title: Nanoparticle delivered vascular disrupting agents (VDAs): use of TNF-alpha conjugated gold nanoparticles for multimodal cancer therapy.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, United States.
authors.forename: Mithun M
authors.initials: MM
authors.lastname: Shenoi
authors.forename: Isabelle
authors.initials: I
authors.lastname: Iltis
authors.forename: Jeunghwan
authors.initials: J
authors.lastname: Choi
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Koonce
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Metzger
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: John C
authors.initials: JC
authors.lastname: Bischof
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D006046:Gold; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D058726:Nanoconjugates / Q000008:administration & dosage* / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000628:therapy; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D058726:Nanoconjugates; D014409:Tumor Necrosis Factor-alpha; D006046:Gold
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