Biomedical Engineering Reference
In-Depth Information
RGD-integrin interaction and subsequently was proteolytically processed to generate
a CendR motif with cell-penetrating activities, further facilitating the penetration
of drug into the tumor. Therefore, drugs chemically conjugated to the iRGD could
be selectively transported deep into the tumor parenchyma, and significantly
improve the sensitively of tumor-imaging agents and the activity of an antitumor
drug. Recent studies further demonstrated that co-administration of drugs and the
iRGD peptide resulted in penetration of extravascular tumor tissue (Sugahara et al.
2010 ). They demonstrated in murine tumor models that systemic injection with
iRGD can improve the therapeutic index of various therapeutic agents, such as a
small molecule drugs (doxorubicin), nanoparticles (nab-paclitaxel and doxorubicin
liposomes), and a monoclonal antibody (trastuzumab). Although the mechanism of
action still requires further investigation, this system may represent a valuable strat-
egy to enhance the efficacy of anticancer agents and to accelerate clinical transla-
tion of modification-intolerable drugs.
3.3.2
LHRH Peptide
Luteinizing-hormone-releasing hormone (LHRH), also known as luliberin and
Gonadotropin-releasing hormone (GnRH), are known to be internalized and are
good agents for tumor targeting (Dharap et al. 2003, 2005 ; Kim et al. 2008 ).
Although LHRH receptors are present on the surface of most healthy human cells,
they are over-expressed in ovarian, prostate and breast cancer cells. Through direct
conjugation, the LHRH peptide or its analogues have been applied for the delivery
of anticancer drugs and siRNAs. For example, Dharap et al. have shown that a
LHRH-PEG-camptothecin (CPT), a cytotoxic quinoline alkaloid which inhibits the
DNA enzyme topoisomerase I, significantly enhanced the drugs cytotoxicity
against cancer cells (Dharap et al. 2003 ). Recently, a LHRH peptide analogue was
appended to an siRNA via a PEG linker to target ovarian cancer cells (Kim et al.
2008 ). Once effective cellular internalization of the LHRH-targeted siRNA conju-
gates takes place the disulfide bond between PEG and siRNA is reductively cleaved
to release the siRNA into the cytosol.
3.3.3
Peptide Transduction Domains (PTDs)
PTDs (also called cell-penetrating peptides), are short cationic peptide sequences
with a maximum of 30 amino acids that mediate translocation across cell membranes
(El-Sayed et al. 2009 ; Pangburn et al. 2009 ). Despite the different theories on the
mechanism of PTD-mediated uptake, it is now widely accepted that PTDs bind the
anionic cell surface through electrostatic interaction and then are rapidly internalized
into cells by macropinocytosis, a specialized type of fluid phase endocytosis that all
cells appear to perform (Nakase et al. 2004 ; Wadia et al. 2004 ). This feature therefore
enhances the cellular uptake in a non-cytotoxic manner, making PTDs attractive can-
didates for intracellular drug delivery. PTDs such as trans-activating transcriptional
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