Research Projects

Cancer is a leading cause of death worldwide, with nearly 10 million deaths reported globally in 2020, and the burden is expected to rise due to aging populations and lifestyle changes. In India, cancer incidence is increasing rapidly, with over 1.4 million new cases annually, driven by factors such as tobacco use, pollution, and late-stage diagnosis. Conventional treatments like chemotherapy and radiation often face limitations such as the development of drug resistance, severe side effects, off-target effects, and tumor recurrence, necessitating newer approaches like combination anticancer drug therapy. This strategy uses multiple drugs to target cancer cells through different mechanisms, offering advantages such as synergistic effects, reduced resistance, and improved efficacy while minimizing toxicity. By overcoming the drawbacks of single-drug treatments, combination therapy represents promising advancements in the fight against cancer. In recent years, artificial ion transporters (AITs) have been introduced as a new class of anticancer agents that induce cytotoxicity via the perturbation of ion homeostasis. In this project, we propose to integrate AITs with traditional anticancer drugs to enhance the efficacy and precision of the therapy and reduce side effects. Our initial approach will be to develop anion-selective AITs that can be specifically targeted to the endoplasmic reticulum (ER), as several anticancer drugs and AITs target this organelle. Fluorescence-based ion transport studies will be conducted to affirm the efficiency of AITs, and electrophysiology experiments will be performed to delve into the ion channel formation mode. NMR studies and theoretical calculations will be done to understand self-assembly and ion binding by AITs. The study is expected to provide a few efficient and selective ER-targeting anion transporters. This will be followed by the development of light-activatable ER-targeting drug-transporter conjugate systems that release the AIT and drug simultaneously in the ER upon photoirradiation. Two well-known anticancer drugs, camptothecin and dipyridamole – traditionally described to induce ER stress – will be used for the drug-transporter conjugate design. Different ortho-nitrobenzyl (ONB) groups will be incorporated as the photoactivatable moieties. Previous studies from our group have successfully demonstrated photorelease of AITs from corresponding ONB-linked protransporters and their efficient anticancer activity. We expect that the designed drug-transporter conjugate systems, upon photoirradiation, will release the anticancer drug and the AIT simultaneously within the ER and hence show better cytotoxicity when compared to the drugs being used alone (i.e., control experiments). Moreover, the inherent fluorescence of dansyl groups (an ER targeting group), camptothecin, and dipyridamole will be useful for the live imaging of the AITs and drug-transporter conjugates in the ER. The cytotoxicity of drug-transporter conjugates before and after photoirradiation will be studied using 2D and 3D cancer models, and attempts will be made to gain mechanistic insights into the same. It is expected that drug-transporter conjugates will have enhanced bioavailability in the ER. In the next step, nanoparticles of the drug-transporter conjugates will be prepared for selective delivery in cancer cells. Previous studies have shown that the nanoparticles can increase the half-life of drugs and induce their accumulation, specifically into tumor tissues, while protecting the normal cells from the cytotoxicity of drugs, thereby reducing the adverse effects of cancer therapy. We anticipate that the development of light-activatable ER-targeting drug-transporter conjugate systems will enable precise accumulation of therapeutic agents in the ER, triggering efficient cytotoxicity in cancer cells, over and above the standard anticancer drugs prescribed to the patients.