Increased Survival by Pulmonary Treatment of Established Lung Metastases with Dual STAT3/CXCR4 Inhibition by siRNA Nanoemulsions.

Abstract

Lung metastasis is a common and deadly occurrence in many types of solid tumors. Chemokine receptor CXCR4 and transcription factor signal transducer and activator of transcription 3 (STAT3) are among potential therapeutic targets in lung metastatic cancer. Both CXCR4 and STAT3 play important roles in the proliferation, angiogenesis, and metastasis of cancer cells. Here, we report on the development of a pulmonary delivery (p.d.) system based on perfluorocarbon (PFC) nanoemulsions for combined delivery of a partially fluorinated polymeric CXCR4 antagonist (FM) and anti-STAT3 small interfering RNA (siRNA). We have prepared FM-stabilized PFC (FM@PFC) as a delivery system of therapeutic siRNA adsorbed on the surface of the emulsion. These FM@PFC/siRNA nanoemulsions inhibited both CXCR4 and STAT3, as demonstrated by effective anti-invasive ability in vitro and related antimetastatic activity in vivo. The combined nanoemulsions provided a comprehensive anticancer effect in the model of established lung metastasis of breast carcinoma, which was dependent on induction of cancer cell apoptosis, anti-angiogenic effect, anti-invasive activity, and overcoming of the immunosuppressive tumor microenvironment. Direct comparison with intravenous (i.v.) injection showed superior activity of pulmonary administration as indicated by significantly increased animal survival. Overall, this work established the suitability of the PFC nanoemulsions for p.d. of combination anticancer treatments and as a promising method to treat lung metastasis.

• Authors: Zhaoting Li, Gang Chen, Ling Ding, Yixin Wang, Chenfei Zhu, Kaikai Wang, Jing Li, Minjie Sun, David Oupicky
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 27 Issue 12 Pg. 2100-2110 (12 04 2019) ISSN: 1525-0024 [Electronic] United States
• PMID: 31481310 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• CXCR4 protein, human
• RNA, Small Interfering
• Receptors, CXCR4
• STAT3 Transcription Factor
• STAT3 protein, human

Topics

• Animals
• Apoptosis
• Breast Neoplasms (genetics, metabolism, pathology, therapy)
• Cell Movement
• Cell Proliferation
• Drug Delivery Systems
• Female
• Humans
• Lung Neoplasms (genetics, metabolism, secondary, therapy)
• Mice
• Nanoparticles (administration & dosage, chemistry)
• Neovascularization, Pathologic
• RNA, Small Interfering (administration & dosage, genetics)
• Receptors, CXCR4 (antagonists & inhibitors)
• STAT3 Transcription Factor (antagonists & inhibitors, genetics)
• Signal Transduction
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays