  The poor delivery of nanoparticles to target cancer cells hinders their
success in the clinical setting. In this work, an alternative target readily
available for circulating nanoparticles has been selected to eliminate the need
for nanoparticle penetration in the tissue: the tumor blood vessels. A tumor
endothelium-targeted nanoparticle (employing an RGD-containing peptide) capable
of co-delivering two anti-vascular drugs (one anti-angiogenic drug and one
vascular disruption agent) is here presented. Furthermore, the nanodevice
presents two additional anti-vascular capabilities upon activation by
Near-Infrared light: provoking local hyperthermia (by gold nanorods in the
system) and generating toxic reactive oxygen species (by the presence of a
photosensitizer). RGD-targeting is shown to increase uptake by HUVEC cells, and
while the nanoparticles are shown not to be toxic for these cells, upon
Near-Infrared irradiation their almost complete killing is achieved. The
combination of all four therapeutic modalities is then evaluated in an ex ovo
fibrosarcoma xenograft model, which shows a significant reduction in the number
of blood vessels irrigating the xenografts when the nanoparticles are present,
as well as the destruction of the existing blood vessels upon irradiation.
These results suggest that the combination of different anti-vascular
therapeutic strategies in a single nanocarrier appears promising and should be
further explored in the future.
