Dataset Information

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.

SUBMITTER: Li Z

PROVIDER: S-EPMC6904825 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Li Zhaoting Z Chen Gang G Ding Ling L Wang Yixin Y Zhu Chenfei C Wang Kaikai K Li Jing J Sun Minjie M Oupicky David D

Molecular therapy : the journal of the American Society of Gene Therapy 20190822 12

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 de ...[more]

PMID: 31481310

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Project description:Brain metastasis is a major cause of mortality in melanoma patients. The blood-brain barrier (BBB) prevents most anti-tumor compounds from entering the brain, which significantly limits their use in the treatment of brain metastasis. One strategy in the development of new treatments is to assess the anti-tumor potential of drugs currently used in the clinic. Here, we tested the anti-tumor effect of the BBB-penetrating antipsychotic trifluoperazine (TFP) on metastatic melanoma. H1 and Melmet1 human metastatic melanoma cell lines were used in vitro and in vivo. TFP effects on viability and toxicity were evaluated in proliferation and colony formation assays. Preclinical, therapeutic efficacy was evaluated in NOD/SCID mice, after intracardial injection of tumor cells. Molecular studies using immunohistochemistry, western blots, immunofluorescence and transmission electron microscopy were used to gain mechanistic insight into the biological activity of TFP. Our results showed that TFP decreased cell viability and proliferation, colony formation and spheroid growth in vitro. The drug also decreased tumor burden in mouse brains and prolonged animal survival after injection of tumor cells (53.0 days vs 44.5 days), TFP treated vs untreated animals, respectively (P < 0.01). At the molecular level, TFP treatment led to increased levels of LC3B and p62 in vitro and in vivo, suggesting an inhibition of autophagic flux. A decrease in LysoTracker Red uptake after treatment indicated impaired acidification of lysosomes. TFP caused accumulation of electron dense vesicles, an indication of damaged lysosomes, and reduced the expression of cathepsin B, a main lysosomal protease. Acridine orange and galectin-3 immunofluorescence staining were evidence of TFP induction of lysosomal membrane permeabilization. Finally, TFP was cytotoxic to melanoma brain metastases based on the increased release of lactate dehydrogenase into media. Through knockdown experiments, the processes of TFP-induced lysosomal membrane permeabilization and cell death appeared to be STAT3 dependent. In conclusion, our work provides a strong rationale for further clinical investigation of TFP as an adjuvant therapy for melanoma patients with metastases to the brain.

Project description:BackgroundCXCR4, a transmembrane-receptor located on epithelial cells that is activated by CXCL12, may have a role in IPF via migration of CXCR4+ fibrocytes to the lung. However, its expression has not been fully characterised in idiopathic pulmonary fibrosis (IPF) or other fibrotic interstitial lung diseases (ILDs). CXCL12 is constitutively expressed in the bone marrow, and levels of CXCR4 regulate control of this signalling pathway. The aim of this study was to profile the expression of CXCR4 in lung tissue and peripheral circulation of patients with IPF and other fibrotic ILDs.MethodsExpression of CXCR4 on peripheral blood mononuclear cells (PBMCs) was examined by flow cytometry in 20 patients with IPF and 10 age-matched non-disease control (NDC) donors. Levels of CXCL12 in human plasma were measured by ELISA. Expression of CXCR4, CXCL12, CD45, and e-cadherin was assessed in IPF (n = 10), other fibrotic ILD (n = 8) and NDC (n = 10) lung tissue by multiplex immunohistochemistry (OPAL) and slides were scanned using a Vectra 3 scanner. Cells were quantified with computer automated histological analysis software (HALO).ResultsIn blood, the number of CXCR4+ cells was lower but the level of CXCL12 was higher in patients with IPF compared to NDC donors. Elevated CXCR4 expression was detected in lung tissue from patients with IPF and other fibrotic ILDs compared to NDC. There were higher levels of CXCR4+/e-cadherin+/CXCL12+ (epithelial) cells in IPF lung tissue compared to NDC, but there was no difference in the numbers of CXCR4+/CD45+/CXCL12+ (myeloid) cells between the two groups.ConclusionsThis report demonstrates that CXCR4 is overexpressed not only in IPF but also in other ILDs and expression is particularly prominent within both honeycomb cysts and distal airway epithelium. This observation supports the hypothesis that CXCR4 may drive tissue fibrosis through binding its specific ligand CXCL12. Although CXCR4 expressing cells could be either of epithelial or myeloid origin it appears that the former is more prominent in IPF lung tissue. Further characterization of the cells of the honeycomb cyst may lead to a better understanding of the fibrogenic processes in IPF and other end-stage fibrotic ILDs.

Dataset Information

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

Publications

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

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