Mesoporous silica nanoparticle delivery of chemically modified siRNA against TWIST1 leads to reduced tumor burden

Abstract

Growth and progression of solid tumors depends on the integration of multiple pro-growth and survival signals, including the induction of angiogenesis. TWIST1 is a transcription factor whose reactivation in tumors leads to epithelial to mesenchymal transition (EMT), including increased cancer cell stemness, survival, and invasiveness. Additionally, TWIST1 drives angiogenesis via activation of IL-8 and CCL2, independent of VEGF signaling. In this work, results suggest that chemically modified siRNA against TWIST1 reverses EMT both in vitro and in vivo. siRNA delivery with a polyethyleneimine-coated mesoporous silica nanoparticle (MSN) led to reduction of TWIST1 target genes and migratory potential in vitro. In mice bearing xenograft tumors, weekly intravenous injections of the siRNA-nanoparticle complexes resulted in decreased tumor burden together with a loss of CCL2 suggesting a possible anti-angiogenic response. Therapeutic use of TWIST1 siRNA delivered via MSNs has the potential to inhibit tumor growth and progression in many solid tumor types. Chemically modified siRNA against TWIST1 was complexed to cation-coated mesoporous silica nanoparticles and tested in vitro and in vivo. In cell culture experiments, siRNA reduced expression of TWIST1 and its target genes, and reduced cell migration. In mice, injections of the siRNA-nanoparticle complex led to reduced tumor weight. Data suggest that diminished tumor burden was the result of reduced CCL2 expression and angiogenesis following TWIST1 knockdown.

TWIST1 drives cisplatin resistance and cell survival in an ovarian cancer model, via upregulation of GAS6, L1CAM, and Akt signalling

“…Furthermore, an inhibitor of STAT3 reduced downstream activity of TWIST1, which led to impeded migration and invasion of melanoma cells49. Our group has also demonstrated the efficacy of TWIST1 siRNA in reducing melanoma growth in vivo via inhibition of apoptosis11.…”

“…TWIST1 is reactivated in many cancers, where it drives an epithelial to mesenchymal transition (EMT), leading to metastasis89. In a variety of tumour types, TWIST1 has also been linked to angiogenesis, resistance to apoptosis, and cancer cell stemness101112. In ovarian cancer, TWIST1 protein is degraded in CSCs, maintaining CSCs in an epithelial state.…”

Frontiers in Toxicity and Functionalization of Nanomaterials

“…For instance, the MSN system utilized by Wu et al released siRNA and doxorubicin into the cytoplasm after the coating with poly-(β-aminoesters) induced endosome bursting [17]. In the same way, cationic polyethyleneimine (PEI) coating can trigger the proton sponge effect which was applied by Finlay and colleagues to deliver TWIST1 siRNA to xenograft tumors and reduce tumor burden [80]. Other methods use fusion lipids, cationic polymers or peptides to destabilize the endosomal membrane by proton absorption and acidification [81].…”

Development of mesoporous silica-based nanoparticles with controlled release capability for cancer therapy

“…Using this method, knockdown of the expression of AKT as well as downregulation of the RAS/RAF/MEK signaling was accomplished in human cancer cells. More recently, siRNA against TWIST, one of the key regulators of epithelial–mesenchymal transition (EMT) was shut down in a mouse tumor model [70]. We can envision multifunctional MSNs that can have siRNA delivery capability together with controlled release of anticancer drugs.…”