10.1021/mp300505w.s001 Mithun M. Shenoi Mithun M. Shenoi Isabelle Iltis Isabelle Iltis Jeunghwan Choi Jeunghwan Choi Nathan A. Koonce Nathan A. Koonce Gregory J. Metzger Gregory J. Metzger Robert J. Griffin Robert J. Griffin John C. Bischof John C. Bischof Nanoparticle Delivered Vascular Disrupting Agents (VDAs): Use of TNF-Alpha Conjugated Gold Nanoparticles for Multimodal Cancer Therapy American Chemical Society 2013 nanoparticle preconditioning tumor vasculature tumor growth delays MRI CNGRCG VDA Nanoparticle Delivered Vascular Disrupting Agents tumor necrosis factor hindlimb murine xenograft model supraphysiological temperature regimes increases tumor multimodal cancer therapies TNF Multimodal Cancer TherapySurgery cancer therapy 2013-05-06 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Nanoparticle_Delivered_Vascular_Disrupting_Agents_VDAs_Use_of_TNF_Alpha_Conjugated_Gold_Nanoparticles_for_Multimodal_Cancer_Therapy/2418394 Surgery, radiation and chemotherapy remain the mainstay of current cancer therapy. However, treatment failure persists due to the inability to achieve complete local control of the tumor and curtail metastatic spread. Vascular disrupting agents (VDAs) are a class of promising systemic agents that are known to synergistically enhance radiation, chemotherapy or thermal treatments of solid tumors. Unfortunately, there is still an unmet need for VDAs with more favorable safety profiles and fewer side effects. Recent work has demonstrated that conjugating VDAs to other molecules (polyethylene glycol, CNGRCG peptide) or nanoparticles (liposomes, gold) can reduce toxicity of one prominent VDA (tumor necrosis factor alpha, TNF-α). In this report, we show the potential of a gold conjugated TNF-α nanoparticle (NP-TNF) to improve multimodal cancer therapies with VDAs. In a dorsal skin fold and hindlimb murine xenograft model of prostate cancer, we found that NP-TNF disrupts endothelial barrier function and induces a significant increase in vascular permeability within the first 1–2 h followed by a dramatic 80% drop in perfusion 2–6 h after systemic administration. We also demonstrate that the tumor response to the nanoparticle can be verified using dynamic contrast-enhanced magnetic resonance imaging (MRI), a technique in clinical use. Additionally, multimodal treatment with thermal therapies at the perfusion nadir in the sub- and supraphysiological temperature regimes increases tumor volumetric destruction by over 60% and leads to significant tumor growth delays compared to thermal therapy alone. Lastly, NP-TNF was found to enhance thermal therapy in the absence of neutrophil recruitment, suggesting that immune/inflammatory regulation is not central to its power as part of a multimodal approach. Our data demonstrate the potential of nanoparticle-conjugated VDAs to significantly improve cancer therapy by preconditioning tumor vasculature to a secondary insult in a targeted manner. We anticipate our work to direct investigations into more potent tumor vasculature specific combinations of VDAs and nanoparticles with the goal of transitioning optimal regimens into clinical trials.