Biomedical Engineering Reference
In-Depth Information
the tripeptide RGD, ICAM-1 antibody and nicotinic acid (Bareford and Swaan
2007
). Perhaps the most widely used endocytic targeting ligands for the functional-
izing of nanoscale drug delivery systems are transferrins (comprehensively
reviewed in (Qian et al.
2002
), a family of large nonheme iron-binding glycopro-
teins. The efficient cellular uptake of transferrins (Tf) has been and still is being
explored for the intracellular delivery of anticancer agents, and also proteins and
therapeutic genes. Iron-loaded transferrin binds to a specific cell-surface receptor
(TfR1) and upon endocytosis via clathrin-coated pits the transferrin-receptor com-
plex is routed into the endosomal compartment avoiding lysosomal digestion. This
is an important feature of TfR1 for drug delivery, since normally glycoproteins
taken up via receptor-mediated endocytosis are destined to eventually fuse with
lysosomes. Such intracellular sorting of endocytosed transferrin from other endo-
cytosed asialoglycoprotein has been found to occur immediately after cell internal-
ization (Stoorvogel et al.
1987
). Following loss of the clathrin coat, the endosome
containing the Tf-TfR1 complex then starts taking up protons which causes the
quick acidification of the lysosomal lumen to a pH of around 5.5. Recently a homo-
logue to TfR1 was cloned, called TfR2 (Trinder and Baker
2003
). Of importance
for anticancer drug delivery, TfR2 was found to be frequently expressed in human
cancer cell lines (Calzolari et al.
2007
). Encapsulation of doxorubicin into lipo-
somes bearing transferrin on the distal end of liposomal polyethylene glycol (PEG)
chains resulted in significantly increased doxorubicin uptake into glioma cells,
which are known to overexpress the transferrin receptor with the extent of over-
expression correlated to the severity of the tumor (Eavarone et al.
2000
). Transferrin
modification of Doxorubicin-loaded palmitoylated glycol chitosan (GCP) vesicles
resulted in higher uptake and increased cytotoxicity as compared to GCP
Doxorubicin alone (Dufes et al.
2004
). Tf vesicles were taken up rapidly with a
plateau after 1-2 h and Doxorubicin reached the nucleus after 60-90 min.
Low-density lipoprotein (LDL) represents another endocytic targeting ligand.
Furthermore, LDL itself actually provides a highly versatile natural nanoplatform
for the delivery of diagnostic and therapeutic agents to normal and neoplastic cells
that over express LDL receptors (LDLR) (Glickson et al.
2008, 2009
). LDL-loading
of contrast or therapeutic agents has been achieved by covalent attachment to pro-
tein side chains, intercalation into the phospholipid monolayer and extraction and
reconstitution of the triglyceride/cholesterol ester core (Zheng et al.
2005
). Glickson
and coworkers have constructed a semi-synthetic nanoparticle by coating magnetite
iron oxide nanoparticles with carboxylated cholesterol and overlaying a monolayer
of phospholipid to which Apo A1, Apo E or synthetic amphoteric alpha-helical
polypeptides were adsorbed for targeting HDL, LDL or folate receptors, respec-
tively (Zheng et al.
2002
). These semisynthetic particles have potential utility for
the in situ loading of magnetite into cells for magnetic resonance imaging (MRI)
monitored cell tracking or gene therapy (Zheng et al.
2005
). In addition to the sur-
face ligand, carrier geometry also might play a role in the endocytic process (Muro
et al.
2008
). Disks were found to display longer half-lives in circulation and higher
targeting specificity in mice, whereas spheres underwent a more rapid endocytosis.
Most interestingly from the aspect of intracellular drug delivery it was also found
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