Abrogation of the triple-negative breast tumor growth in orthotopic mouse models through survivin silencing using liposome-mediated delivery of siRNA

Abstract

Survivin has been reported to be expressed abundantly in most of the tumor cells including lung cancer and breast cancers. To combat aggressive cancers like triple-negative breast cancer (TNBC) it is necessary to design and develop a new, bifunctional chemical with both selective anti-proliferative activity and siRNA transfection capabilities by targeting a specific gene. The cationic lipids deliver small interfering RNA (siRNA) and also display inherent anti-cancer activities; therefore, the cationic lipid therapies have become very popular for treating malignant cancers. In the current study, we made an attempt to synthesize a series of acid-containing cationic lipids, anthranilic acid-containing mefenamic lipid and indoleacetic acid-containing etodolac lipids, and elucidated their bi-functional activity for selective anticancer activity and survivin siRNA mediated anti-cancer activity. Our results, showed that, lipoplexes with siRNA-Etodo:Dotap (ED) and siRNA-Mef:Dotap (MD) exhibited homogeneous particle size and positive zeta potential. Further, biological investigations resulted in enhanced survivin siRNA delivery with high stability, improved transfection efficiency, and efficacy. Additionally, our findings showed that survivin siRNA lipoplexes (ED and MD) in A549 cells and 4T1 cells exhibited stronger survivin knockdown, enhanced apoptosis, and G2/M phase arrest in both the cell types. In vivo results revealed that, treatment with survivin complexed lipoplexes showed significant reduction of tumour growth and tumour weight compared to control. Thus, our novel quaternary amine-based liposomes formulations are predicted to open up new possibilities in the development of a simple and widely utilized platform for siRNA delivery and anti-cancer activities.

Practical Fischer Indolization Using Bench-Stable Arylhydrazine Sulfonate as the Surrogate of Arylhydrazine

“…Indoles are of considerable significance in both synthetic and medicinal chemistry because of the large number of naturally occurring bioactive compounds and drugs whose structures incorporate this N-heterocyclic framework. [1][2][3][4] For example, tetrahydrocarbazoles and tryptamine units are privileged heteroaromatic scaffolds that are present in a variety of compounds with diverse biological properties or pharmaceutical activities (Scheme 1a). [5][6][7][8][9][10][11][12][13][14] The classic Fischer indolization, with arylhydrazine through 3,3-sigmatropic rearrangement of arylhydrazone intermediates and acidcatalyzed elimination of ammonia, remains the most commonly used synthetic approach.…”