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

Abstract

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.

• Authors: Naris Nilubol, ZiQiang Yuan, Giulio F Paciotti, Lawrence Tamarkin, Carmen Sanchez, Kelli Gaskins, Esther M Freedman, Shugeng Cao, Jielu Zhao, David G I Kingston, Steven K Libutti, Electron Kebebew
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 110 Issue 9 Pg. 1019-1029 (09 01 2018) ISSN: 1460-2105 [Electronic] United States
• PMID: 29481652 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Animals
• Capillary Permeability (drug effects)
• Cell Line, Tumor
• Disease Models, Animal
• Endothelium, Vascular (drug effects, 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, pathology, therapy)
• Pancreatic Neoplasms (genetics, pathology, therapy)
• Polyethylene Glycols (pharmacology)
• Recombinant Proteins
• Theranostic Nanomedicine
• Thyroid Neoplasms (genetics, pathology, therapy)
• Tumor Necrosis Factor-alpha (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays