Nanoparticles for multimodal antivascular therapeutics: Dual drug release, photothermal and photodynamic therapy.

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. STATEMENT OF SIGNIFICANCE MVR2019: The combination of antivascular drugs with different mechanisms of action (such as antiangiogenic drugs and vascular disruption agents) has been recently proposed as a promising approach to maximize the therapeutic potential of anti-vascular therapeutics. Given the capacity of nanoparticles to co-deliver different drugs in optimizable ratios, nanomedicine appears to have a huge potential for the development of this kind of multimodal antivascular. To showcase this, an multimodal anti-vascular nanodevice for cancer therapy is here presented. This tumor endothelium-targeted nanosystem is capable of co-delivering two anti-vascular drugs (anti-angiogenic and vascular disruption agent) while also providing two additional therapeutic modalities that can be activated by Near-Infrared light: provoking local hyperthermia (photothermal therapy) and generating toxic reactive oxygen species (photodynamic therapy).