Novel Dual-Action Targeted Nanomedicine in Mice With Metastatic Thyroid Cancer and Pancreatic Neuroendocrine Tumors

J Natl Cancer Inst. 2018 Sep 1;110(9):1019-1029. doi: 10.1093/jnci/djy003.


Background: The advantages of nanomedicines include preferential delivery of the payload directly to tumor tissues. CYT-21625 is the novel, first-in-class gold nanomedicine designed to target tumor vasculature and cancer cells by specifically delivering recombinant human tumor necrosis factor alpha (rhTNF) and a paclitaxel prodrug.

Methods: We analyzed TNF receptor expression in publicly available gene expression profiling data and in thyroid tissue samples. Mice with metastatic FTC-133 and 8505C xenografts and the MEN1 conditional knock-out mice were treated weekly with CYT-21625 and gold nanoparticles with rhTNF only (CYT-6091); controls included mice treated with either paclitaxel or saline. In vivo luciferase activity was used to assess the effects on tumor growth. Computed tomography, magnetic resonance imaging, and 18F-Fludeoxyglucose positron emission tomography were used to study tumor selectivity in mice with insulin-secreting pancreatic neuroendocrine tumors (PNETs). All statistical tests were two-sided.

Results: Anaplastic thyroid cancer (ATC) expressed statistically significantly higher levels of TNF receptor superfamily 1A and 1B messenger RNA (n = 11) and protein (n = 6) than control samples (n = 45 and 13, respectively). Mice (n = 5-7 per group) with metastatic ATC (P < .009) and FTC-133 xenografts (P = .03 at week 3, but not statistically significant in week 4 owing to reduced sample size from death in non-CYT-21625 groups) treated with CYT-21625 had a statistically significantly lower tumor burden. Treatment with CYT-21625 resulted in loss of CD34 expression in intratumoral vasculature, decreased proliferating cell nuclear antigen, and increased cleaved caspase-3. Intratumoral vascular leakage occurred only in mice with PNET and ATC treated with CYT-6091 and CYT-21625. CYT-6091 and CYT-21625 preferentially deposited in PNETs and statistically significantly decreased serum insulin levels (n = 3 per group, P < .001). There were no toxicities observed in mice treated with CYT-21625.

Conclusions: CYT-21625 is effective in mice with PNETs and metastatic human thyroid cancer with no toxicities. Thus, CYT-21625 should be studied in patients with advanced PNETs and thyroid cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Capillary Permeability / drug effects
  • Cell Line, Tumor
  • Disease Models, Animal
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Gene Expression
  • Gene Expression Profiling
  • Gold / pharmacology
  • Humans
  • Mice
  • Mice, Knockout
  • Molecular Targeted Therapy*
  • Neoplasm Grading
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Neovascularization, Pathologic / therapy
  • Neuroendocrine Tumors / genetics
  • Neuroendocrine Tumors / pathology*
  • Neuroendocrine Tumors / therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Neoplasms / therapy*
  • Polyethylene Glycols / pharmacology
  • Recombinant Proteins
  • Theranostic Nanomedicine*
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / pathology*
  • Thyroid Neoplasms / therapy*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Necrosis Factor-alpha / therapeutic use
  • Xenograft Model Antitumor Assays


  • CYT-6091
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Polyethylene Glycols
  • Gold