Research Projects

Cancer is a pressing global health challenge, with millions of new cases and deaths reported annually. Traditional (surgery, chemotherapy, etc.) as well as new-generation targeted (photodynamic therapy, sonodynamic therapy, etc.) therapies frequently fail against solid hypoxic tumors (oxygen-deprived tumors), which leads to metastasis and drug resistance, causing a greater number of deaths. The complexity and heterogeneity of these tumors make single-mode treatment modalities inefficient. To address these challenges, in this project, we propose to develop an innovative combination of sonodynamic therapy (SDT) and carbon monoxide (CO) gas therapy, leveraging the deep-tissue penetration (up to 10 cm) of ultrasound (US) and the multifaceted therapeutic effects of CO. For this, we will develop unprecedented molecular designs of ultrasound-responsive Mn(I)/Re(I) tricarbonyl complexes incorporating tumor-recognizing moiety (TRM), hypoxia-specific carbonic anhydrase IX (CAIX) inhibitors, and donor-acceptor-donor (D-A-D) moieties. The glucose/biotin/folic acid/vitamin B6 will be used as a TRM due to over-expression of their different receptors/transporters on the cancer cell membranes, and it will tune the selectivity of our sonosensitizers towards different cancer cells over normal cells. The D-A-D moiety will facilitate e- acceptance from NADH and disrupt the NAD⁺/NADH ratio, potentially leading to cell death under US exposure. The CAIX inhibitors will target hypoxic tumors by downregulating HIFs (Hypoxia-inducible factors) and disrupting the acidic pH balance. The scientific hypothesis centers around the development of ultrasound-responsive Re(I)/Mn(I) tricarbonyl complexes that can selectively target cancer cells and on US exposure, release CO, generate reactive oxygen species (ROS), and disrupt mitochondrial metabolism, thereby offering a synergistic and targeted approach to treat deeply buried hypoxic tumors. The proposed challenging synthesis and development of multitargeting anticancer agents has been a core expertise of our lab, which will help us to synthesize and characterize these complexes successfully. Different parameters and ultrasound dosages will be optimized to ensure optimal CO release, NADH oxidation, and ROS generation. Attempts will be made to release CO in a controlled manner and to isolate the Re(I)/Mn(I) tricarbonyl complex after stepwise CO release (e.g., [LM(CO)3→LM(CO)2→LM(CO)→LM; L= ligand] since no such research have not been reported in the literature so far. Furthermore, the developed Re(I)/Mn(I) tricarbonyl complexes will be screened against different cancer cells (cisplatin sensitive as well as cisplatin resistant) and normal cells with/without ultrasound exposure to determine their cytotoxic behaviour under hypoxic (1-2% O2) conditions. The detailed in vitro and in vivo anticancer profile of selected lead complexes will be explored under hypoxic (1-2% O2) conditions. A wide range of cell-death/hypoxic-specific protein expression will be analysed with western blotting studies in different cancer cells to determine the cell death mechanism of the Re(I)/Mn(I) tricarbonyl complexes under hypoxic (1-2% O2) conditions. The significance of this project lies in its potential to revolutionize cancer treatment by overcoming the limitations of current therapies. If successful, the developed complexes could offer a targeted, multifaceted approach to eradicate drug-resistant hypoxic tumors effectively with minimal off-target toxicity and could induce immunogenic cell death to enhance anti-tumour immunity. This research could pave the way for preclinical development and clinical translation, providing a foundation for future smart metal-based cancer therapeutics. By integrating cutting-edge chemistry, biology, and ultrasound technology, this work stands at the forefront of therapeutic innovation, addressing one of the most formidable challenges, i.e., hypoxic cancer treatment, in modern medicine.