Biomedical Engineering Reference
In-Depth Information
most abundantly present component of this system is efflux P-glycoprotein,
which is a product of the ABCB1gene. Inhibition of P-glycoprotein in pre-
clinical studies has enhanced the penetration of paclitaxel into the brain,
indicating the feasibility of achieving improved drug delivery to the brain by
suppression of P-glycoprotein [22].
Endocytosis and transcytosis allow the internalization, sorting and traf-
ficking of many plasma macromolecules. Endocytosis is a process where
molecules from the circulation are internalized in vesicles and are directed
to endosomes or lysosomes within the cell. Endocytosis can be isolated into
bulk-phase (fluid phase or pinocytosis) endocytosis and mediated endo-
cytosis (receptor and absorptive mediated). Bulk-phase endocytosis is the
noncompetitive, non-saturable, temperature and energy dependent non-
specific uptake of extracellular fluids. Transcytosis refers to the transcellular
movement of molecules.
Receptor mediated endocytosis or clathrin-dependent endocytosis pro-
vides for a highly specific and energy mediated transport enabling eukary-
otic cells to selective uptake macromolecules as specific cargo. Cells have
different receptors for the uptake of many different types of ligands, includ-
ing hormones, growth factors, enzymes, and plasma proteins. This process
occurs at the brain for macromolecular substances, such as transferrin, in-
sulin, leptin, and IGF-I & IGF-II, and is a highly specific type of energy
dependent transport [23].
Adsorptive endocytosis/transcytosis facilitates the transport of large
peptides such as IgG, histone, albumin, native ferritin, horse radish per-
oxidase and dextran. Adsorptive-mediated endocytosis is characterized by
an electrostatic interaction between a positively charged substance and the
negatively charged sites on the brain endothelial cell surface (e.g. glycopro-
tein) [24]. Adsorptive processes largely depend upon electrostatic interac-
tions that allow the positively charged moiety of the substrate to bind to the
negatively charged cell membrane. Receptor mediated transport is mainly
employed in the transport of macromolecules like peptides and proteins
across the BBB, by conjugating the substance with ligands such as lacto-
ferrin, transferrin and insulin. It is an important transport mechanism of
predominant interest in drug delivery.
Cell-mediated transcytosis is a recently identified route of drug transport
across the BBB [25]. This transport route relies on immune cells such as
monocytes or macrophages to cross the intact BBB. Unlike the aforemen-
tioned transport pathways which normally permit only solute molecules
with specific properties, cell-mediated transcytosis is unique in that it can
be used for virtually any type of molecule or material as well as particulate
carrier systems.
