Purpose: The current work describes the synergistic enhancement of hyperthermic cancer therapy by selective thermal sensitization and induction of vascular injury at the tumor site. The specificity of this response was mediated by CYT-6091: a pegylated colloidal gold-based nanotherapeutic designed to selectively deliver an inflammatory cytokine, tumor necrosis factor alpha (TNF), to solid tumors. Materials and methods: FSaII murine fibrosarcoma-bearing C3H mice received an intravenous injection of either soluble TNF or CYT-6091 (50-250 μg/kg TNF). Four hours later the tumors were exposed to localized heating (42.5 or 43.5°C, 60 min). Tumor responses were assessed by growth delay and/or perfusion. Results: Both soluble TNF and CYT-6091 reduced tumor perfusion by 80% of control (no treatment), 4 hours post administration. However, soluble TNF was toxic to the tumor burdened mice and resulted in 40% mortality alone and 100% mortality when combined with hyperthermia. Conversely, no toxicities were noted with CYT-6091 alone or when combined with hyperthermia. Additionally, CYT-6091 combined with heat yielded significant tumor regression in vivo as compared to heat or CYT-6091 alone as demonstrated by tumor growth delay. Pretreatment with soluble TNF or CYT-6091 followed by heating reduced in vitro tumor and endothelial cell survival by 40-50% (TNF) and 70-75% (CYT-6091) of the control cell (i.e. tumor and endothelial) values, respectively. Conclusions: CYT-6091, by selectively delivering TNF to solid tumors, improves the safety of TNF treatment. In addition, the targeted delivery of TNF augments cancer thermal therapy efficacy possibly by inducing a tumor-localized inflammatory response.
Bibliographical noteFunding Information:
The authors thank Hui Yao for CEUS images, and Esaote, S.p.A., Italy for Ultrasound system and contrast agent. The work was funded by: U.S. Army Department of Defense; Grant Numbers: DAMD 17-03-1-0432 and DAMD 17-01-1-33, National Cancer Institute; Grant Number: CA44114 and Biomedical Engineering Institute, University of Minnesota.
- Gold nanoparticle
- Perfusion defect
- Thermal therapy
- Tumor necrosis factor