Document Detail


Nanoparticle delivered vascular disrupting agents (VDAs): use of TNF-alpha conjugated gold nanoparticles for multimodal cancer therapy.
MedLine Citation:
PMID:  23544801     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Mithun M Shenoi; Isabelle Iltis; Jeunghwan Choi; Nathan A Koonce; Gregory J Metzger; Robert J Griffin; John C Bischof
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-04-17
Journal Detail:
Title:  Molecular pharmaceutics     Volume:  10     ISSN:  1543-8392     ISO Abbreviation:  Mol. Pharm.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-05-06     Completed Date:  2013-12-16     Revised Date:  2014-05-08    
Medline Journal Info:
Nlm Unique ID:  101197791     Medline TA:  Mol Pharm     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1683-94     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / administration & dosage*
Cell Line, Tumor
Combined Modality Therapy
Gold
Humans
Hyperthermia, Induced
Male
Metal Nanoparticles / administration & dosage,  chemistry
Mice
Mice, Nude
Nanoconjugates / administration & dosage*,  chemistry
Prostatic Neoplasms / blood supply,  drug therapy*,  therapy
Tumor Necrosis Factor-alpha / administration & dosage*
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
2R01 CA075284/CA/NCI NIH HHS; CA44114/CA/NCI NIH HHS; KL2 RR033182/RR/NCRR NIH HHS; P30 CA77598/CA/NCI NIH HHS; P50 CA101955/CA/NCI NIH HHS; R01 CA075284/CA/NCI NIH HHS; UL1 TR000114/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Nanoconjugates; 0/Tumor Necrosis Factor-alpha; 7440-57-5/Gold
Comments/Corrections

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