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Nanoparticle Delivered Vascular Disrupting Agents (VDAs): Use of TNF-Alpha Conjugated Gold Nanoparticles for Multimodal Cancer Therapy
journal contribution
posted on 2013-05-06, 00:00 authored by Mithun
M. Shenoi, Isabelle Iltis, Jeunghwan Choi, Nathan A. Koonce, Gregory J. Metzger, Robert J. Griffin, John C. BischofSurgery, 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.
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nanoparticlepreconditioning tumor vasculaturetumor growth delaysMRICNGRCGVDANanoparticle Delivered Vascular Disrupting Agentstumor necrosis factorhindlimb murine xenograft modelsupraphysiological temperature regimes increases tumormultimodal cancer therapiesTNFMultimodal Cancer TherapySurgerycancer therapy
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