition to these physical barriers, the physico-
chemical properties of molecules and particles such as size, shape, charge and
aqueous solubility affect the rate of diffusion through tissues (Minchinton and
Tannock 2006 ). For instance, small molecules diffuse readily due to their low steric
hindrance, and globular proteins diffuse slower than their linear counterparts.

2.4 Approaches to Enhance Uptake and Penetration

of Intravenously-Administered Therapeutic Agents

A wide range of studies have been done on chemical permeation enhancers for oral
delivery for both paracellular and trancellular routes (Muranishi 1990 ). In the first
case the enhancers alter the cell membrane structure while in the second case they
make the tight junctions between the cells more open. Included in this group of
molecules are melittin, surfactants such as sodium cholate, and palmitoyl carnitine
(Whitehead and Mitragotri 2008 ; Godin 2006 ). Further in this chapter we will focus
on the cellular barriers present mostly when the substance is administered intrave-
nously. In this context, many approaches have been studied to overcome transport
barriers and promote the delivery of therapeutic agents to the target lesion. Some of
these are focused on directly improving drugs in terms of structure, lipophilicity, and
formulation. Other methods target the environment, modifying, for instance, the
blood flow or enhancing intestinal and vascular extravasation as well as interstitial
penetration (Cairns et al. 2006 ). A promising strategy is the use of carriers such as
micro- and nano-particles to enhance the delivery of already employed drugs,
exploiting, in the case of cancer, the EPR effect (Iyer et al. 2006 ) and taking advan-
tage of the large variety of possible chemistries involved in the assembly of these
particles (Ferrari 2010 ). Moreover these carriers can be decorated with molecules
such as antibodies, aptamers and peptides which selectively recognize markers on
the surface of the cells at the site of action. Several studies have also evaluated the
use of pH-sensitive and temperature-sensitive carriers for the triggered release of the
payload in the tumor microenvironment (Hafez et al. 2000 ; Lee et al. 2008 ). Among
the approaches that target the environment, enhancing, for instance, the diffusion