Research Projects

According to GLOBOCAN statistics 2022, breast cancer is the second most incident type of cancer and the fourth leading cause of cancer-related mortality, globally(1). Triple negative breast cancer(TNBC) is the most aggressive clinical subtype of breast cancer and accounts for about 15-20% of global breast cancer cases. TNBC is characterized by the lack of expression of HER2, ER, and PR receptors(2). Although multimodal approaches involving chemotherapy, surgery, and radiation therapy are currently in use for treating TNBC, high rates of disease recurrence, metastasis, and chemoresistance critically limit the clinical benefits(3). Thus, the current scenario warrants the need for the development of novel therapeutic strategies to alleviate the global burden of TNBC. Punicalagin (PN) is a bioactive polyphenol that is abundantly found in Punica granatum L. Existing literature suggests that PN possesses strong anti-angiogenic, chemopreventive, anti-cancer, anti-inflammatory, and hepatoprotective properties. Previous studies have documented the inhibitory potential of PN against cancers of the lung, colon, breast, pancreas, and prostate(4-5). Recent studies have reported the ability of PN to induce autophagic cell death in TNBC cells via suppression of the PI3K/Akt pathway and inhibit angiogenesis in HUVEC cells by targeting VEGF(6-7). However, the inadequate bioavailability and poor intestinal absorption of PN limit its in vivo therapeutic efficacy (5). In recent years, nanogels have gained much prominence as effective drug delivery systems. Loading nutraceuticals in nanogels can enhance their bioavailability, stability, prolong intra-tumoral retention time, and augment their anti-tumor effects(8-9). The tunable and swelling properties of nanogels enable controlled drug release and confer higher drug loading capacities, making them superior to typical nanoparticles (10). Hybrid nanogels composed of natural polymers like chitosan and gelatin provide a non-toxic, biocompatible, biodegradable, and flexible base to load anti-cancer agents(11). Given the robust pro-apoptotic and anti-cancer potential of PN and its inhibitory effects on VEGF and PI3K/Akt pathways, we hypothesize that loading PN in a natural polymer-derived nanogel may be a promising strategy to enhance its bioavailability and intra-tumoral retention time, thereby rendering it effective against chemo-sensitive and chemo-resistant TNBC. The proposed study primarily intends to develop punicalagin-loaded chitosan-gelatin hybrid nanogel (PCGN) for TNBC therapy and to perform the pre-clinical evaluation of the anti-cancer efficacy of PCGN against TNBC using appropriate in vitro and in vivo models. Further, this study also aims to investigate the therapeutic potential of PCGN against TNBC cells that are resistant to first-line chemotherapeutics. It is anticipated that the findings of the current study may pave the way for developing a safe and effective formulation for the treatment of TNBC.