Noninvasive imaging of tumor hypoxia after nanoparticle-mediated tumor vascular disruption

Abstract

We have previously demonstrated that endothelial targeting of gold nanoparticles followed by external beam irradiation can cause specific tumor vascular disruption in mouse models of cancer. The induced vascular damage may lead to changes in tumor physiology, including tumor hypoxia, thereby compromising future therapeutic interventions. In this study, we investigate the dynamic changes in tumor hypoxia mediated by targeted gold nanoparticles and clinical radiation therapy (RT). By using noninvasive whole-body fluorescence imaging, tumor hypoxia was measured at baseline, on day 2 and day 13, post-tumor vascular disruption. A 2.5-fold increase (P<0.05) in tumor hypoxia was measured two days after combined therapy, resolving by day 13. In addition, the combination of vascular-targeted gold nanoparticles and radiation therapy resulted in a significant (P<0.05) suppression of tumor growth. This is the first study to demonstrate the tumor hypoxic physiological response and recovery after delivery of vascular-targeted gold nanoparticles followed by clinical radiation therapy in a human non-small cell lung cancer athymic Foxn1 nu mouse model.

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

“…Notably, arsenic trioxide (Trisinox; ATO) is used clinically to treat promyelocytic leukemia and has been shown to cause vascular disruption in solid tumors [77][78][79], though at low doses it interferes with mitochondrial activity and actually increased tumor oxygenation, as revealed by ESR and 19 F MR oximetry [80]. Selective vascular destruction has also been achieved using antibody targeted tissue factor (anti-VCAM-1.TF) [6,81] and physical approaches based on photodynamic therapy [82][83][84][85], microwave heating [86] or high dose radiation [87] potentially enhanced with high-z nanoparticles [88]. The application of imaging for non-invasive assessment of vascular disrupting agent activity is presented in Table 2.…”

Nanotechnology Tools Enabling Biological Discovery

“…Virani et al observed hypoxia dynamic changes (i.e., increased levels of hypoxia) in the TME during a vascular disruption intervention when gold nanoparticles were used to potentiate the radiotherapy treatment. Despite increased hypoxia, the researchers observed long-term tumor suppression . Thus, this counterintuitive finding suggests that the identification of transient hypoxic conditions can be an opportunity to further improve radiation therapy outcomes .…”

“…Despite increased hypoxia, the researchers observed long-term tumor suppression. 162 Thus, this counterintuitive finding suggests that the identification of transient hypoxic conditions can be an opportunity to further improve radiation therapy outcomes. 162 Other recent papers report tumor hypoxia modulation through ingenious chemistry manipulation on nanoparticle surfaces or through nanoparticle design.…”

“…162 Thus, this counterintuitive finding suggests that the identification of transient hypoxic conditions can be an opportunity to further improve radiation therapy outcomes. 162 Other recent papers report tumor hypoxia modulation through ingenious chemistry manipulation on nanoparticle surfaces or through nanoparticle design. The modulation of hypoxia in the tumor site is carried out by delivering, countering, or exploiting molecular O 2 .…”