Research Projects

Breast cancer is the leading site of cancer in females. Triple negative breast cancer (TNBC) is a subtype of breast cancer, which is difficult to treat due to innate apoptosis resistant tumor cells and easy recurrence. TNBC is more aggressive subtype of breast cancer with no effective targeted therapy. Therefore, there is need to develop drug candidates suitable for TNBC. Scientific objectives: (i) This proposal aims to develop a series of chlorin macrocyles (porphyrin analogue, used in photo-dynamic therapy, PDT) linked to ferroptosis inducing drugs; (ii) a novel design is proposed to make Chlorin based Photo-sensitizers (PSs), where ferroptosis inducers (small anti-cancer drugs) are covalently linked to chlorins; (iii) absorption, fluorescence, singlet oxygen quantum yields will be determined; (iv) Chlorin-drug hybrids will be tested for cell toxicity (under light and dark conditions), reactive oxygen species (ROS) generation, co-localization and bioimaging studies will be done in breast cancer cells /TNBC; (v) Western blot analysis to understand ferroptosis linked pathways, in-vivo studies in mouse with orthotropic breast cancer model, histopathology, toxicological profiling (LD₅₀), PK/PD studies, PDT treatment and tumor imaging in mouse to test highly potent chlorin-drug hybrids. Hypothesis: TNBC is a stubborn type of cancer and its treatment is challenging due to higher reoccurrence and heterogeneous nature. TNBC cells markedly show redox state imbalance and high concentrations of iron and lipids. Which make them potentially vulnerable to Ferroptosis (non-apoptotic cell death). Small chemotherapy drugs viz. erastin, sorafenib, temozolomide, olaperib are found to induce ferroptosis in cancer cells. Covalent linking of photosensitizer such as Chlorin (PDT agent) to chemotherapy drugs is an effective strategy to enhance cell death in TNBC by ferroptosis-related pathways. Combination of photo-dynamic therapy agent with ferroptosis inducers is a distinct design to tackle drug resistance in oncology. Main experiment: Synthesis of a series of meso-aryl chlorins will be carried out from porphyrin precursors. Ferroptosis inducing drugs will be coupled with trans-functionalized chlorins. All molecules will be characterized by NMR, MASS, IR, UV-vis, Fluorescence spectroscopy techniques. In-vitro studies in breast cancer cells and TNBC: ROS generation, cellular uptake and co-localization, bioimaging, cell toxicity in light and dark conditions (IC50 values) western blot analysis for ferroptosis related pathways will be performed. In-vivo studies: toxicological profiling (LD₅₀), PK/PD studies will be done with most potent hit molecule(s), orthotopic tumor model generation in mouse. Significance in the field of research: The ferroptosis targeting chemotherapy drugs have been studied on TNBC cancer patients. But the amalgamation of chemotherapy drugs (ferroptosis inducers) with PDT agent (chlorin photosensitizers) is unique design. This proposal will try to develop bioimaging agents based on chlorin-drug hybrids for timely diagnosis of breast cancer. Also, detailed in-vitro and in-vivo studies will shed light on the mode of actions and cellular pathways involved in the ferroptosis modulation and lipid metabolism in TNBC cells. Applications: The timely detection of breast cancer is extremely important in cancer therapy, the proposed chlorin-drug hybrids will be distinctly useful for the breast cancer diagnosis (photo-dynamic diagnosis, PDD). As chlorin unit is highly fluorescent in nature and will produce bright red color in cancer cells after light irradiation. The chloring-drug hybrid molecules promised to be an effective plan to fight with drug resistant tumor and re-occurrence of breast cancer. Typically, PDT agents are inactive in dark conditions and show high toxicity by producing ROS after light irradiation. Thus, cancer cells cannot develop resistance against photosensitizing drugs, which is an added advantage of PDT.