Biomedical Engineering Reference
In-Depth Information
In this chapter we will review the main mechanisms of drug uptake for the most
common routes of administration starting from the macro-level of absorption (across
intestinal epithelium or vascular endothelium), then moving to cellular uptake, and
finally arriving at the level of intracellular trafficking and subcellular targeting. The
objective of this chapter is to enhance our understanding of mass transport to facili-
tate the development of carriers for cancer therapy and diagnostics. Unique charac-
teristics that originate from the tumor microenvironment will be emphasized, as well
as the ability to use these traits to achieve preferential accumulation of imaging and
therapeutic agents at the cancer lesion. Nanoparticles, which are being explored as
drug carriers, are discussed with an emphasis on the ability to tune their chemical
and physical properties to achieve preferential accumulation at the lesion.
2
Epithelial/Endothelial/Stromal Barriers: Mechanisms
to Cross Barriers
2.1
Gastrointestinal Administration: Epithelial Barriers
When given orally, a drug must cross barriers such as the mucus layer and the
unstirred water layer, or the epithelia cell membrane of the intestine and the underly-
ing tissues before reaching the systemic circulation and arriving at the site of action.
In general, biological membranes are composed primarily of lipid bilayers, contain-
ing cholesterol and phospholipids which provide stability and determine their per-
meability characteristics. Proteins that are involved in receptor-mediated transport
and the regulation of cellular metabolism are also embedded in these membranes.
Since epithelial cells are polarized, the membrane facing the two sides, that is, the
apical (facing the intestinal lumen) and the basolateral (facing the internal milieu and
the blood supply) have different lipid and protein compositions and thus different
permeability properties. As shown in Fig.
1
, transepithelial transport of drugs can be
achieved either across the cells (via transcellular or intracellular pathways) or
through the junctions between cells (paracellular or intercellular pathways).
Transcellular transport involves drugs crossing the barrier through exploitation
of one of the following mechanisms: passive diffusion, facilitated passive diffusion,
active transport or pinocytosis (Fig.
1
) (Stenberg et al.
2000
; Gad
2008
; Siccardi
et al.
2005
).
2.1.1
Passive Transcellular Diffusion
Most drugs are transported across the gastrointestinal epithelium by passive diffu-
sion moving from a compartment at higher concentration, the intestinal lumen, to
one of lower concentration, the blood circulation, where the drug is more diluted
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