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

Zhaoting Li; Gang Chen; Ling Ding; Yixin Wang; Chenfei Zhu; Kaikai Wang; Jing Li; Minjie Sun; David Oupicky

doi:10.1016/j.ymthe.2019.08.008

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

Mol Ther. 2019 Dec 4;27(12):2100-2110. doi: 10.1016/j.ymthe.2019.08.008. Epub 2019 Aug 22.

Authors

Zhaoting Li¹, Gang Chen¹, Ling Ding², Yixin Wang¹, Chenfei Zhu¹, Kaikai Wang¹, Jing Li³, Minjie Sun¹, David Oupicky⁴

Affiliations

¹ State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
² State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China; Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
³ Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁴ Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: david.oupicky@unmc.edu.

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.

Keywords: CXCR4; STAT3; immune suppression; lung metastasis; nanoemulsion; perfluorocarbon; polyplex; pulmonary delivery.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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