Recent Advances in Angiogenesis and ... - Bentham Science

Recent Advances in Angiogenesis and Antiangiogenesis Recent Advances in Angiogenesis and Antiangiogenesis, 2009 87
Recently, the use of VTAs, such as ligand-targeted
liposomes and drug conjugates, has started to fulfill its
promise [23]. This strategy builds on the clinical
success of nanomedicines such as Caelyx ® , which are
used to improved therapeutic outcome and/or
minimized damage to normal tissues such as heart or
bone marrow, thereby increasing the selective toxicity
of chemotherapeutics in cancer [24]. Further increases
in therapeutic activity can be achieved by using
ligand-targeted nanomedicines that have surfaceconjugated,
tumor-selective antibodies or peptides
[25], particularly when targeting is by internalizing
ligands that facilitate the delivery of the therapeutic
contents to intracellular sites of activity via the
endosome/lysosome pathway [25, 26]. Indeed,
compared to normal blood vessels, tumor blood
vessels have an abnormal wall structure, being highly
disorganized and heterogeneous, with complex
branching patterns and lack of hierarchy [27].
Moreover, endothelial cells in angiogenic vessels
express several proteins that are absent or barely
detectable in established blood vessels, including αv
integrins [28], receptors for angiogenic growth factors
[29], and other types of membrane-spanning
molecules, such as the aminopeptidases N (CD13) and
A (APA) [30, 31]. In vivo panning of phage libraries in
tumor-bearing mice have proven useful for selecting
peptides that bind to receptors that are either overexpressed
or are selectively expressed on tumorassociated
vessels and that home to neoplastic tissues
[32]. Thus, it may be possible to develop ligandtargeted
chemotherapy strategies, based on peptides
that are selective for tumor vasculature. Among the
various tumor-targeting ligands identified to date,
peptides containing the asparagine-glycine-arginine
(NGR) motif, which binds to CD13, have proven
useful for delivering various anti-tumor compounds to
tumor vasculature [33, 34]. Although there are several
subpopulations of CD13 [35], relatively widely
distributed in the body, only one isoform is believed to
be the receptor for the NGR-containing peptides. This
isoform has been shown to be expressed exclusively in
angiogenic vessels, such as the neovasculature found
in tumor tissues [36]. Consequently, since this CD13
isoform, recognized by NGR-containing peptides, is
expressed on endothelial cells within most, if not all,
solid tumors, an alternative strategy that has been
pursued to increase the delivery of anti-cancer/antiangiogenic
compounds (such as doxorubicin-DXR) to
tumors was based on the use of vascular targeted
liposomes.
3. TUMOR VASCULAR TARGETING
TECHNOLOGY
This strategy has been developed that might overcome
problems of tumor cell heterogeneity by using
vascular targeted liposomes to exploit the obvious
advantages of anti-angiogenic therapies. Indeed, it has
been shown that pronounced tumor regressions can be
achieved in mice by systemic delivery of a liposomal
anti-angiogenic chemotherapeutic drug that is targeted
to the tumor vasculature [33]. There are several
advantages of targeting chemotherapeutic agents to
proliferating endothelial cells in the tumor vasculature
rather than directly to tumour cells. First, acquired
drug resistance, resulting from genetic and epigenetic
mechanisms reduces the effectiveness of available
drugs [37]. Anti-angiogenic therapy has the potential
to overcome these problems or reduce their impact.
This therapy targets the tumor vasculature, derived
from local and circulating endothelial cells that are
considered, although controversial, genetically stable.
Second, the fact that a large number of cancer cells
depend upon a small number of endothelial cells for
their growth and survival might also amplify the
therapeutic effect [38]. Third, anti-angiogenic
therapies may also circumvent what may be a major
mechanism of intrinsic drug resistance, namely
insufficient drug penetration into the interior of a
tumor mass due to high interstitial pressure gradients
within tumors [39]. A strategy that targets both the
tumor vasculature and the tumor cells themselves may
be more effective than strategies that target only tumor
vasculature, since this strategy can leave a cuff of
unaffected tumor cells at the tumor periphery that can
subsequently re-grow and kill the animals [40].
Fourth, oxygen consumption by neoplastic and
endothelial cells, along with poor oxygen delivery,
creates hypoxia within tumors. These characteristics of
solid tumors compromise the delivery and
effectiveness of conventional cytotoxic therapies as
well as molecularly targeted therapies [38, 39].
Finally, the therapeutic target is partially independent
of the type of solid tumor; killing of proliferating
endothelial cells in the tumor microenvironment can
be effective against a variety of malignancies.
In order to better mimic physiological and
pathological features of the tumor microenvironment
observed in patients suffering with cancer and,
consequently, to build novel and more specific tumorand
vasculature-targeted therapies, the importance of
choosing the correct animal models to be used,
became mandatory. Most preclinical studies on tumor
angiogenesis and anti-angiogenic therapy usually
employ rapidly growing transplantable mouse tumors,
or human tumor xenografts, which are grown as solid,
localized tumors in the subcutaneous space. For
several reasons this approach almost certainly
exaggerates the anti-tumor responses. Principally, in
such experimental situations, unlike in the clinic,
distant metastases are usually not the focus of the
treatment, but it is precisely such secondary tumors
which are ultimately responsible for cancer's lethality.