Glucosyltriazole amphiphile treatment attenuates breast cancer by modulating the AMPK signaling.

Breast cancer is the second most frequent cancer among women. Out of various subtypes, triple-negative breast cancers (TNBCs) account for 15% of breast cancers and exhibit more aggressive characteristics as well as a worse prognosis due to their proclivity for metastatic progression and limited therapeutic strategies. It has been demonstrated that AMP-activated protein kinase (AMPK) has context-specific protumorigenic implications in breast cancer cells. A set of glucosyltriazole amphiphiles, consisting of acetylated (9a-h) and unmodified sugar hydroxyl groups (10a-h), were synthesized and subjected to in vitro biological evaluation. Among them, 9h exhibited significant anticancer activity against MDA-MB-231, MCF-7, and 4T1 cell lines with IC50 values of 12.5, 15, and 12.55 µM, respectively. Further, compound 9h was evaluated for apoptosis and cell cycle analysis in in vitro models (using breast cancer cells) and antitumour activity in an in vivo model (orthotopic mouse model using 4T1 cells). Annexin-V assay results revealed that treatment with 9h caused 34% and 28% cell death at a concentration of 15 or 7.5 µM, respectively, while cell cycle analysis demonstrated that 9h arrested the cells at the G2/M or G1 phase in MCF-7, MDA-MB-231 and 4T1 cells, respectively. Further, in vivo, investigation showed that compound 9h exhibited equipotent as doxorubicin at 7.5 mg/kg, and superior efficacy than doxorubicin at 15 mg/kg. The mechanistic approach revealed that 9h showed potent anticancer activity in an in vivo orthotopic model (4T1 cells) partly by suppressing the AMPK activation. Therefore, modulating the AMPK activation could be a probable approach for targeting breast cancer and mitigating cancer progression.

Cationic pH-Responsive Polycaprolactone Nanoparticles as Intranasal Antigen Delivery System for Potent Humoral and Cellular Immunity against Recombinant Tetravalent Dengue Antigen.

Research on amalgamation of an antigen with a delivery system for developing a potent mucosal vaccine that elicits both cellular and humoral response has captured immense attention these days. Cationic delivery systems being the first choice for mucosal antigen delivery, despite being effective, are associated with inherent problems like cytotoxicity. Therefore, the quest for developing a precise system that can effectively deliver antigen to immune cells without adverse toxic effect has led to the use of partial cationic systems which are mostly humoral immune mediators. The art of fine-tuning cationic nature, avoiding side effects, and being immune responsive are the needs of the hour. Herein, we try to optimize the cationic nature of polycaprolactone (USFDA approved) by conjugating it with hydrazine. The polymer was modified using two stoichiometry ratios (5 and 10 equiv) of hydrazine monohydrate and characterized using FTIR and XRD. Free amine quantification of the modified polymers concluded that both the modified polymers had 232 and 457 µM/mg amine groups, respectively. A cytotoxicity assay performed using RAW 264.7 macrophages proved the safety of cationic polymers. In vitro assays for antigen colocalization and cross-presentation have revealed that the modified polymers could effectively execute the anticipated function. In vivo evaluation in BALB/c mice using recombinant dengue antigen for intranasal immunization affirmed that the modified polymer having 457 µM/mg of free amine groups effectively stimulated humoral and potent cellular immune response. The overall data suggests that the modified polymeric nanoparticles-with their cationic, pH-responsive, and adjuvanting characteristics-proved to be a versatile system for effective mucosal antigen delivery.